International Stem Cell Corporation (OTCQB:ISCO) announced that the company’s proprietary ISC-hpNSC readily expandable neural stem cells improved cognitive performance and motor coordination in laboratory afflicted with traumatic brain injuries. ISC-hpNSCs consists of a highly pure population of neural stem cells derived from human parthenogenetic stem cells.
This preclinical study was conducted by scientists at the University of South Florida Morsani College of Medicine. The study examined rodents that had suffered from controlled cortical impact injury (rather well-known to be an established model of traumatic brain injury model).
The University of South Florida researchers divided their laboratory animals into four different cohorts. One group was treated with vehicle (the buffer in which the stem cells were delivered). This group of animals were the control group for this experiment. The next three groups were treated with ISC-hpNSCs, but the animals were given these cells in three different ways. Interestingly, laboratory animals that had received injections of ISC-hpNSCs showed the highest levels of improvements in cognitive performance and motor coordination when compared to those animals injected with only vehicle. Improvements in cognitive tests in animals transplanted with ISC-hpNSCs appeared only a few days after implantation.
ISCO’s new traumatic brain injury program will use the same cellular product (ISC-hpNSC) as their ongoing Parkinson’s disease program, which is presently in clinical trials. The safety data from the Parkinson’s disease trial can be used for future trials in patients with traumatic brain injuries.
Cell banks of ISC-hpNSCs were made under so-called “Good Manufacturing Practices,” which means that they are clean enough to be used in human patients. All of these stem cells have been extensively tested for sterility, purity, identity and safety. These extensive preclinical studies conducted during the development of the Parkinson’s disease program nicely demonstrate the safety of ISC-hpNSCs, even at high doses.
There is no approved treatment for traumatic brain injuries, and these injuries can cause long-term neurological disability. However, transplantation of neural stem cells may improve some of the symptoms of traumatic brain injury. Over 1.7 million people in North America suffer annually from traumatic brain injury, with associated medical costs exceeding $70 billion. According to the World Health Organization, the global incidence for traumatic brain injury is approximately 10 million people annually.
Preclinical studies in rodents and non-human primates have shown improvement in Parkinson’s disease symptoms and increase in brain dopamine levels following the intracranial administration of ISC-hpNSCs.
Heart failure is a life-limiting condition that affects over 40 million patients worldwide. Fortunately, people who suffer from heart disease now may have new hope. A new study suggests that damaged tissue can be regenerated by means of a stem cell treatment that was injected into the heart during surgery.
This small-scale study was published in the Journal of Cardiovascular Translational Research. It treated and then followed 11 patients who, during coronary artery bypass graft surgery, had stem cells directly injected into their heart muscle near the site of the tissue scars that had resulted from previous heart attacks.
The most common cause of heart failure is “Ischemic cardiomyopathy” or ICM. ICM occurs when the heart has enlarged to such a degree that the vasculature can no longer supply the heart with adequate blood. ICM can also result from multiple sites of blockage in the coronary arteries of the heart that prevent adequate circulation in the heart.
In this study, researchers delivered a novel stem cell mesenchymal precursor cell type (iMP) during coronary artery bypass surgery (CABG) in patients with ICM whose ejection fractions were below 40%. The iMP cells are derived from what seem to be very young mesenchymal stem cells that lack the typical cell-surface proteins of mesenchymal stem cells. The cells have the ability to form a variety of mesodermal-derived tissues. Also, these cells suppress immunological rejection by the patient’s body, and therefore, they can be implanted into a patient’s body, even though their tissue types do not match. Therefore, these cells can not only be expanded in culture, but can also potentially differentiate into heart-based cell types, including heart muscle and blood vessels.
This study was a phase IIa safety study that was NOT placebo-controlled, double-blinded. It enrolled 11 patients, all of whom underwent scintigraphy imaging (SPECT) before their surgery. SPECT is an effect means to detect “hibernating myocardium” that does not properly contract. Hibernating myocardium is not suitable for iMP implantation.
During the CABG surgery, iMP cells were implanted in the heart muscle (intramyocardially). Stem cells were injected into predefined areas that were viable and close to infarct areas that usually showed poor vascularization. Such areas, because of their poor vascularization could not be treated with grafting because of their poor target vessel quality.
After surgery, SPECT imaging was used to identify changes in scar area. Fortunately, Intramyocardial implantation of iMP cells with CABG was safe. The huge surprise came with the reduction of the heart scar. Subjects showed a 40% reduction in the size of scarred tissue. Remember that heart scars form after a heart attack, and can increase the chances of further heart failure. This scarring, however, was previously thought to be permanent and irreversible. The patients also showed improved myocardial contractility and perfusion of nonrevascularized areas of the heart in addition to significant reduction in left ventricular scar area at 12 months after treatment.
“Quite frankly it was a big surprise to find the area of scar in the damaged heart got smaller,” said Prof Stephen Westaby from John Radcliffe hospital in Oxford, who undertook the research at AHEPA university hospital in Thessaloniki, Greece, with Kryiakos Anastasiadis and Polychronis Antonitsis.
Clinical improvement was correlated with significant improvements in quality of life at 6 months after the treatment all patients.
Jeremy Pearson, the associate medical director at the British Heart Foundation (BHF), said: “This very small study suggests that targeted injection into the heart of carefully prepared cells from a healthy donor during bypass surgery, is safe. It is difficult to be sure that the cells had a beneficial effect because all patients were undergoing bypass surgery at the same time, which would usually improve heart function.
“A controlled trial with substantially more patients is needed to determine whether injection of these types of cells proves any more effective than previous attempts to improve heart function in this way, which have so far largely failed.”
Dr. Westaby noted that improvements in the health of their patients were partly a result of the heart bypass surgery. However, he added that the next study would include a control group who will undergo CABG but not receive stem cell treatment, in order to measure exactly what impact the treatment has.
“These patients came out of heart failure partly due to the bypass grafts of course, but we think it was partly due to the fact that they had a smaller area of scar [as a result of the stem cell treatment]. Certainly this finding of scar being reduced is quite fascinating,” he said.
These results suggest that the delivery of iMP cells can induce regeneration of heart muscle and other heart tissues in patients with ischemic heart failure.
This paper was published: Anastasiadis, K., Antonitsis, P., Westaby, S. et al. J. of Cardiovasc. Trans. Res. (2016) 9: 202. doi:10.1007/s12265-016-9686-0.
Traumatic brain injuries can result from a variety of causes, ranging from car accidents, falls, occupational hazards, and sports injuries. The cause of traumatic brain injury (TBI) differs from that of ischemic stroke, but many of the clinical manifestations are somewhat similar (motor deficits). Such injuries can cause lifelong motor deficits, and there are currently no approved medicines for the treatment of persistent disability from traumatic brain injury.
SanBio, Inc., has completed the regulatory requirements to conduct a clinical trial using their proprietary SB623 regenerative cell therapy to treat patients who suffer from TBI. The obligatory 30-day review period of clinical trial notification by the Japanese Pharmaceuticals and Medical Devices Agency (PMDA) was completed on March 7, 2016. No safety concerns were voiced, and the trial can proceed.
SanBio’s clinical trial is entitled “Stem cell therapy for traumatic brain injury” or STEMTRA, and it will study the safety and efficacy of SB623 cell therapy in treating patients who suffer from chronic motor impairments following a TBI.
Enrollment in this clinical trial started in the United States in October, 2015. The trial will include clinical sites and patients in Japan and will enroll ~52 patients. The enrollment of Japanese patients is expected to accelerate the overall enrollment of human subjects.
SanBio spokesperson, Damien Bates, the Chief Medical Officer and Head of Medical Research at SanBio, said: “SanBio’s regenerative cell medicine, SB623, has improved outcomes in patients with persistent motor deficits due to ischemic stroke, and our preclinical data suggest that it may also help TBI patients. This is the first global Phase 2 clinical trial for TBI allogeneic stem cells, and the approval to conduct the trial in Japan, as well as in the United States, brings us one step closer to determining SB623’s efficacy for treatment whose who suffer from the effects of traumatic brain injury.”
SB623 are modified mesenchymal stem cells that transiently express a modified human Notch1 gene that only contains the intracellular domain of the Notch1 protein. This activated gene drives mesenchymal stem cells to form a cell type that habitually supports neural cells and promotes their health, survival, and healing. When administered into damaged neural tissue, SB623 reverses neural damage. Since SB623 cells are allogeneic (from a donor), a single donor’s cells can be used to treat many patients. In cell culture and animal models, SB623 cells restore function to damaged neurons associated with stroke, traumatic brain injury, retinal diseases, and Parkinson’s disease. SB623 cells function by promoting the body’s natural regenerative process.
Since the therapeutic mechanism of action of SB623 cells and the proposed route of administration are similar in the two trials (the stroke and TBI trials), the results of the TBI trial should be similar to those of the stroke trial.
The Japanese regulatory agencies grant marketing approval for regenerative medicines earlier countries as a result of an amendment to the Pharmaceutical Affairs Law in 2014. This particular amendment defined regenerative medicine products as a new category in addition to conventional drugs and medical devices, and the conditional and term-limited accelerated approval system for regenerative medicine products has started.
Two regenerative medicine products have already gained marketing approval under this new system, and the government-led industrialization of regenerative medicine products has gradually been realized.
SanBio has begun the preparation of clinical trial facilities in Japan and expects the launch of the clinical trial in 2016. the company hopes to market the medicine in Japan by taking advantage of the accelerated approval system.
A presentation at the annual meeting of the Association for Research in Vision and Ophthalmology in Seattle, Washington has reported the safe transplantation of stem cells derived from a patient’s skin to the back of the eye in an effort to restore vision. The subject for this research project suffered from advanced wet age-related macular degeneration that did not respond to current standard treatments.
A small skin biopsy from the patient’s arm was collected and reprogrammed into induced pluripotent stem cells (iPSCs). The iPSCs were then differentiated into retinal pigmented epithelial (RPE) cells, which were transplanted into the patient’s eye. The transplanted cells survived without any adverse events for over a year and resulted in slightly, though significantly, improved vision.
iPSCs are adult cells that have been reprogrammed to an embryonic stem cell-like state, which can then be differentiated into any cell type found in the body.
Abstract Title: #3769: Transplantation of Autologous induced Pluripotent Stem Cell-Derived Retinal Pigment Epithelium Cell Sheets for Exudative Age Related Macular Degeneration: A Pilot Clinical Study by Yasuo Kurimoto and others from the laboratory of Masayo Takahashi’s laboratory at the RIKEN Center for Developmental Biology in Kobe, Japan.
Unfortunately, this clinical trial has been suspended because iPSCs made from other patients proved to possess too many genetic abnormalities. Therefore, Takahashi and her colleagues have decided that allogeneic iPSCs differentiated into RPEs will probably do a better job than the patient’s own skin cell-derived iPSCs.
Stem Cells, Inc., has released the six-month results from cohort I of an ongoing Phase 2 clinical trial of human neural stem cells for the treatment of chronic cervical spinal cord injuries. The data displayed significant improvements in muscle strength had occurred in five of the six patients treated. Of these five patients, four of them also showed improved performance on functional tasks that assesses dexterity and fine motor skills. Furthermore, these four patients improved in the level of spinal cord injury according to the classification system provided by the International Standards for Neurological Classification of Spinal Cord Injury or ISNCSCI.
Stem Cells, Inc., expects to release their detailed final 12-month results on this first open-cohort later this quarter.
Chief medical officer, Stephen Huhn, presented these data at the American Spinal Injury Association annual meeting in Philadelphia, on Friday, April 15. Dr. Huhn also believes that the interim results are very encouraging and reason to be quite hopeful.
“The emerging data continue to be very encouraging,” said Dr. Huhn. “We believe that these types of motor changes will improve the independence and quality of life of patients and are the first demonstration that a cellular therapy has the ability to impact recovery in chronic spinal cord injury. We currently have thirteen sites in the United States and Canada that are actively recruiting patients. We have enrolled and randomized 19 of the 40 total patients in the statistically powered, single-blind, randomized controlled, Cohort II. We are projecting to complete enrollment by the end of September so that we can have final results in 2017.”
The present Phase 2 clinical trial is a multi-center enterprise that includes physicians and scientists at 13 different sites in the united States and Canada. Incidentally, these sites are presently actively recruiting patients.
Stem Cells, Inc., has enrolled and randomized 19 of the 40 total patients in this statistically powered, single-blind, randomized controlled, cohort II.
The Phase 2 study, “Study of Human Central Nervous System (CNS) Stem Cell Transplantation in Cervical Spinal Cord Injury,” will determine the safety and efficacy of transplanting the company’s proprietary human neural stem cells (HuCNS-SC cells) into patients with traumatic injury of the cervical region of the spinal cord.
Cohort I is an open label dose-ranging cohort in six AIS-A or AIS-B subjects. For those of you not familiar with the American Spinal Injury Impairment Scale (ASI A-E scale), here is a summary of the classification scheme:
ASI – A = Complete paralysis; No sensory or motor function is preserved in the sacral segments S4-5.
ASI – B = Sensory Incomplete; Sensory but not motor function is preserved below the neurological level and includes the sacral segments S4-5 (light touch or pin prick at S4-5 or deep anal pressure) AND no motor function is preserved more than three levels below the motor level on either side of the body.
ASI – C = Motor Incomplete; Motor function is preserved below the neurological level**, and more than half of key muscle functions below the neurological level of injury (NLI) have a muscle grade less than 3 (Grades 0-2).
ASI – D = Motor Incomplete; Motor function is preserved below
the neurological level**, and at least half (half or more) of key muscle functions below the NLI have a muscle grade > 3.
ASI – E = Normal; If sensation and motor function as tested with the ISNCSCI are graded as normal in all segments, and the patient had prior deficits, then the AIS grade is E. Someone without an initial SCI does not receive an AIS grade.
Cohort II is a randomized, controlled, single-blinded cohort in forty AIS-B subjects. Cohort III, which will only be conducted at the discretion of the sponsor, is an open-label arm that involves six AIS-C subjects.
The primary efficacy outcome will focus on changes in the upper extremity strength as measured in the hands, arms, and shoulders. This trial will enroll up to 52 subjects.
StemCells, Inc. has demonstrated the safety and efficacy of their HuCNS-SC cell in preclinical studies in laboratory rodents. Additional Phase I studies yielded positive human safety data. Furthermore, completed and ongoing clinical studies in which its proprietary HuCNS-SC cells have been transplanted directly into all three components of the central nervous system: the brain, the spinal cord and the retina of the eye, have further demonstrated the safety of HuCNS SC cells in human patients.
StemCells, Inc. clinicians and scientists believe that HuCNS-SC cells may have broad therapeutic application for many diseases and disorders of the CNS. Because the transplanted HuCNS-SC cells have been shown to engraft and survive long-term, there is the possibility of a durable clinical effect following a single transplantation.
The HuCNS-SC platform technology is a highly purified composition of human neural stem cells (tissue-derived or “adult” stem cells). Manufactured under cGMP standards, the Company’s HuCNS-SC cells are purified, expanded in culture, cryopreserved, and then stored as banks of cells, ready to be made into individual patient doses when needed.
In a study led by Martin Fussenegger of ETH Zurich, stem cells extracted from the fat of a 50-year-old test subject were transformed into mature, insulin-secreting pancreatic beta cells.
Fussenegger and his colleagues isolated stem cells from the fat of a 50-year-old man and used these cells to make induced pluripotent stem cells (iPSCs). These iPSCs were then differentiated into pancreatic progenitor cells and then into insulin-secreting beta cells but means of a “genetic software” approach.
Genetic software refers to the complex synthetic network of genes required to differentiate pancreatic progenitor cells into insulin-secreting beta cells. In particular, three genes, all of which expression transcription factors, Ngn3, Pdx1, and MafA, are particularly crucial for beta cell differentiation.
Fussenegger and his team designed a a protocol that would express within these fat-based stem cells the precise concentration and combination of these transcription factors. This feature is quite important because the concentration of these factors changes during the differentiation process. For example, MafA is not present at the start of beta cells maturation, but appears on day four on the final data of maturation when its concentration rises precipitously. The concentration of Ngn3 rises and then falls and the levels of Pdx1 rise at the beginning and towards the end of maturation.
The Zurich team used ingenious genetic tools to reproduce these vicissitudes of gene expression as precisely as possible. By doing so, they were able to differentiate the iPSC-derived pancreatic progenitor cells into insulin-secreting beta cells.
The fact that Fussenegger’s team was able to use a synthetic gene network to form mature beta cells from adult stem cells is a genuine breakthrough. The genetic network approach also seems to work better than the traditional technique of adding various chemicals and growth factors to cultures cells. “It’s not only really hard to add just the right quantities of these components (growth factors) at just the right time, it’s also inefficient and impossible to scale up,” said Fussenegger.
This new process can successfully transform three out of four fat stem cells into beta cells. Also the beta cells made with this method have the same microscopic appearance of natural beta cells in that they contain internal granules full of insulin. They also secrete insulin in response to increased blood glucose concentrations. Unfortunately the amount of insulin made by these cells is lower than that made by natural beta cells.
Pancreatic islet transplants have been performed in diabetic patients, but such transplantations also require treatment with potent antirejection drugs that have potent side effects.
“With our beta cells, there would likely be no need for this action (administering antitransplantation drugs), since we can make them using endogenous cell material taken from the patient’s own body. This is why our work is of such interest in the treatment of diabetes,” said Fussenegger.
Fussenegger and his group have made these beta cells in the laboratory, but they have yet to transplant them into a diabetic patient. However, the success of this synthetic genetic software technology might also be useful in the reprogramming of adult cells into other types of cells that are useful for therapeutic purposes.
Jan Nolta and her colleagues at the Stem Cell Program and Institute for Regenerative Cures at UC Davis have published a remarkable paper in the journal Molecular Therapy regarding Huntington’s disease and a potential stem cell-based strategy to delay the ravages of this disease.
Huntington’s disease (HD) is an inherited neurodegenerative disease. It is inherited as an autosomal dominant disease, which means that someone need only inherit one copy of the disease-causing allele of the HTT gene to have this disease. HD is characterized by progressive cell death in the brain, particularly in a portion of the brain known as the striatum and by widespread brain atrophy.
The portion of the brain known as the striatum lies underneath the surface of the forebrain (subcortical) and it receives neural inputs from the cerebral cortex and is the primary source of neural inputs to the basal ganglia system. The basal ganglia system (BGS) is located underneath the surface of the brain but even deeper within the cerebral hemispheres. The BGS is part of the corpus striatum, it consists of the subthalamic nucleus and the substantia nigra. The BGS help with voluntary motor control, procedural learning relating to routine behaviors. otherwise known as “habits,” eye movements, and cognitive, and emotional functions. The ventral striatum is very important in addiction because it is the reward center on consists of the nucleus accumbens, olfactory tubercle, and islands of Calleja.
HD takes its largest toll on the striatum, which affects voluntary movement, routine behaviors, and personality. Disturbances of both involuntary and voluntary movements occur in individuals with HD. Chorea, an involuntary movement disorder consisting of nonrepetitive, non-periodic jerking of limbs, face, or trunk, is the major sign of the disease. Chorea is present in more than 90% of individuals, increasing during the first ten years. The choreic movements are continuously present during waking hours, cannot be suppressed voluntarily, and are worsened by stress. HD patients show impaired voluntary motor function early on and show a clumsiness in common daily activities.
With advancing disease duration, other involuntary movements such as slowness of movement (bradykinesia), rigidity, and involuntary muscle contractions that cause repetitive or twisting movements (dystonia) occur. Eye movement becomes progressively worse. So-called “gaze fixation” is observed in ~75% of symptomatic individuals. Unclear speech occurs early and Swallowing difficulties occur later.
Animal models of HD used in the past have injected molecules into the brain that kill off striatal cells and mimic at least some of the characteristics of HD in laboratory animals. Unfortunately, such a model system is fat too clean, since implanted cells tend to survive perfectly well. However the brains of HD patients are like unto a toxic waste dumps and implanted cells are quickly killed off. Therefore, a better animal model system was required, and it came in the form of R6/2 and YAC128 mice. R6/2 mice have a part of the human HTT gene that has 150 CAG triplets, and show the characteristic cell death in the striatum and behavioral deficits. The only problem with this mouse strain is that the neurodegenerative decline is very rapid rather than slow and progressive. YAC128 mice have a full-length copy of the HTT gene and show a slower, more progressive neurological decline that more closely approximates the human clinical condition.
In this paper from the Nolta laboratory, they used a growth factor that is known to decrease precipitously in HD brains; a growth factor called Brain-Derived Neurotrophic Factor (BDNF). BDNF is known to mediate the survival and function of striatal neurons and the reduction of BDNF in the brains of HD patients correlates with the onset of symptoms and the greater the reduction in BDNF, the greater the severity of the disease (see Her LS & Goldstein LS, J Neurosci 2008; 28, 13662-13676).
However injecting BDNF into the brain is problematic, since the protein has a very short half-life. Delivering the growth factor by means of genetically engineered viruses shows promise, but most of the viral vectors used in such experiments are recognized by the immune system as foreign invaders. Therefore, Nolta and her colleagues decided to genetically engineer mesenchymal stem cells (MSCs) to overexpress BDNF and implant these cells into the brains of R6/2 and YAC128 mice.
MSCs have an added advantage over viral vectors: these cells migrate to damaged areas where they can exert their healing properties (see Olson SD et al., Mol Neurobiol 45; 2012: 87-98).
Nolta and her coworkers actually tested human MSCs in HD model mice. After completing all the necessary control experiments to ensure that their isolated and engineered MSCs were secreting BDNF, Nolta and others implanted them into the brains of R6/2 and YAC128 mice.
HD mice show greater anxiety, which is manifested in a so-called “open field assay” by not remaining the center of the field. The control HD mice did not stay long in the center of the open field, but the normal mice did. The MSC-BDNF-implanted mice spend far more time in the center of the field. Mind you, not as much as wild-type mice, but significantly more than their HD counterparts.
Next the volume of the striata of these mice were determined and compared to the normal mice. While all the HD mice showed shrinking of the striatum, the MSC-NDNF-implanted YAC128 mice show significantly less shrinking of the striatum. Then the degree of neurogenesis (formation of new neurons) was measured in normal, HD, HD + implanted MSCs, and HS + MSC-BDNF mice. This experiment measures the degree of healing that is occurring in the brain. The brain from HD + MSC and HD + MSC-BDNF mice showed significantly more new brain cell growth. This is probably the reason for the delayed onset of symptoms and the delayed shrinking of the striatum.
Finally, Nolta and others measured the lifespans of the R6/2 mice and compared them with R6/2 mice that had been implanted with MSCs-BDNF. Animals transplanted with the MSCs that made the most BDNF lived 15% longer than the nontreated R6/2 mice.
MSCs have been shown in several experiments to promote neuronal growth, decrease cell death and decrease inflammation through the secretion of trophic factors. MSCs can modify the toxic environment that is part of the brain of an HD patient and help damaged tissue out by inducing neural regeneration and protection (see Crigler L, et al., Experimental neurology, 198; 2–6, 54-64; Kassis I, et al., Archives of Neurology 65; 2008: 753-761).
The downside of using MSCs that they will only survive in the brain for a few months. However, several studies have shown that the benefits of modified MSC implantation persist after the MSCs are gone, since the neural reconstruction wrought by the secreted BDNF stay after the MSCs have died off (see Arregui L, et al., Cell Mol Neurobiol 31; 2011: 1229-1243 and many others).
At best this treatment would delay the ravages of HD, but delaying this disease might very well be the first step towards a cure. Hopefully, clinical trials will not be fat behind.
Mesoblast Limited announced that the number of subjects treated in their ongoing Phase 3 clinical trial in chronic heart failure (CHF) that is testing their proprietary cell-based medicine MPC-150-IM will be substantially reduced.
CHF is characterized by an enlarged heart, coupled with insufficient blood supply to the organs and extremities of the body. Unfortunately, this is a progressing condition that tends to get worse with time. CHF is caused by many different factors such as chronic high blood pressure, faulty heart valves, infections, or congenital heart problems.
Mesoblast centers their company around the isolation and expansion of so-called mesenchymal precursor cells (MPCs) from bone marrow. Mesenchymal stem cells are found in many different tissues and organs throughout our bodies. They play vital roles in maintaining tissue health. However, relatively speaking, mesenchymal stem cells are rare cells. They are found around blood vessels and respond to signals associated with tissue damage. They secrete mediators and growth factors that promote tissue repair and control the immune response to prevent it from going out of control.
Mesoblast uses an array of monoclonal antibodies to isolate primitive mesenchymal stem cells that are actually precursors to mesenchymal stem cells or mesenchymal precursor cells (MPCs). These cells are then expanded in culture without being differentiated into any other cell type.
Initially, Mesoblast planned to test their product on 1,165 subjects, but have scaled that number back to approximately 600 patients.
Mesoblast’s development and commercial partner, Teva Pharmacueticals has communicated this reduction in the number of subjects to the US Food and Drug Administration (USFDA). “The reduction in the size of the Phase 3 trial may significantly shorten the time to trial completion,” said Mesoblast CEO Silviu Itescu.
The reduction in the number of patients was due to a proposed change in the primary endpoint of the trial. The revised primary endpoint is now a comparison of recurrent heart failure-related major adverse cardiovascular events (HF-MACE) between patients treated with Mesoblast’s MPC-150-IM cells and the control patients who were not treated with these cells.
Why the change in the primary endpoint? The reason lies in the success that MPC-150-IM cells had their Phase 2 clinical trial. In this trial, a single injection of MPC-150-IM cells successfully prevented HF-MACE over three years. This second, confirmatory study will be conducted in parallel with a patient population that has an identical clinical profile; approximately 600 of them using the same primary endpoint.
In the completed Phase 2 trial, patients treated with MPC-150-IM had no HF-MACE over 36 months of follow-up, compared with 11 HF-MACE in the control group. From this same clinical trial, of those patients who suffered from advanced heart failure (defined by baseline Left Ventricular Systolic Volume being greater than 100 milliliters), 71 percent of the controls (who received no cells) had at least on HF-MACE versus none of those who received a single injection of MPC-150-IM cells. As it turns out, this Phase 2 patient population closely resemble the patients being recruited in the Phase 3 trial.
“Patients with advanced heart failure continue to represent among the largest unmet medical needs, where existing therapies are inadequate and the economic burden is the greatest. The current Phase 3 trial targets this patient population, continues to recruit well across North America, and is now expanding to Europe,” said Itescu.
The Australian government has recently given its approval for a clinical trial of what is almost certainly a medical first. The Carlsbad-based stem cell company, International Stem Cell Corp. (ISCO), a publicly traded biotechnology company, has developed a unique stem cell technology to address particular conditions.
The clinical trial that has been approved will examine the use the ISCO’s unique stem cell products in the treatment of Parkinson’s disease. Twelve Parkinson’s patients will receive implantations of these cells sometime in the first quarter of 2016, according to Russell Kern, ISCO’s chief scientific officer. The implanted cells will be neural precursor cells, which are slightly immature neurons that will complete their maturation in the brain, hopefully into dopamingergic neurons, which are the precise kind of neurons that die off in patients with Parkinson’s disease.
Parkinson’s disease (PD) is a progressive disorder of the nervous system that affects voluntary movement. PD develops gradually and sometimes begins with a slight tremor in only one hand, but PD may also cause stiffness or slowing of movement. PD worsens over time.
PD patients suffer from tremor, or shaking of the limbs, particularly when it is relaxed and at rest. Over time, PD reduces the ability to move and slows movement (bradykinesis) which makes simple tasks difficult and time-consuming. Muscle stiffness may occur and this limits the range of motion and causes pain. PD patients also suffer from stooping posture and balance problems and a decreased ability to perform unconscious movements. For example, they have trouble swinging their arms while they walk, blinking, or smiling. They might also experience speech problems that can range from slurring of the speech to monotone speech devoid of inflexions, or softer speech with hesitations before speaking. Writing might also become problematic.
PD is caused by the gradual death of neurons in the midbrain that produce a chemical messenger called dopamine. The drop in dopamine levels in the system of the brain that controls voluntary movement leading to the signs and symptoms of Parkinson’s disease.
Several different animal experiments with a variety different cell types have established that transplantation to dopamine-making neuronal precursors into the midbrains of laboratory animals with artificially-induced PD can reverse the symptoms of PD. Dopaminergic neurons can be derived from embryonic stem cells (ESCs), mesenchymal stem cells (MSCs), umbilical cord blood hematopoietic stem cells (HSCs), induced pluripotent stem cells (iPSCs), and NSCs (see Petit G. H., Olsson T. T., Brundin P. Neuropathology and Applied Neurobiology. 2014;40(1):60–67). Also, since the 1980s, various cell sources have been tested, including autografts of adrenal medulla, sympathetic ganglion, carotid body-derived cells, xenografts of fetal porcine ventral mesencephalon, and allografts of human fetal ventral mesencephalon (fVM) tissues have been implanted into the midbrains of PD patients (Buttery PC, Barker RA. J Comp Neurol. 2014 Aug 15;522(12):2802-16). While the results of these trials were varied and not terribly reproducible, these studies did show that the signs and symptoms of PD could be reversed, in some people, by implanting dopamine-making neurons into the midbrains of PD patients.
ISCO has derived neural precursor cells from a completely new source. ISCO scientists have taken unfertilized eggs from human egg donors and artificially activated them so that they self-fertilize, and then begin dividing until they form a blastocyst-stage embryo from which stem cells are derived. This new class of stem cells, which were pioneered by ISCO, human parthenogenetic stem cells (hpSCs) have the best characteristics of each of the other classes of stem cells. Since these stem cells are created by chemically stimulating the oocytes (eggs) to begin division, the oocytes are not fertilized and no viable embryo is created or destroyed. This process is called parthenogenesis and parthenogenetic stem cells derived from the parthenogenetically-activated oocytes, are produced from unfertilized human egg cells.
Why did ISCO decide to do this trial in Australia? According to Kern, ISCO chose to conduct their clinical trial in Australia because its clinical trial system is more “interactive,” which allows for better collaboration with Australia’s Therapeutic Goods Administration on trial design. This clinical trial, in fact, is the first stem cell trial for PD according to the clinical trial tracking site clinicaltrials.gov. The test will be conducted by ISCO’s Australian subsidiary, Cyto Therapeutics.
The approach pioneered in this clinical trial might cure or even provide an extended period of relief from the symptoms of PD. If this clinical trial succeeds, the stem cell clinical trial dam might very well break and we will see proposed clinical trials that test stem cell-based treatments for other neurodegenerative diseases such as Huntington’s disease, Lou Gehrig’s disease (ALS), frontotemporal dementia, or even Alzheimer’s disease.
ISCO has spent many years developing their parthenogenetic technology with meager financing. However the company’s total market value amounts to something close to $11.1 million, presently.
hpSCs are pluripotent like embryonic stem cells. Because they are being used in the brain, they will not be exposed to the immune system. Therefore an exact tissue type match is not necessary for this type of transplantation. In their publications, ISCO scientists have found their cells to be quite stable, but other research groups who have worked with stem cells derived from parthenogenetically-activated embryos have found such cells to be less stable than other types of pluripotent stem cells. The stability of the ISCO hpSCs remains an open question. The lack of a paternal genome might pose a safety challenge for the use of hpSCs.
Rita Vassena and her colleagues in the laboratory of Juan Carlos Izpisua Belmonte at the Salk Institute for Biological Studies in La Jolla, CA examined the gene expression patterns of mesenchymal stem cells derived from hpSCs and found that the overall gene expression patterns were similar to MSCs made from embryonic stem cells or induced pluripotent stem cells. However, upon further differentiation and manipulation, the gene expression patterns of the cells began to show more variability and further depart from normal gene expression patterns (Vassena R, et al Human Molecular Genetics 2012; 21(15): 3366-3373). Therefore, the derivatives of hpSCs might not be as stable as cellular derivatives from other types of stem cells. The good news about hpSCs established from parthenogenetic ESCs were reported to be morphologically indistinguishable from embryonic stem cells derived from fertilized embryos, and seem to show normal gene expression or even correct genomic imprinting in chimeras, when pESCs were used in tissue contribution (T.Horii, et al Stem Cells, vol. 26, no. 1, pp. 79–88, 2008).
For those of us who view the early embryo as the youngest members of the human community who have the right not to be harmed, hpSCs made by ISCO remove this objection, since their derivation does not involve the death of any embryos.
The ISCO approach to Parkinson’s is similar to that of a San Diego group called Summit for Stem Cell, which is going to use induced pluripotent stem cell derivatives. This nonprofit organization is presently raising money for a clinical trial to test the efficacy of their treatment.
Both groups intend to transplant the cells while they are still slightly immature, so that they can complete their development in the brain. Animal studies suggest that implanting immature precursors are better than transplanting mature dopaminergic neurons into the midbrain. The precursors then differentiate into dopamine-making neurons, and other cells differentiate into supportive glial cells, which support the dopamine-making neurons.
“It’s a dual action,” Kern said. “Also, neural stem cells reduce inflammation, and inflammation is huge in Parkinson’s.”
Summit 4 Stem Cell will also take a similar approach, according to stem cell scientist Jeanne Loring, a leader of the Summit 4 Stem Cell project. The cells make proper connections with the brain better when they are still maturing, said Loring, who’s also head of the regenerative medicine program at The Scripps Research Institute in La Jolla. This is all provided that Summit 4 Stem Cell can raise the millions of dollars required for the clinical trial and secure the required approvals from the U.S. Food and Drug Administration.
Loring said she views ISCO as a partner in fighting Parkinson’s. One of her former students is working for the company, she said. “The whole idea is to treat patients by whatever means possible,” Loring said.
ISCO’s choice of Australia for its streamlined regulatory process makes sense, Loring said. Her team, with U.S.-based academics and medical professionals, doesn’t have the same flexibility as ISCO in looking for clinical trial locations, she said.
Jianjun Wang from Wayne State School of Medicine in Detroit, Michigan and Xi-Yong Yu from Guangzhou Medical University and a host of graduate students and postdoctoral research fellows in their two laboratories have teamed up to make human cardiac progenitor cells (CPCs) from human skin fibroblasts through direct reprogramming. Direct reprogramming does not go through a pluripotent intermediate, and, therefore, produces cells that have a low chance of generating tumors.
To begin their study, Wang, and Yu and their colleagues isolated fibroblasts from the lower regions of the skin (dermis) and grew them in culture. Then they reprogrammed these cells in a relatively novel manner. This is a little complicated, but I will try to keep it simple.
Reprogramming cells usually requires scientists to infect cells with recombinant viruses that have been genetically engineered to express particular genes in cells or force cells to take up large foreign DNA. Both of these techniques can work relatively well in the laboratory, but you are left with cells that are filled with foreign DNA or recombinant viruses. It turns out that directly reprogramming cells only requires transient expression of specific genes, and once the cells have recommitted to a different cell fate, the expression of the genes used to get them there can be diminished.
To that end, some enterprising scientists have discovered that inducing cells to up modified proteins can also reprogram cells. Recently a new reagent called the QQ-reagent system can escort proteins across the cell membrane. The QQ-reagent has been patented and can sweep proteins into mammalian cells with high-efficiency and low toxicity (see Li Q, et al (2008) Methods Cell Biol 90:287–325).
Wang and Yu and their coworkers used genetically engineered bacteria to overexpress large quantities of four different proteins: Gata4, Hand2, Mef2c, and Tbx5. Then they mixed these proteins with their cultured human fibroblasts in the presence of the QQ reagent. This reagent drew the proteins into the cells and the fibroblasts were reprogrammed into cardiac progenitor cells (CPCs). Appropriate control experiments showed that cells that were treated with QQ reagent without these proteins were not reprogrammed. Wang and Yu and they research groups also exposed the cells to three growth factors, BMP4 and activin A, to drive the cells to become heart-specific cells, and basic fibroblast growth factor to turn the cells towards a progenitor cell fate.
The next set of experiment was intended to show that their newly reprogrammed were of a cardiac nature. First, the cells clearly expressed heart-specific genes. Flk-1 and Isl-1 are genes that earmark cardiac progenitor cells, and by the eighth day of induction, the vast majority of cells expressed both these genes.
Second, cardiac cells can differentiate into three different cell types: heart muscle cells, blood vessels cells, and smooth muscle cells that surround the blood vessels. In mesoderm progenitors made from embryonic stem cells, inhibition of the Wnt signaling pathway can drive such cells to become heart muscle cells (see Chen, et al Nat Chem Biol 5:100–107; Willems E, et al Circ Res 109:360–364; Hudson J, et al Stem Cells Dev 21:1513–1523). However, Wang, Yu and company showed that treating the cells with a small molecule called IWR-1 that inhibits Wnt signaling drove their cells to differentiate into, not only heart muscle cells, but also endothelial (blood vessel) cells and smooth muscle cells when the cells were grown on gelatin coated dishes. When left to differentiate in culture, the cells beat synchronously and released calcium in a wave-like fashion that spread from one cell to another, suggesting that some cells were acting as pacemakers and setting the beat.
Then these cells were transplanted into the heart of mice that had suffered heart attacks. When compared to control hearts that received fluid, but no cells, the hearts of the animals that received protein-induced CPCs showed decreased scarring by 4 weeks after the transplantations. They also showed the growth of new heart muscle. A variety of staining experiments established that the engrafted protein-induced CPCs positive for heart muscle- and endothelial-specific cell markers. These experiments showed that transplantation of cardiac progenitor cells can not only help attenuate remodeling of the left ventricular after a heart attack, but that the protein-induced CPCs (piCPCs) can develop into cells of the cardiac lineage.
These are exciting results. It shows that direct reprogramming can occur without introducing genes into cells by means that can complicate the safety of the implanted cells. Also, because the cells are differentiated into progenitor cells, they still have the ability to proliferate and expand their numbers, which is essential for proper regeneration of a damaged tissue.
After a heart attack, the ventricle wall scars over and can become thin. However, piCPCs that have been directly reprogrammed from mature, adult cells can be used to replace dead heart muscle in a living animal.
Despite these exciting advances, further questions remain. For example, are the physiological properties of cells made from piCPCs similar enough to match the functional parameters of the heart into which they are inserting themselves? More work is necessary to answer that question. Functional equivalence is important, since a heart that does not function similarly from one end to the other can become arrhythmic, which is clinically dangerous. Further work is also required to precisely determine how well cells derived from piCPCs mature and coupling with neighboring cells. Therefore, larger animal studies and further studies in culture dishes will be necessary before this technique can come to the clinic. Nevertheless, this is a tremendous start to what will hopefully be a powerful and fruitful technique for healing damaged hearts.
Lung diseases are no fun for anyone. The constant feeling of suffocation, withering weakness, and significant limitations on human activity are indicative of a loss of lung capacity. Chronic obstructive pulmonary disease or idiopathic pulmonary fibrosis are among the top five causes of mortality, according to the World Health Organization (CottinV Eur Respir Rev 22:26–32). Regenerating damaged lungs, therefore, represent one of the Holy Grails of regenerative medicine.
Animal studies have used infusions of mesenchymal stem cells (MSCs) from isolated from human bone marrow, adipose tissue, placental tissue, or cord blood to treat animals with various types of lung disease (MoodleyY, et al.Am J Pathol 175:303–313; OrtizLA, et al. Proc Natl Acad Sci USA 104:11002–11007; OrtizLA, et al. Proc Natl Acad Sci USA 100:8407–8411). Also, a Phase I clinical trial has assessed the safety of fat-based MSCs as a treatment for lung damage in human patients. Because this study was only designed to test the safety of this procedure, little to nothing can be said of the efficacy of this test (Tzouvelekis A,J Transl Med. 2013 Jul 15;11:171).
Recently, several laboratories have identified resident stem cells in the lung and some researchers have even managed to isolate them and growth them in culture (Desai TJ, et al., (2014) Alveolar progenitor and stem cells in lung development, renewal and cancer. Nature 507:190–194; Kajstura J, et al., (2011) Evidence for human lung stem cells. N Engl J Med 364:1795–1806; Kim CF, et al., (2005) Identification of bronchioalveolar stem cells in normal lung and lung cancer. Cell 121:823–835; Wansleeben C, et al. (2013) Stem cells of the adult lung: Their development and role in homeostasis, regeneration, and disease. Wiley Interdiscip Rev Dev Biol 2:131–148; Barkauskas CE, et al. (2013) Type 2 alveolar cells are stem cells in adult lung. J Clin Invest 123:3025–3036; Hogan BL, et al. (2014) Repair and regeneration of the respiratory system: Complexity, plasticity, and mechanisms of lung stem cell function. Cell Stem Cell 15:123–138). Could such cells work better than MSCs?
At this point it is difficult to say, since there are a fair amount known about isolating and growing MSCs in culture, but there is relatively little known about resident lung stem cell populations. However, a new paper might change that feature of the debate.
Ke Cheng and his colleagues from North Carolina State University have developed a rapid, reproducible, and scalable method to generate clinically applicable amounts of resident lung progenitor cells. This technique capitalizes on the “Spheroid method” used for tumor cells. Spheroids are three-dimensional structures that grow as small balls of cells in culture. Cheng and others applied the spheroid culture method to lung cells with great success.
Lung cells were acquired from lung biopsies taken from human patients. The tissues were appropriately minced, treated with enzymes to disintegrate the structural components, and then grown in culture. The cells that grew were eventually seeded onto a special culture system for growing spheroids. In this culture system, spheroids formed, consisting of internal clumps of lung progenitor cells surrounded by a shell of stroma-like cells. These cells expressed the cadre of genes you would expect them to. Cheng and his coworkers called these cells “lung spheroid cells” or LSCs.
When Cheng and his group implanted LSCs into Matrigel, the cell appropriately differentiated into lung-specific cell types and formed structures that greatly resembled the tiny air sacs in lungs, known as alveoli. These structures, based on their expression patterns of particular genes are where specific proteins were found in the cells, seemed for a mature lung structure. Interestingly, when the culture medium that had been used to grow the LSCs (conditioned media) was given to other cultured cells, it promoted survival or proliferation of human lung epithelial cells and tube formation of human endothelial cells on Matrigel.
Now the $64,000 question is this: “How do LSCs stack up against MSCs at treating lung damage?”
To address this question, Cheng and others used a mouse model of pulmonary fibrosis. To induce pulmonary fibrosis in mice, Severe Combined Immune Deficient (SCID) mice were given intratracheal washes of the anticancer drug bleomycin, which induces a condition in mice that, to some degree, resembles human pulmonary fibrosis. Different groups of mice with this lung damage were given either intravenous infusions of LSCs, MSCs or saline as a control.
The administered LSCs reduced the amount of cell death and scarring observed in the lungs. LSCs also increased the formation of new blood vessels and decreased the expression of pro-fibrotic genes. While the infusion of MSCs did improve the lung tissue in these mice, the LSCs were clearly superior.
Can LSCs provide the kind regenerative “OOMPH” damaged lungs need? The culture system that was developed by Cheng and others can produce large quantities of cells from even small biopsies. This makes the procedure suitable and efficacious for clinical situations in which a patient is receiving infusions of their own cells or someone else’s cells. An added advantage to this system in the absence of any need for cell sorting, which is expensive, and requires highly-trained technicians who operate large, expensive machines. Also, none of the mice treated in this study showed any signs of tumors, which underscores the clinical safety of LSCs.
Cultured MSCs might also provide an excellent model system to study lung pathologies. Making LSCs from patients with cystic fibrosis, inherited versions of emphysema, or other pulmonary diseases could provide an accessible and effective model system for drug testing and pathological studies.
GVHD occurs when newly transplanted donor cells attack the recipient’s body. It can occur after a bone marrow or stem cell transplant if the cells have not been properly matched or even if the donor and recipient are relatively well matched. The chances of suffering GVHD are around 30 – 40% if the donor and recipient are genetically related and close to 60 – 80% when the donor and recipient are not related.
GVHD can be either acute or chronic and the symptoms of GvHD can be either mild or severe. Typically, acute GVHD comes on within the first 6 months after a transplant. Common acute symptoms include: Abdominal pain or cramps, nausea, vomiting, and diarrhea, Jaundice (yellow coloring of the skin or eyes) or other liver problems, skin rash, itching, redness on areas of the skin. Chronic GVHD usually starts more than 3 months after a transplant, and can last for the lifetime or the patient. The symptoms of chronic GvHD include: dry eyes or vision changes, dry mouth, white patches inside the mouth, and sensitivity to spicy foods, fatigue, muscle weakness, and chronic pain, joint pain or stiffness, skin rash with raised, discolored areas, as well as skin tightening or thickening, shortness of breath, weight loss.
Endonovo uses a novel method to enhance stem cells. Their so-called “Cytotronics platform” utilizes Time-Varying Electromagnetic Field (TVEMF) technology to expand and enhance the therapeutic properties of stem cells and other types of cells for regenerative treatments and tissue engineering. This platform can potentially optimize cell-based therapies so that they have greater therapeutic potential than they had prior to their treatment.
The Cytotronics™ platform dates back to experiments conducted at NASA to expand stem cells in culture. NASA’s goal was to create stem cell therapies that could be used to treat astronauts during long-term space exploration. NASA scientists showed that Time-Varying Electromagnetic Fields (TVEMF) could stimulate the expansion of stem cells in the lab. Additionally, TVEMF increased the expression of dozens of genes related to cell growth, tumor suppression, cell adhesion and extracellular matrix production.
By testing and tweaking this technology over a period of 15 years, Endonovo scientists created a novel protocol for augmenting the therapeutic properties of cells in culture through physics rather than genetic engineering. The Cytotronics™ platform seems to be able to make stem cells that express higher levels of key genes necessary for tissue healing and regeneration.
As an example of the efficacy of this technology. Endonovo scientists have shown that Cytotronic™ expansion of peripheral blood stem cells resulted in an over 80-fold expansion of CD34+ cells in as little as 6 days.
Endonovo is using the Cytotronic platform to enhance the regenerative properties of mesenchymal stem cells (MSCs), which have the capacity to staunch inflammation in patients with GvHD and other inflammatory diseases.
However, despite their promise, MSC-based therapies suffer from poor engraftment and short-term survival when transplanted into sick patients. These remain major limitations to the effective therapeutic use of MSCs. If there was a safe and effective way to beef up the survival and regenerative properties of MSCs, such a technique would be indispensable. This makes MSCs prime candidates for the Cytotronic Platform.
Dr. Donnie Rudd, Chief Scientist & Director of Intellectual Property at Endonovo, said: “Our Cytotronics platform is particularly suited to address many of the issues that have plagued stem cell therapies that have recently failed, such as their loss of potency and self-renewal when expanded ex vivo, their poor engraftment and their limited ability to survive when transplanted.”
Earlier this year, Endonovo announced a protocol for the creation of a cell mixture from a portion of the human umbilical cord co-cultured with adipose-derived stem cells. This resulting cell mixture contains a rich source of highly-proliferative, immunosuppressive cells that are not recognized by the patients immune system, since they contain neither of the major histocompatibility markers (HLA double negative). These cells are “immune privileged,” which means that are not recognized as foreign cells by the patient’s immune system, and therefore are a significant source of cells for MSC-based therapies.
Endonovo Therapeutics has used this new technology to create a biologically potent, off-the-shelf, allogeneic treatment for Graft-Versus-Host disease and a wide-array of other conditions. They would like to test these products in clinical trials eventually.
Endonovo hopes that stem cells enhanced by the Cytotronics™ platform will become a major innovation in the regenerative medicine market.
“We are very excited to be a leader in the development of next-generation, ex vivo enhanced cells for regenerative medicine,” stated Endonovo CEO, Alan Collier. “We have seen several stem cell therapies fail in clinical trials over the last couple of years, which points to a critical need for the development of methods to increase the biological and therapeutic properties of stem cells.”
“We believe that enhancing the biological and therapeutic properties of stem cells using bioelectronics is the future of cell-based therapies,” concluded Mr. Collier.
Capricor Therapeutics, Inc., located in Beverly Hills, CA, has announced their six-month safety and adverse event data from a Phase I clinical trial of their CAP-1002 product for patients with advanced heart failure. This clinical trial is part of the DYNAMIC or which is short for Dilated cardiomYopathy iNtervention with Allogeneic MyocardIally-regenerative Cells trial whose goal is to evaluate CAP-1002 in patients with advanced heart failure.
CAP-1002 is Capricor’s lead investigational allogeneic, cardiosphere-derived cell (CDC) therapy. Allogeneic means that the cells come from someone other than the patient. The advantage of allogeneic cells is that they come from healthy donors whose cells have not been ravaged by old age or other conditions. These cells do not need to be matched to the patient’s immune system in this case because they help the heart through indirect means (see Tseliou E, et al., J Am Coll Cardiol. 2013 Mar 12;61(10):1108-19). Cardiospheres are cells taken from the hearts of healthy patients that grow in culture as small balls of cells. Because these cells are derived from the heart and grow as spheres, they are called cardiospheres (see Cheng K, et al., JACC Heart Fail. 2014 Feb;2(1):49-61.).
Cardiospheres have been shown in small clinical trials (the CADUCEUS trial) to replace the heart scar with heart muscle (see Malliaras K, et al., Am Coll Cardiol. 2014 Jan 21;63(2):110-22). Animal studies in rats showed similar results (see above).
CAP-1002 is an off-the-shelf “ready to use” cardiac cell therapy that consists of cells that come from donor heart tissue and is infused directly into a patient’s coronary artery during a catheterization procedure. This Phase I study is meant to determine if CAP-1002 is safe and effective in treating heart function and structure. In particular, Capricor scientists are interested in determining if CAP-1002 cells can decrease heart scar tissue and promote the growth of heart muscle. In doing so, this regenerative treatment might delay or even prevent the onset of heart failure. The US Food and Drug Administration has granted CAP-1002 an orphan drug designation for the treatment of cardiomyopathy associated with Duchenne Muscular Dystrophy.
Capricor’s Cardiosphere-Derived Cells are a unique therapeutic product that were created in the laboratory of company Co-Founder and Scientific Advisory Board Chairman, Dr. Eduardo Marbán, who is the Director of the Heart Institute at Cedars-Sinai Medical Center.
All patients in this trial have advanced heart failure and have progressed to a more advanced stage of the disease. Patients received CAP-1002 in up to three coronary arteries, which delivers the cells to the more of the diseased parts of the heart. Since these patients have significant fibrosis in all areas of the heart, this delivery system is optimal for these patients. Cell delivery will also utilize methods that do not stop blood flow, which will decrease patient discomfort during cell delivery.
The data from this trial, so far, comes from 14 patients who were diagnosed with either dilated cardiomyopathy or non-ischemic dilated cardiomyopathy. These patients have ejections fractions of 35% or less and are classified as New York Heart Association class III or Ambulatory Class IV heart failure.
The data collected to date show that CAP-1002 cells are safe and well tolerated and produced no adverse cardiac events at one month or six months after they were infused into the patient’s hearts. Although DYNAMIC was designed as a Phase I clinical trial that does not assess the efficacy of CAP-1002 cells, patients have also been tested for their subject wellbeing, exercise capacity (six-minute walk test), ejection fraction, and ventricular volumes.
According to the principal investigator Dr. Raj Makkar of Cedar-Sinai Medical Center, the data so far are rather encouraging, even beyond the positive safety data, since they are seeing “concordance between the clinical improvement and the physiological measurements of trends for improved ejection fraction and reverse re-modeling.” Dr. Makkar, however, emphasized that this clinical trial only tested a small cohort of patients, and these data must be confirmed in larger clinical trials.
Karl Willert, PhD, associate professor in the Department of Cellular and Molecular Medicine at the University of California, San Diego and his colleagues have generated a new cell line in his laboratory that can potentially all the tissues in our bodies that are generated from mesoderm.
During embryonic development, 14 days after fertilization, the embryo is transformed from a single-cell thick sheet to a three-layered structure by a process called gastrulation. Gastrulation forms an outer layer of cells known as the ectoderm, which forms the skin and the nervous system, a middle layer of cells known as the mesoderm, which forms the muscles, heart, blood vessels, kidneys, gonads, dermis, adrenal glands, bones, and several other important tissues, and an innermost layer of cells called the endoderm, which forms the gastrointestinal tract as its associated structures. These three layers, the ectoderm, mesoderm, and the endoderm, are collectively known as the “primary germ layers” and they are formed at gastrulation.
Willert, in collaboration with co-corresponding author David Brafman from Arizona State University, used a high-throughput screening platform that had been previously developed in Brafman’s laboratory to define the exact cellular microenvironment that would drive pluripotent stem cells efficiently differentiate into mesodermal progenitor cells. Such cells could theoretically differentiate into any of the derivatives of the mesodermal germ layer, and these cells would also show a greatly reduced capacity to form tumors, since they are no longer pluripotent, but only multipotent.
After using their screening platform to differentiate human embryonic stem cells into cells that expressed mesodermal-specific genes, Willert and his team settled upon a microenvironment that differentiated these stem cells into intermediate mesodermal progenitor (IMP) cells that could be propagated in culture. Interestingly, these IMP cells had the ability to differentiate into mature kidney cells, without the risk of forming tumors. Oddly, these cells were not able to differentiate into other types of mesodermal derivatives.
“This work nicely complements recent advances in tissue engineering and the goal of rebuilding or recreating functional organs, such as what we’ve seen with the creation of ‘mini-kidneys’,” said Willert. “It represents a novel source of cells.” This study was published November 10, 2015 in the online journal eLIFE.
Extensive analyses showed that their IMP cells lacked tumor-forming potential. However, they retained the ability to differentiate into cells that compose the adult kidney. The ability to generate expandable populations of IMPs cells with limited differentiation have several advantages over pluripotent human stem cell cultures. First, pluripotent stem cell cultures can be differentiate into specific cell types but even under the best of conditions, such cell preparations can harbor undifferentiated cells that retain the potential to seed tumor growth. Secondly, it is much easier to manipulate and differentiate IMP cells than pluripotent stem cells. That simplifies the protocols for handling these cells, which also decreases the time and expense required to make anything from these cells. Third, since IMP cells have limited differentiation capabilities, they are less likely than pluripotent stem cells to differentiate into unwanted cell types.
“Our cells can serve as building blocks to generate kidneys that may one day be suitable for cell replacement and transplantation,” said Willert. “I think such a therapeutic application is still a few years in the future, but engineered kidney tissue can serve as a powerful model system to study how the human kidney interacts with and filters drugs. Such an application would be of tremendous value to the pharmaceutical industry.”
Even though Willert’s IMP cells differentiated into kidney cells, Willert is optimistic that they are capable of differentiating into other mesodermal-derived cell types, like gonads. “We have only characterized their potential to differentiate into cells that contribute to the kidney. We are now investigating to what extent these cells can generate other tissues and organs that derive from intermediate mesoderm, including reproductive organs.”
Willert and his colleagues are using the same protocol to generate other expandable progenitor cell lines from pluripotent stem cells derived from other germ layers, such as ectoderm and endoderm.
Induced pluripotent stem cells (iPSCs) are made from mature, adult cells by a combination of genetic engineering and cell culture techniques. Master genes are transfected into mature cells, which are then cultured as they grow and revert to more immature states. Eventually, a population of cells grow in culture that have some, though not all of the characteristics, of embryonic stem cells. Because these cells are pluripotent, they should, theoretically have the ability to differentiate into any adult cell type. Also, since they are derived from a patient’s own cells, they should be tolerated by the patient’s immune system and should not experience tissue rejection.I
Or should they? Experiments with cells derived from iPSCs have generated mixed results. If C57BL/6 (B6) mice are transplanted with iPSC-derived cells, such cells show some levels of recognition by the immune system. However, another study has concluded that various lineages of B6 iPSC-derived cells are not recognized by the immune system when transplanted under the kidney capsule of B6 mice. Why the contradiction?
Yang Xu and his colleagues at the University of California, San Diego have attempted to resolve this controversy by utilizing a mouse model system. Xu and his colleagues used the same B6 transplantation model and transplanted a variety of different cells derived from iPSCs that were made from cells that came from the same laboratory mice.
Xu and others showed that iPSC-derived and embryonic stem cell (ESC)-derived cells are either tolerated or rejected, depending upon WHERE they are transplanted. You see the immune system depends upon a network of cells called “dendritic cells” to sample the fluids that circulate throughout the body and identify foreign substances. Some locations in our bodies are chock-full of dendritic cells, while other locations have a paucity of dendritic cells. When iPSC or ESC-derived cells are transplanted under the kidney capsule, they survive and thrive. The kidney capsule has a distinct lack of dendritic cells. However, if these same cells, which were so nicely tolerated under the kidney capsule, are transplanted under the skin or injected into muscles, they were rejected by the immune system. Why? These two sites are loaded with dendritic cells.
Therefore, the rejection of iPSC-derived cells by the patient’s body is more of a function of where the cells are transplanted than the cells themselves. Mind you, poor quality iPSCs can produce derivatives that are rejected by the immune system, but high-quality iPSCs can differentiate into cells that are accepted by the immune system, but it is wholly dependent on where they are transplanted.
Perhaps, transplanted IPSC derivatives will need the immune system suppressed for a short period of time and after they become integrated into the patient’s body, the immune suppression can be lifted. Alternatively it might be possible to induce tolerance to the transplanted cells with immunological tricks. Either way, understanding why iPSCs-derived cells are rejected or accepted by the patient’s immune system is the next step to using these amazing cells for regenerative medicine.
Xu’s paper appeared in the journal Stem Cells – DOI: 10.1002/stem.2227.
Japanese and Australian researchers have used induced pluripotent stem cell (iPSC) technology to reprogram human skin cells to make the most mature human kidneys yet to be grown in a culture. These mini kidneys have hundreds of filtering units (nephrons) and blood vessels and appear to be developing just as kidneys would in an embryo.
“The short-term goal is to actually use this method to make little replicas of the developing kidney and use that to test whether drugs are toxic to the kidney,” said lead researcher Professor Melissa Little, of the Murdoch Children’s Research Institute. “Ultimately we hope we might be able to scale this up so we can … maybe bioengineer an entire organ.”
In other previous research, Professor Little and her co-workers generated cells that self-organized into the nephrons and collecting ducts needed for the kidney to filter blood and produce urine. They used a precise combination of called growth factors to direct embryonic stem cells to develop into the different cell types.
In the journal Nature, Professor Little and her collaborators report they have made a developing kidney from a type of skin cell called a fibroblast. Little and her team reprogrammed adult fibroblasts to become “induced pluripotent stem cells,” which act like embryonic stem cells, and can become any cell in the body. By adopting their growth factor recipe, Little and others were able to grow these cells into larger and more complex, three-dimensional kidneys than previously made.
“These kidneys have something like 10 or 12 different cell types in them … all from the one starting stem cell,” said Professor Little. “What we had previously were little flat structures over the surface of a dish … Now we have an organoid that is about 5-6 millimetres across, has about 100 filtering units in it, and is starting to form blood vessels. It’s starting to mature and the cell types are starting to do more of the functions of the final kidney.”
Scientists in Little’s laboratory demonstrated that the genes expressed in the mini kidneys as they formed faithfully recapitulated the expression of those same genes in a developing kidney in a first trimester embryo.
“It is actually mirroring what is happening in human development,” said Professor Little.
Little and her group also found that the laboratory-grown kidney was damaged when it was treated with known renal toxins. Little suggested that the iPSCs cells they had created were functioning as a kidney, but further tests would be required to demonstrate that.
It might be possible to use these bioengineered kidneys to test the renal toxicity of drugs. Likewise, the production of mini kidneys using cells from kidney patients might provide a way to study inherited forms of kidney disease.
“You can take a fibroblast [from someone with inherited kidney disease], make a stem cell out of it, generate a little kidney and use that as our model for their disease,” said Professor Little.
Perhaps most exciting, laboratory-generated kidneys might one day provide rejection-free transplants for patients, and gene editing could be used to fix the genetic defect that caused an inherited kidney disease.
Professor Jamie Davies of the University of Edinburgh, who was not involved with this work, but commented on it for Nature, emphasized this was not a full-fledged, functional kidney. “The structure’s fine-scale tissue organization is realistic, but it does not adopt the macro-scale organization of a whole kidney. For example, it is not ‘plumbed’ into a waste drain, and it lacks large-scale features that are crucial for kidney function, such as a urine-concentrating medulla region. There is a long way to go until clinically useful transplantable kidneys can be engineered, but [this] protocol is a valuable step in the right direction.”
Davies also mentioned that these mini kidneys had the potential to replace “poorly predictive” animal drug safety tests, and called on researchers to team up with toxicologists to test the potential of their system.
Stroke treatments have seen some remarkable advances in the past few years. Stem cell treatments for stroke have even seen some successes in clinical trials, showing that stem cell transplantation aimed at neural repair after a stroke is a possible way to ameliorate the effects of stroke.
Now, collaboration between teams of American and Japanese researchers has shown that a newly-identified stem cell has the ability to successfully treat stroke in rats. When administered to rats who have suffered from an experimentally-induced stroke, MUSE or multilineage-differentiating stress-enduring cells induced the regeneration of neurons and resulted in “significant improvements in neurological and motor functions” compared to control groups that were not transplanted with MUSE cells. MUSE cells also do not cause tumors.
The study has increased the number of therapeutic arrows in the quiver of neurologists and neuroscientists and lengthens the list of cells that might one day be considered for human clinical trials if continued pre-clinical tests prove successful. Future clinical studies aimed at regenerating neurological and motor function in patients who have suffered ischemic stroke.
The paper describing this study appeared in a recent issue of Stem Cells (Sept. 2015).
“Muse cells are unique stem cells that are able to self-renew and display high-efficiency for differentiating into neuron-like cells,” explained lead author Dr. Cesar V Borlongan, Distinguished Professor and Vice-Chairman for Research at the University of South Florida (USF) College of Medicine Department of Neurosurgery and Brain Repair and Director of USF’s the Center of Excellence for Aging and Brain Repair. “Unlike mesenchymal stem cells (MSCs) that have previously been used in stem cell transplantation in stroke-related clinical trials, in the present study Muse cells were found to possess functional characteristics of neurons as they attain the attributes of the host microenvironment. When MUSEcells were transplanted into to the brains of rats modeled with stroke, they attained neuronal characteristics.”
MUSE cells are found in many different tissues, including bone marrow, skin and fat. Since these cells can be derived from dermal fibroblasts (a type of connective tissue cell that provides the structural framework for animal tissues and plays a critical role in wound healing), they can be accessed with relative ease, without the need for the painful, invasive procedures required for obtaining other kinds of stem cells. Furthermore, while some stem cells used in stem cell transplantation studies have been found to cause cancer, MUSE cells do not produce tumors and exhibit exceptional tissue repair potential when introduced into the blood stream.
Some researchers think that fetal stem cells might be better candidates for replacing lost neural circuitry. The main reason in favor of fetal stem cells is that they preferentially differentiate into neuronal cells. However, the accessibility to fetal stem cells is limited and, like embryonic stem cells, the immaturity of these cells may present safety issues, such as tumor development. Additionally, the use of fetal and embryonic stem cells has many ethical difficulties to say the least. Since MUSE cells can be derived from adult tissue rather than fetal or embryonic tissue, the ethical quandaries associated with using them is minimal.
Not only do MUSE cells also have the practical advantage of being non-tumorigenic, they are readily accessed commercially and can also be easily collected from patient skin biopsies. MUSE cells also do not have to be “induced,” or genetically manipulated in order to be used, since they already display inherent stem cell properties after isolation. MUSE cells also spontaneously home toward the stroke-damaged sites.
“Ours is the first study to show that human skin fibroblast-derived Muse cells can have neuron-like function, possess an inherent ability to assume ‘stemness’ properties, and to readily differentiate into neural-lineage cells after integration into the stroke brain,” said co-lead author Dr. Mari Dezawa, Department of Stem Cell Biology and Histology, Tohoku University Graduate School of Medicine in Sendai, Japan. “Our results show that Muse cells are a feasible and promising source for cell-based approaches to ischemic stroke therapy.”
Type 1 diabetes results from the inability of the endocrine portion of the pancreas to secrete sufficient quantities of the hormone insulin. The cells that make insulin, beta cells, have been destroyed. Consequently, type 1 diabetics must inject themselves with insulin routinely in order to stay alive. Is there a better way?
A new strategy suggests that maybe pancreatic cells can be “rebooted” to produce insulin and that sure reprogramming could potentially help people with type 1 diabetes manage their blood sugar levels without the need for daily injections. This therapeutic approach is simpler and potentially safer than giving people stem cells that have been differentiated into pancreatic beta cells.
Philippe Lysy at the Cliniques Universitaires Saint Luc, which is part of the Catholic University of Louvain in Belgium, and his colleagues have reprogrammed pancreatic duct cells extracted from dead donors who were not diabetic at the time of death. The duct cells do not produce insulin, but they have a natural tendency to grow and differentiate into specific types of cells.
Lysy and his team grew the cells in the laboratory and encouraged them to become insulin-producing cells by exposing them to fatty particles. These fatty particles are absorbed into the cells after which they induce the synthesis of the MAFA transcription factor. MAFA acts as a genetic “switch” that binds to DNA and activates insulin production.
Implantation of these altered cells into diabetic mice showed that the cells were able to secrete insulin in a way that controls blood sugar levels. “The results are encouraging,” says Lysy.
Lysy’s colleague, Elisa Corritore, reported these results at this week’s annual meeting of the European Society for Pediatric Endocrinology in Barcelona, Spain. Lysy and others are preparing to submit their results for publication.
This work, if it continues to pan out, might lead to the harvesting of pancreatic ducts from deceased donors and converted in bulk into insulin-making cells. Such “off-the-shelf” cells could then be transplanted into people with type 1 diabetes to compensate for their inability to make their own insulin.
“We would hope to put the cells in a device under the skin that isolates them from the body’s immune system, so they’re not rejected as foreign,” says Lysy. He says devices like this are already being tested for their ability to house insulin-producing cells derived from stem cells.
Previous attempts to get round this problem have included embedding insulin-producing cells in a seaweed derivative prior to transplantation in order to keep them from being destroyed by the recipient’s immune system.
Lysy thinks that since insulin-producing cells originate from pancreatic tissue, they have an inherently lower risk of becoming cancerous after the transplant. This has always been a worry associated with tissues produced from embryonic stem cells, since these have the capability to form tumors if any are left in their original state in the transplanted tissue.
The basic premise of the work looks solid, says Juan Dominguez-Bendala, director of stem cell development for Translational Research at the University of Miami Miller School of Medicine’s Diabetes Research Institute in Florida. “However, until a peer-reviewed manuscript is published and all the details of the work become available to the scientific community, it is difficult to judge if this advance represents a meaningful leap in the state of the art.”
Lysy expects it will take between three and five years before the technique is ready to be tested in human clinical trials.
Masayo Takahashi, an ophthalmologist at the RIKEN Center for Developmental Biology (CDB) in Kobe, Japan, has pioneered the use of induced pluripotent stem cells (iPSCs) to treat patients with degenerative retinal diseases.
Takahashi isolated skin cells from her patients, and then had them reprogrammed into iPSCs in the laboratory through a combination of genetic engineering and cell culture techniques. These iPSCs have many similarities with embryonic stem cells, including pluripotency, which is the potential to differentiate into any adult cell type.
Once induced pluripotent stem cell lines were established from her patient’s skin cells, they had their genomes sequenced for safety purposes, and then differentiated into retinal pigmented epithelial (RPE) cells. RPE cells lie beneath the neural retina and support the photoreceptors that respond to light. When the RPE cells die off, the photoreceptors also begin to die.
Takahashi watched the transplantation of the RPE cells that she had grown in the laboratory into the back of a woman’s damaged retina. This transplant would constitute the first test of the therapeutic potential of iPSCs in people. Takahashi described the transplant as “like a sacred hour.”
Takahashi has collaborated with Shinya Yamanaka, the discoverer of iPSC technology. She devised ways to convert the iPS cells into sheets of RPE cells. She then tested the resulting cells in mice and monkeys, jumped the various regulatory loops, recruited patients for her clinical trial, and practiced growing cells from those patients. Finally, she was ready to try the transplants in people with a common condition called age-related macular degeneration, in which wayward blood vessels destroy photoreceptors and vision. The transplants are meant to cover the retina, patch up the epithelial layer and support the remaining photoreceptors. Watching the procedure, “I could feel the tension of the surgeon,” Takahashi said.
This transplant surgery occurred approximately a year ago. Some new data on this patient is available.
As of 6 months after the transplant, the procedure appears to be safe. The one-year safety report should appear soon. Prior to the transplant, the patient was a series of 18 anti-vascular endothelial growth factor (anti-VEGF) ocular injections for both eyes to cope with the constant recurrence of the disease. However, data presented by Dr. Takahashi showed that the patient had subretinal fibrotic tissue removed during the transplant surgery in order to make room for the RPE cells. Once the RPE cells were implanted, the patient experienced no recurrence of neovascularization at the 6-month point. This is significant because she has not had any other anti-VEGF injections since the transplant. Her visual acuity was stabilized and there have been no safety related concerns to date.
I must grant that this is only one patient, but so far, these results look, at least hopeful. Hopefully other patients will be treated in this trial, and hopefully, they will experience the same success that the first patient is enjoying. We also hope and pray that the first patient will continue to experience relief from her retinal degeneration.
As to the treatment of the second patient of this trial, Takahashi has hit a snag. Some mutations were detected in the iPS cell-derived RPE cells prepared for the second patient. No one knows if these mutations make these cells dangerous to implant. Regulatory guidelines, at this point, are also no help. Apparently, the cells have three single-nucleotide change and three copy-number changes that are present in the RPE cells that were not detectable in the patient’s original skin fibroblasts. The copy-number changes were, in all cases, single-gene deletions. One of the single-nucleotide changes is listed in a database of cancer somatic mutations, but only linked to a single cancer. Further evaluation of these mutations shows that they were not in “driver genes for tumor formation,” according to Dr. Takahashi.
Tumorigenicity tests in laboratory animals has established that the RPE cells are safe. Remember that the presence of a mutation does not necessarily mean that these RPE cells can be tumorigenic.
However, Takahashi has still decided to not transplant these cells into the second patients. Part of the reason is caution, but the other reason is compliance with new Japanese law on Regenerative Medicine, which became effective after iPS trial was begun. This law, however, does not specify how safe a cell line has to be before it can be transplanted into a patient.
RIKEN’s decision to halt the trial is probably a good idea. After all, this is the first trial with iPSCs and it is important to get it right. Even though the RPE cells were widely thought to be safe to use, Takahashi decided not to implant another patient with RPEs derived from their own cells. Instead, they decided to use RPEs made from donated iPSC lines. Therefore, Takahashi is in discussions government officials to determine how this change of focus for the trial affects their compliance with Japanese law.
Frankly, this might be a very savvy move on Takahashi’s part. As Peter Karagiannis, a spokesperson for the Center for iPS Cell Research and Application, noted: “As of now, autologous would not be a feasible way of providing wide-level clinical therapy. At the experimental level it’s fine, but if it’s going to be mass-produced or industrialized, it has to be allogeneic.”
Therefore, the RIKEN institute is moving forward with allogeneic iPSC-derived RPEs. RIKEN will work in collaboration with the Center for iPS Cell Research and Application (CiRA) in Kyoto, Japan, which has several well characterized, partially-matched lines whose safety profiles have been established by strict, rigorous safety testing methods. However, immunological rejection remains a concern, even if these cells are transplanted into an isolated tissue like the eye where to immune system typically is not allowed. The simple fact is that no one knows if the cells will be rejected until they are used in the trial.
An additional concern is that CiRA has not typed its cells for minor histocompatibility antigens, which can cause T cell–mediated transplant rejection.
Nevertheless, Takahashi and her team deserve a good deal of credit for their work and vigilance.
Stem cell transplantation is a promising potential treatment for retinal degenerative diseases. Because retinal degeneration often leads to blindness, stem cells might be one of the up-and-coming tools in the battle against blindness.
The laboratory of Shaomei Wang (Cedars-Sinai Medical Center, Los Angeles) have assessed the effectiveness of stem cell-based therapeutic strategies using the Royal College of Surgeons (RCS) rat model, which mimics the disease progression of age-related macular degeneration (AMD). In RCS mice, the retinal pigment epithelium or RPE degenerates and is disrupted, which leads to the death of photoreceptors (Mullen RJ and LaVail MM Inherited retinal dystrophy: primary defect in pigment epithelium determined with experimental rat chimeras. Science 1976;192:799-801). The work by Wang and his colleagues has shown that human cortical-derived neural progenitor cells (hNPCctx) could dramatically rescue vision in the RCS rat (see Wang S, and others, Investigative ophthalmology & visual science 2008;49:3201-3206; Gamm DM, and others, Wang S, Lu B, et al. PLoS One 2007;2:e338). Unfortunately, the fetal origin of these cells presents an obstacle, because such cells are not readily available and come from aborted fetuses.
To overcome such obstacles, Wang and his colleagues assessed the ability of a stable neural progenitor cell line (iNPCs) derived from induced pluripotent stem cells (iPSCs) to preserve vision after sub-retinal injection into RCS rats (Sareen D, and others, J Comp Neurol 2014;522:2707-2728). A report in the journal Stem Cells by Wang and others establishes that iNPC injection leads to the reversal of AMD-related symptoms, the preservation of visual function, and may represent a patient-specific therapeutic option (Tsai Y, and others, Stem Cells 2015;33:2537-2549).
Wang and his others showed that an iNSC-treated eye scored higher in all functional tests used (optokinetic response (OKR), electroretinography (ERG), and luminance threshold responses (LTR)), compared to an untreated eye, in RCS mice at 150 days post-transplant. This improvement nicely correlates with the improved protection of photoreceptors in iNPC-treated eyes, which presented with normal cone morphology and the reversal of disease-associated changes throughout the retina.
So how do iNPCs help preserve the photoreceptors and visual function? Wang and his team found that iNPCs survived up to 130 days in RCS retinas, which when normalized to lifespan, represents around 16 years in humans. Additionally, they discovered that iNPCs were able to migrate to an area between the retinal pigment epithelial and photoreceptor layers. This allows the injection of cells into non-affected neighboring regions of the retina, which will not to worsen any compromised retinal components. iNPCs did, however, continue to express NSC/NPC markers and did not mature neural/retinal markers, suggesting that grafted-iNPCs remained phenotypically uncommitted progenitor cells and did not differentiate towards a retinal phenotype.
Further investigations found that iNPC-treatment reduced levels of toxic undigested bits of the photoreceptor cell membranes. Accumulation of these photoreceptor outer segments (POS) cause the photoreceptors to die off. Typically, the RPE cells goggle up these toxic membrane bits, degrade them, and recycle their components for the photoreceptors. The fact that these POS bits were not accumulating in the retinas of RCS mice suggested to Wang and his colleagues that the grafted-iNPCs restored POS degradation in RCS rats. They subsequently found that iNPCs expressed phagocytosis-related genes and could gobble up and degrade POS in culture. They extended these findings in living creatures by identifying the different stages of POS digestion and even viewed engulfed membranous discs inside the cytoplasm of iNPCs.
Overall, iNPC injection appears to be a safe and effective long-term treatment for Acute Macular Degeneration in the RCS rat preclinical model, and holds great promise for the translation into a patient-specific treatment for the preservation of existing retinal structure and vision during the early stages of AMD in humans. Wang noted that iNPC treatment in this model occurred at later stages of degeneration, which represents a more clinical relevant stage. However, an unstudied possibility is restoring phagocytosis by iNPCs to treat loss of visual acuity early on in the course of the disease.