First Stem Cell Trial for Alzheimer’s Disease Will Enroll Patients Next Year


A research group from the University of Miami Miller School of Medicine will be conducting the first clinical trial that will test the ability of stem cells to treat Alzheimer’s disease.

According the Bernard Baumel, assistant professor of neurology at the Miller School of Medicine and the principal investigator for this phase I clinical trial, said “We believe infusions of these types of stem cells have the potential to be beneficial to individuals with Alzheimer’s disease.” Because this trial is a phase 1 clinical trial, it will test the safety of this treatment strategy.

Baumel and his colleagues plan to test the safety of mesenchymal stem cells (MSCs) as a treatment for Alzheimer’s disease.  In order to acquire high-quality MSCs for this clinical trials, Dr. Baumel is collaborating with his colleague Joshua Hare, Louis Lemberg Professor of Medicine and director of the Miller School’s Interdisciplinary Stem Cell Institute (ISCI).  Dr. Hare is an expert in the use and manipulation of MSCs who has developed a life sciences company called Longeveron that isolates, characterized and stores MSCs for clinical applications.

“Stem cells are very potent anti-inflammatories,” Dr. Baumel said. “Because the amyloid plaques found in the brains of Alzheimer’s disease patients are associated with inflammation, infusions of stem cells may help to improve or stabilize that condition. Those new brain cells may then be able to replace damaged cells in Alzheimer’s patients.”

Previous work in several different laboratories has demonstrated the anti-inflammatory capacities of MSCs (Chen PM, et al J Biomed Sci. 2011; 18:49), but other laboratories have even observed that, under certain conditions, MSCs can differentiate into brain cells (Tsz Kin Ng, et al World J Stem Cells. 2014 Apr 26; 6(2): 111–119). Therefore, MSCs potentially provide a powerful one-two punch for treating Alzheimer’s disease patients.

This clinical trial is called “Allogeneic Human Mesenchymal Stem Cell Infusion Versus Placebo in Patients with Alzheimer’s Disease,” and enrollment for this trial will begin in early 2016 and continue through to 2018. Patients enrolled in the study will have their undergo cognitive function tests before and after the treatment, quality of life assessments and brain volume measurements in order to acquire some knowledge of the potential effectiveness of this cell-based treatment strategy.

Patients with mild Alzheimer’s disease but who are otherwise healthy will be encouraged to enroll in this study.

Combination of Mesenchymal Stem Cells and Schwann Cells Used to Treat Spinal Cord Injury


Spinal cord injuries represent an immensely difficult problem for regenerative medicine. The extensive nature of the damage to the spinal cord is difficult to repair, and the transformation that the injury wrecks in the spinal cord makes the spinal cord inhospitable to cellular repair.

Fortunately some headway is being made, and several clinical trials have shown some success with particular stem cells. Neural stem cells can differentiate into new neurons and glial cells and replace dead or damaged cells (see Tsukamoto A., et Al., Stem Cell Res Ther 4,102, 2013 ). Oligodendrocyte progenitor cells (OPCs) derived from embryonic stem cells or other sources can replace the myelin sheath that died off as a result of the injury (Alsanie WF, Niclis JC, Petratos S. Stem Cells Dev. 2013 Sep 15;22(18):2459-76).  Olfactory ensheathing cells can move across the glial scar and facilitate the regrowth of severed axons across the scar (Tabakow P, et al., Cell Transplant. 2014;23(12):1631-55). Mesenchymal stem cells can mitigate the inflammation in the damaged spinal cord, and, maybe, stimulate endogenous stem cell populations to repair the spinal cord (Geffner L.F., et al., Cell Transplant 17,1277, 2008). Therefore, several cell types seem to have some ability to heal the damaged spinal cord.

A new clinical trial from the Zali laboratory at Shahid Beheshti University of Medical Sciences, in Tehran, Iran, has examined the used of two different stem cells to treat spinal cord injury patients. This trial was a small, Phase I trial that only tested the safety of these treatments.

Zali and his colleagues assessed the safety and feasibility of transplanting a combination of bone marrow mesenchymal stem cells (MSCs) and Schwann cells (SCs) into the cerebral spinal fluid (CSF) of patients with chronic spinal cord injury. SCs are cells that insulate peripheral nerves with a myelin sheath. Even though SCs are not found in the central nervous system, they do the same job as oligodendrocytes, and several experiments have shown that when transplanted into the central nervous system, SCs can do the job of oligodendrocytes in the central nervous system.

In this trial, six subjects with complete spinal cord injury according to International Standard of Neurological Classification for Spinal Cord Injury (ISNCSCI) developed by the American Spinal Injury Association were treated with co-transplantation of their own MSCs and SCs by means of a lumbar puncture. The neurological status of these patients was ascertained by the ISNCSCI and by assessment of each patient’s functional status according to the Spinal Cord Independent Measure. Before and after cell transplantation, the spinal cord of each patient was imaged by means of magnetic resonance imaging (MRI). All patients also underwent electromyography, urodynamic study (UDS) and MRI tractograghy before the procedure and after the procedure if patients reported any changes in motor function or any changes in urinary sensation.

In a span of 30 months following the procedure, radiological findings were unchanged for each patients. There were no signs or indications of neoplastic tissue overgrowth in any patient. In one patients, their American Spinal Injury Association class was downgraded from A to B. This same patients had increased bladder compliance, which correlated quite well with the axonal regeneration detected in MRI tractography. None of these patients showed any improvement in motor function.

To summarize, there were no adverse effects detected around 30 months after the transplantations. These results suggest that this stem cell combination is safe as a treatment for spinal cord injury. While improvement of observed in one patients, because the trial was not designed to investigate the efficacy of the treatment, it is difficult to make any hard-and-fast conclusions about the efficacy of this treatment at this time. However, the fact that one patient did improve is at least encouraging.

These data were reported in the journal Spinal Cord (Spinal Cord. 2015 Nov 3. doi: 10.1038/sc.2015.142).

Gene Therapy Sprouts New Neurons in Alzheimer’s Patients’ Brains


The journal JAMA Neurology has published a new study that describes an experimental gene therapy that reduces the rate at which nerve cells in the brains of Alzheimer’s patients degenerate and die. See Tuszynski, M. H., et al. (2015). Nerve Growth Factor Gene Therapy: Activation of Neuronal Responses in Alzheimer Disease. JAMA Neurology, published online August 24, 2015. DOI: 10.1001/jamaneurol.2015.1807.

In this study, targeted injections of a growth factor called “nerve growth factor” or NGF into the brain of patients rescued dying cells around the injection site, enhanced the growth of these cells and induced them to sprout new nerve fibers. Surprisingly, in some cases, these beneficial effects persisted for 10 years after the therapy was first delivered.

Alzheimer’s disease (AD) is the world’s leading form of dementia. It affects approximately 47 million people worldwide, and this number is expected to almost double every 20 years. Despite the huge amounts of time, effort, and money devoted to developing an effective cure, the vast majority of new drugs for AD have failed in clinical trials.

While these new results are preliminary findings, they come from the first human trials designed to test the potential benefits of NGF gene therapy for AD patients.

NGF was discovered in the 1940s by Rita Levi-Montalcini, who demonstrated, quite convincingly, that a small protein that she had isolated and purified promoted the survival of certain sub-types of sensory neurons during development of the nervous system. Since that time, others have shown that it also promotes the survival of neurons that produce acetylcholine in the basal forebrain; these cells die off at an alarming rate in AD patients.

In 2001, Mark Tuszynski and his coworkers at the University of California, San Diego School of Medicine initiated a clinical trial based on these laboratory findings. This trial was the first of its kind, and it was designed to investigate the ability of NGF gene therapy to slow or prevent the neuronal degeneration and cell death characteristic of AD.

In phase I of this trial, eight patients with mild AD received so-called “ex vivo” therapy to deliver the NGF gene directly into the brain. This trial extracted skin fibroblasts from the skin on the patient’s backs, and then genetically engineered those cells to express the NGF genes. These NGF-expressing cells were then implanted into the patients’ basal forebrain. Since NGF is too large to cross the blood-brain barrier, it had to be administered directly into the brain. Also, outside the brain, exogenous NGF can stimulate other nerve cells can cause unwanted side-effects such as pain and weight loss.

One of these patients died just 5 weeks after receiving the therapy. Tuszynski’s team secured permission to perform an autopsy of this patient, and in 2005 they reported that the treatment led to robust growth responses, and did not cause any adverse effects (Tuszynski, M. H., et al. (2005). A phase 1 clinical trial of nerve growth factor gene therapy for Alzheimer disease. Nature Medicine, 11: 551 – 555).

The latest results come from postmortem examination of these patients’ brains, all of whom had also been recruited in a safety trial between March 2001 and October 2012. Additionally, two other were included who had received in vivo therapy that included injecting a modified virus that carried the NGF gene into the basal forebrain.

Some of the participants died about one year after undergoing therapy, and others survived for 10 years after the treatment. These autopsies showed that all of them had responded to the treatment.

Essentially, all the brain tissue samples taken from around the implantation sites contained diseased neurons, as expected, but the cells were overgrown, and had sprouted axonal fibers that had grown towards the region into which NGF had been delivered. In contrast, samples taken from the untreated side of the brain exhibited no such response.

This trial was conducted to test the safety of the treatment and it did confirm that none of the patients experienced long-term adverse effects from the treatment, even after long periods of time. These results also suggest that NGF is successfully taken up by nerve cells following targeted delivery. Also the cells synthesize NGF protein so that its concentration dramatically increases in and around the delivery site. Probably the most exciting part of these findings is that the responses to NGF can persist for many years after the gene has been delivered into the brain.

Cholinergic Neuronal Hypertrophy and Sprouting Shown is labeling for p75, a neurotrophin receptor expressed on cholinergic neurons of the nucleus basalis of Meynert. Images were obtained 3 years after adeno-associated viral vectors (serotype 2)–nerve growth factor (AAV2-NGF) delivery (A-C) and 7 years after ex vivo gene transfer (D-F). A-C, Cholinergic neurons are labeled for p75 within the zone of transduction (A), 3 mm from the zone of transduction (B), and in a control Alzheimer disease (AD) brain of the same Braak stage (C). Cells near the NGF transduction region appear larger. The inset shows higher-magnification views of a typical neuron from each region. D, Shown is a graft of fibroblasts transduced to secrete NGF (yellow arrowhead) adjacent to the nucleus basalis of Meynert (red arrowheads). E, The graft (G) at higher magnification is densely penetrated by p75-labeled axons arising from the nucleus basalis of Meynert. These axons are sprouting toward the graft, a classic trophic response. F, Shown are p75-labeled axons from the nucleus basalis of Meynert sprouting toward the graft. Individual axons coursing toward the graft are evident (arrowheads). The bar represents 125 µm in A through C, 500 µm in D, and 100 µm in E and F.
Cholinergic Neuronal Hypertrophy and Sprouting
Shown is labeling for p75, a neurotrophin receptor expressed on cholinergic neurons of the nucleus basalis of Meynert. Images were obtained 3 years after adeno-associated viral vectors (serotype 2)–nerve growth factor (AAV2-NGF) delivery (A-C) and 7 years after ex vivo gene transfer (D-F). A-C, Cholinergic neurons are labeled for p75 within the zone of transduction (A), 3 mm from the zone of transduction (B), and in a control Alzheimer disease (AD) brain of the same Braak stage (C). Cells near the NGF transduction region appear larger. The inset shows higher-magnification views of a typical neuron from each region. D, Shown is a graft of fibroblasts transduced to secrete NGF (yellow arrowhead) adjacent to the nucleus basalis of Meynert (red arrowheads). E, The graft (G) at higher magnification is densely penetrated by p75-labeled axons arising from the nucleus basalis of Meynert. These axons are sprouting toward the graft, a classic trophic response. F, Shown are p75-labeled axons from the nucleus basalis of Meynert sprouting toward the graft. Individual axons coursing toward the graft are evident (arrowheads). The bar represents 125 µm in A through C, 500 µm in D, and 100 µm in E and F.

Now, does the observed cellular response to NGF alleviate disease symptoms? Although phase II trials testing the efficacy of the treatment are ongoing, preliminary findings from the initial study suggest that the therapy did indeed slow the rate at which mental function declined in one of the patients involved. These new results indicate that gene therapy is a viable strategy for treating Alzheimer’s and other neurodegenerative diseases, and warrants further research and development.

Cells from placentas safe for patients with multiple sclerosis


A new Phase I clinical trial has demonstrated that Multiple Sclerosis (MS) patients were able to safely tolerate treatment with cells cultured from human placental tissue.  The results of this study were recently published in the journal Multiple Sclerosis and Related Disorders.  This pioneering study was conducted by researchers at Mount Sinai, Celgene Cellular Therapeutics, which is a subsidiary of Celgene Corporation, and collaborators at several other institutions, including the Swedish Neuroscience Institute in Seattle, WA, MultiCare Health System-Neuroscience Center of Washington, London Health Sciences Centre at University Hospital in London, the Clinical Neuroscience Research Unit at the University of Minnesota, the University of Colorado Denver, The Ottawa Hospital Multiple Sclerosis Clinic, and the MS Comprehensive Care Center at SUNY.

Even though this clinical trial was designed solely to determine the safety of this treatment, the data collected from the participating patients suggested that a preparation of cultured cells called PDA-001 may repair damaged nerve tissues in patients with MS.  PDA-001 cells resemble “mesenchymal,” stromal stem cells, which are found in many tissues of the body.  However, in this study, the cells were grown in cell culture systems, which means that one donor was able to supply enough cells for several patients.

“This is the first time placenta-derived cells have been tested as a possible therapy for multiple sclerosis,” said Fred Lublin, MD, Director of the Corinne Goldsmith Dickinson Center for Multiple Sclerosis, Professor of Neurology at Icahn School of Medicine at Mount Sinai and the lead investigator of the study. “The next step will be to study larger numbers of MS patients to assess efficacy of the cells, but we could be looking at a new frontier in treatment for the disease.”

MS is a chronic autoimmune disease.  The body’s immune system attacks the insulating myelin sheath that surrounds and protectively coats the nerve fibers in the central nervous system.  The myelin sheath greatly improves the speed at which nerve impulses pass through these nerves and without the myelin sheath, nerve impulse conduction becomes sluggish, and the nerves also eventually die off.  Long-term, MS causes extensive nerve malfunction and can lead to paralysis and blindness.  MS usually begins as an episodic condition called “relapsing-remitting MS” or RRMS.  Patients will have occasional outbreaks of nerve malfunction, pain, or numbness.  However, many MS patients will see their condition evolves into a chronic condition with worsening disability called “secondary progressive MS” or SPMS.

This Phase I trial examined 16 MS patients, 10 of whom had  RRMS and six of whom were diagnosed with SPMS and were between the ages of 18 and 65.  Six patients were given a high dose of the placental-based cell line PDA-001, and another six were given a lower dose.  The remaining four patients were given placebos.  Dr. Lubin noted that alteration of the immune system by any means can cause MS to worsen in some patients.  Therefore, all participating subjects were given monthly brain scans over a six-month period to ensure they did not acquire any new or enlarging brain lesions, which are indicative of worsening MS activity.  However, none of the subjects in this study showed any paradoxical worsening on MRI and after one year.  The majority had stable or improved levels of disability.

“We’re hoping to learn more about how placental stromal cells contribute to myelin repair,” said Dr. Lublin. “We suspect they either convert to a myelin making cell, or they enhance the environment of the area where the damage is to allow for natural repair. Our long-term goal is to develop strategies to facilitate repair of the damaged nervous system.”

Stroke Patients Improve After Stem Cell Treatments


Neurologists at Imperial College, London have conducted a small pilot study in stroke patients who received stem cell treatments after their strokes. To date, their patients have shown tentative signs of neurological recovery six months after receiving the stem cell treatment.

According to the physicians attending these patients, all five patients who participated in the study have improved after the therapy. Even though these results are hopeful, larger and better controlled trials are required to confirm if the implanted stem cells are responsible for the improvements in these patients. Brain scans of the patients showed that damage caused by the stroke had reduced over time. However, similar improvements are seen in stroke patients as part of the normal recovery process.

When assessed after their six-month check ups, all of the participating patients fared better on standard measures of disability and impairment that are normally caused by stroke. Once again, it is difficult to determine if these improvements result from the stem cell treatments or from standard hospital care.

This pilot study was designed to assess only the safety of the experimental therapy (phase I clinical trial) and with so few patients and no control group to compare them with, it is impossible to draw conclusions about the effectiveness of the treatment at this time.

Paul Bentley is a consultant neurologist at Imperial College London, and his group is presently applying for funding to run a more powerful randomized, controlled trial on this stem cell therapy, which, Bentley hopes, could include at least 50 patients by next year.

“The improvements we saw in these patients are very encouraging, but it’s too early to draw definitive conclusions about the effectiveness of the therapy,” said Soma Banerjee, a lead author and consultant in stroke medicine at Imperial College Healthcare National Health System (NHS) Trust. “We need to do more tests to work out the best dose and timescale for treatment before starting larger trials.”

All five patients who participated in this study were treated within seven days of suffering a severe stroke. Each patient had a bone marrow sample extracted from their hip bones, and these bone marrow cells were processed in the laboratory to isolated the stem cells that give rise to blood cells and blood vessel lining cells (so-called CD34+ cells). These stem cells were infused into one of the main arteries that supplies blood to the brain.

CD34+ cells do not grow into fresh brain tissue, but they might release pro-healing chemicals that suppress inflammation and recruit and stimulate other cells to grow within the damaged brain tissue. Some of the implanted CD34+ cells might also form new blood vessels, said Bentley.

Four out of five of the patients had the most serious type of stroke, and typically, only 4% of these patients survive and are able to live independently after six months. In the pilot study, published in Stem Cells Translational Medicine, all four were alive and three were independent six months later.

“Although they mention some improvement of some of the patients, this could be just chance, or wishful thinking, or due to the special care these patients may have received simply because they were in a trial,” said Robin Lovell-Badge, head of developmental genetics at the MRC’s National Institute for Medical Research in London.

Caution is certainly required in the interpretation of this pilot study, but I think that these results definitely merit a Phase II trial to determine if the improvements are stem cell-independent or stem cell-dependent.

Cord Blood Stem Cells to Treat Acquired Hearing Loss


The Cord Blood Registry has announced the beginning of an FDA-regulated study at the Florida Hospital for Children in Orlando to investigate the potential of a child’s umbilical cord stem cells to treat acquired sensorineural hearing loss.

In the United States, about 15% of children suffer from low or high frequency hearing loss. Sensorineural hearing loss is the most common type of hearing loss, especially at high frequencies. Acquired sensorineural hearing loss results from damage to hair cells in the inner ear (cochlea) and can be caused by illness, medication, noise exposure, birth injury or head trauma. Because the ability to hear affects language development, hearing impairments can lead to poor academic and social development.

This particular study is a Phase I clinical trial, which will determine the safety and efficacy of using cord blood stem cells in children to improve inner ear function, and speech and language development.

In this study, the research group will follow 10 children who range in age from 6 weeks to 6 years, who have been diagnosed with acquired hearing loss for less than 18 months and who have had their own umbilical cord blood processed and stored.

Unfortunately, children who have a known genetic cause of deafness are ineligible for study participation. Patients will receive one intravenous infusion of their own umbilical cord blood stem cells. All patients will be tested at 1 month after the infusion, 6 months, and 1 year post-treatment.

As usual, this clinical trial is inspired by positive results in preclinical tests in laboratory animals.

Phase 2 Clinical Trial that Tests Stem Cell Treatment for Heart Attack Patients to be Funded by California Institute for Regenerative Medicine


A new stem cell therapy that treats heart attack patients with cells from a donor has been approved to begin a Phase 2 clinical trial.

Capricor Therapeutics Inc. a regenerative medicine company, has developed this treatment, which extracts donor stem cells from the heart called “cardiosphere-derived cells,” and then infuses them into the heart of the heart attack patient by means of a heart catheter procedure, which is quite safe. These stem cells are introduced into the heart to reduce scarring in the heart and potentially replace dead heart muscle cells. One clinical trial called the CADUCEUS trial has already shown that cardiosphere-derived cells can reduce the size of the heart scar.

In a previous phase I study (phase I studies typically only ascertain the safety of a treatment), cardiosphere-derived cells were infused into the hearts of 14 heart attack patients. No major safety issues were observed with these treatments, and therefore, phase 2 studies were warranted.

Alan Trounson, Ph.D., president of the California Institute for Regenerative Medicine (CIRM), which is funding the trial, said this about the phase 2 trial approval: “This is really encouraging news and marks a potential milestone for the use of stem cells to treat heart disease. Funding this type of work is precisely what our Disease Team Awards were designed to do, to give promising treatments up to $20 million dollars to develop new treatments for some of the deadliest diseases in America.”

Capricor was given approval by the National Heart Lung and Blood Institute (NHLBI) Gene and Cell Therapy (GST) to move into the next phase of clinical trials after these regulatory bodies had thoroughly reviewed the safety data from the phase 1 study. After NHLBI and GST determined that the phase 1 study met all the required goals, CIRM also independently reviewed the safety data from the Phase 1 and other aspects of the Phase 2 clinical trial design and operations. Upon successful completion of the independent review, Capricor was given approval to move forward into the CIRM-funded Phase 2 component of the study

Capricor CEO Linda Marbán, Ph.D., said, “Meeting the safety endpoints in the Phase 1 portion of the trial is a giant leap forward for the field and for Capricor Therapeutics. By moving into the Phase 2 portion of this trial, we can now attempt to replicate the results in a larger population.”

For the next phase, an estimated 300 patients who have had heart attacks will be evaluated in a double-blind, randomized, placebo-controlled trial. One group of heart-attack patients will include people 30 to 90 days following the heart attack, and a second group will follow patients 91 days to one year after the incident. Other patients will receive placebos and neither the patients nor the treating physicians know who will receive what.  This clinical trial should definitely determine if an “off-the-shelf” stem cell product can improve the function of a heart attack patient’s heart.

The California Institute for Regenerative Medicine (CIRM) is funding this clinical trial, and for this CIRM should be lauded.  However, when CIRM was brought into existence through the passage of proposition 71, it sold itself as a state-funded entity that would deliver embryonic stem cell-based cures.  Now I know that director Alan Trounson has denied that, but Wesley Smith at the National Review “Human Exceptionalism” blog and the LA times blogger Michael Hiltzik have both documented that Trounson and others said exactly that.  Isn’t ironic that one of the promises intimated by means of embryo-destroying research is now being fulfilled by means of non-embryo-destroying procedures?  If taxpayer money is going to fund research like this, then I’m all for it, but CIRM has to first clean up its administrative act before they deserve a another penny of taxpayer money.