Neurons Made from Induced Pluripotent Stem Cells Stably Integrate into the Brain


Jens Schwamborn and Kathrin Hemmer from the Luxembourg Centre for Systems Biomedicine (LCSB) of the University of Luxembourg have shown that implanted neurons made from induced pluripotent stem cells show long-term stability in the brain.

Induced pluripotent stem cells (iPSCs) are made from mature adult cells by means of genetic engineering and cell culture techniques. These cells have embryonic stem cell-like capacities and can, potentially differentiate into any adult cell type. Because neurons made from iPSCs have sometimes not shown instability, the ability of neurons derived from iPSCs to stably integrate into brain has been questioned.

Schwamborn and Hemmer showed that six months after implantation, their iPSCs-derived neurons had become fully functionally integrated into the brain. This successful integration of iPSC-derived neurons into lastingly stable implants raises hope for future therapies that will replace sick neurons with healthy ones in the brains of patients with Parkinson’s disease, Alzheimer‚Äôs disease and Huntington‚Äôs chorea, for example. This work was published in the current issue of Stem Cell Reports.

The LCSB research group hopes to bring cell replacement therapy to maturity as a treatment for neurodegenerative diseases. The replacement of sick and/or dead neurons in the brain could one day cure disorders such as Parkinson’s disease. However, devising a successful therapy in human is a long, arduous process, and for good reasons. “Successes in human therapy are still a long way off, but I am sure successful cell replacement therapies will exist in future. Our research results have taken us a step further in this direction,” declared Schwamborn.

In their latest tests, the LCSB research group, in collaboration with colleagues from the Max Planck Institute and the University Hospital M√ľnster and the University of Bielefeld, made stable neuronal implants in the brain from neurons that were derived from reprogrammed skin cells. They used a newer technique in which the neurons were produced from neural stem cells (NSCs). These NSCs or induced neural stem cells (iNSCs) had, in turn been made from iPSCs that were made from the host animal’s own skin cells, which considerably improves the compatibility of the implanted cells. Mice who received the neuronal implants showed no adverse side effects even six months after implantation. The new neurons were implanted into the hippocampus and cortex regions of the brain. Implanted neurons were fully integrated into the complex network of the brain and they exhibited normal activity and were connected to the original brain cells via newly formed connections known as synapses, which are the contact points between nerve cells.

These tests demonstrate that stem cells researchers are continuing to get a better handle on how to use cells derived from something other than human embryos in order to successfully replace damaged or dead tissue. “Building upon the current insights, we will now be looking specifically at the type of neurons that die off in the brain of Parkinson’s patients ‚Äď namely the dopamine-producing neurons,” Schwamborn reports.

In future experiments, implanted neurons could provide the neurotransmitter dopamine (which is lacking in patients with Parkinson‚Äôs disease) directly into the patient’s brain and transport it to the appropriate sites. Such a result would herald an actual cure for the disease rather than a short-term fix. The first trials in mice are in progress at the LCSB laboratories on the university campus Belval.

Personalized Stem Cells for Curing Parkinson’s Disease


Stem cell treatments for curing Parkinson’s disease have been one of the dreams of stem cell scientists ever since the first embryonic stem cells were derived from mouse embryos in 1981. Unfortunately, this proved to be one of the harder therapeutic nuts to crack. Several experiments have shown that while feasible, getting the recipe right has required a fair amount of tweaking.

brain-labels

Parkinson’s disease (PD) results from the progressive death of neurons in the midbrain that release a neurotransmitter called dopamine, To review briefly, the brain consists of the forebrain, midbrain and hindbrain. The forebrain consists of the two large cerebral hemispheres that occupy the vast majority of the space within your skull. In addition to the left and right cerebral hemispheres is the diencephalon that consists of the thalamus, subthalamus, hypothalamus, and epithalamus. The thalamus serves as a relay station for a whole variety of nerve fiber tracts, the hypothalamus regulates visceral activities by way of other brain regions and the autonomic nervous system. and the epithalamus connects the limbic system to the rest of the brain. The midbrain, which lies below the diencephalon, is part of the brain stem and dopamine produced in two regions of the midbrain, the substantia nigra and ventral tegmental area play roles in motivation and habituation, and refinement of the control of voluntary movement, The hindbrain consists of the metencephalon and the myelencephalon, both of which contain mutiple fiber tracts and nuclei for vital functions.

Midbrain 2

The death of dopamine-producing neurons in the pars compacta region of the substantia nigra region of the midbrain causes PD. The par compacta sends nerve fibers to the cerebral hemispheres, in particular to cluster of neurons called the basal ganglia. The basal ganglia do not initiate movement, but they refine movement and stabilize the limbs and other body parts while moving. Thus the basal ganglia normally exert a constant inhibitory influence on a wide range of movements. preventing movement at inappropriate times. When someone decides to move, this inhibition is reduced for the required motor system, thereby releasing it for activation. Dopamine releases this inhibition, and therefore high levels of dopamine tend to promote movement and low levels of dopamine demand greater exertion to generate any given movement. Thus the net effect of dopamine depletion is to produce hypokinesia, or less overall movement.

Basal ganglia

Now that we have some knowledge of PD and what causes it, we can examine how to cure it. Since the death of dopamine-secreting neurons causes PD, replacing death or moribund neurons should be possible. Several preclinical studies in laboratory animals and clinical studies with human patients has shown that this is possible.

Rodents can contract a synthetic form of PD if they are treated with a drug called 6-hydroxydopamine. This drug kills off their dopamine-secreting neurons and creates a PD-like disease. Embryonic stem cells can be differentiated in the laboratory into dopamine-secreting neurons, which can then be transplanted into the midbrain. In PD rats, this strategy has reversed the symptoms of PD, but tumor growth has been a nagging problem. The biggest problem is that isolating fully differentiated dopamine-secreting cells has proven difficult because of a lack of good, solid indicators that say to the scientists, “This one is a dopamine-secreting neuron and this one is not.” Thus, isolating nice, clean cultures of only dopamine-secreting cells has been kind of tough to do.

Fortunately, Doi and others in the Takahashi lab at the University of Kyoto showed that prolonged maturation culture system (42 days long) can eliminate most of the tumor-making cells. However, this culture system is laboriously long. Now, Takahashi and Doi and others have struck again in a paper published in Stem Cell Reports in which they used induced pluripotent stem cells to derive dopamine-secreting neurons to treat PD rats. ¬†Because induced pluripotent stem cells are made from a patient’s own adult cells and are converted into embryonic-like stem cells by means of a combination of genetic engineering and cell culture techniques, they are patient-specific and do not require the dismembering of human embryos.

The novelty of this paper is that Doi and others used a protein that acts as an earmark for dopamine-secreting midbrain neurons and this protein is called CORIN. CORIN is a protease, which simply means that it clips other proteins into small pieces. Nevertheless, by using the CORIN protein, Takahashi, Doi and others successfully and efficiently isolated dopamine-secreting midbrain neurons from other cells in their cultures.  Additionally, Doi and the gang were able to differentiate the induced pluripotent stem cells into dopamine-secreting progenitor cells.  This means that the cells were poised to differentiate into dopamine-secreting neurons, but were not quite there yet.  This way, the cells would grow in culture, but upon transplantation, they would differentiate into dopamine-secreting neurons rather than form tumors.  High numbers of cells are required for clinical purposes and this technique allows the for production of large number of cells.

The technique used in this paper also produced the cells under conditions that were safe, scalable and potentially usable for clinical use. These high-quality cells never produced any tumors and produced definitive behavioral improvements in the implanted laboratory animals. The problems that remain are one of scale. The grafts of dopamine-secreting cells that survived in the midbrains of these mice were relatively small (about 1 square millimeter in size or the thickness of a dime).  This is probably due to the fact that the cells differentiate when transplanted rather than growing.  Therefore, this technique will need to be adapted to somehow increase the size of the graphs of dopamine-secreting neurons.  In some PD patients such small graphs will probably work just fine, but in others, probably not.  The other issue is that these implanted cells might be subjected to the same bad intracerebral environment as the original cells and die off quickly, thus abrogating any positive clinical effect they might have.  This is another issue that will need to be examined.

The work goes on, without the need to destroy any embryos.

See Daisuke Doi at al., Isolation of Human Induced Pluripotent Stem Cell-Derived Dopaminergic Progenitors by Cell Sorting for Successful Transplantation. Stem Cell Reports 2014, 2: 337-350.

Neural Cells Made from Monkey Skin Cells Integrate into Monkey Brains and Form Neurons


Stem cell scientists from the University of Wisconsin at Madison have transplanted neural cells that were made from a monkey’s skin cells into the brain of that same monkey. The transplanted cells formed variety of new brain cells that were entirely normal after six months.

This experiment is a proof-of-principle investigation that shows that personalized medicine in which regenerative treatments are designed for specific individuals is possible. These neural cells were derived from the monkey’s skin cells and were, therefore, no foreign. Therefore, there is no risk of them being rejected by the host immune system.

Su-Chun Zhang, professor of neuroscience at the University of Wisconsin-Madison, said: “When you look at the brain, you cannot tell that it is a graft. Structurally the host brain looks like a normal brain; the graft can only be seen under the fluorescent microscope.”

Marina Emborg, associate professor of medical physics at UW-Madison and one of the lead co-authors of the study, said: “This is the first time I saw, in a nonhuman primate, that the transplanted cells were so well-integrated, with such a minimal reaction. And after six months, to see no scar, that was the best part.”

The skin-derived neural cells were implanted into the monkey brain by means of a state-of-the-art surgical procedure whereby the surgeon was guided by a live MRI. The three rhesus monkeys used in the study at the Wisconsin National Primate Research Center had brain lesions that caused Parkinson’s disease. Up to one million Americans suffer from Parkinson’s disease, and some 60,000 new patients are diagnosed with it each year. Parkinson’s disease results from the death of midbrain neurons that manufacture the neurotransmitter dopamine.

The cells that were transplanted into the brain were derived from induced pluripotent stem cells (iPSCs), which, like embryonic stem cells, can develop into virtually any cell in the adult human body.

Once the iPSC lines were established, Zhang and his colleagues differentiated them into neural progenitor cells (NPCs), which have the ability to form a wide variety of brain-specific cells. Zhang was the first scientist to ever successfully differentiate iPSCs into NPCs, and therefore, this paper utilized his unique expertise.

According to Zhang, “We differentiate the stem cells only into neural cells. It would not work to transplant a cell population contaminated by non-neural cells. By taking cells from the animal and returning them in a new form to the same animal, this is a first step toward personalized medicine. Now we want to more ahead and see if this leads to a real treatment for this awful disease.”

Another positive sign was the absence of any signs of cancer, which is a troubling but potential outcome of stem cell transplants. Zhang jubilantly but guardedly announced that the appearance of the cells is “normal, and we also used antibodies that mark cells that are dividing rapidly, as cancer cells are, and we do not see that. And when you look at what the cells have become, the become neurons with long axons, as we’d expect. The also build oligodendrocytes that are helping build insulating sheaths for neurons, as they should. That means they have matured correctly, and are not cancerous.”

Zhang and his colleagues at the Waisman Center on the UW-Madison campus designed this experiment as a proof of principle investigation, but because they did not transplant enough dopamine-making cells into the brain, the animal’s behavior did not improve. Thus, although this transplant technique is certainly very promising, it is some ways from the clinic.

As noted by Emborg: “Unfortunately, this technique cannot be used to help patients until a number of questions are answered: Can this technique improve the symptoms? Is it safe? Six months is not long enough.” Emborg continued, “And what are the side effects? You may improve some symptoms, but if that leads to something else, then you have not solved the problem.”

Regardless of these shortcomings, this study still represents a genuine breakthrough. “By taking cells from the animal and returning them in a new form to the same animal, this is a first step toward personalized medicine,” said Emborg.

Cholesterol Derivatives Push Neural Stem Cells to Become Cells for Parkinson’s Disease Treatments


When we hear the word cholesterol we often have very negative thoughts of clogged arteries, heart attacks and strokes. However, cholesterol serves several vital roles in our bodies. It regulates the fluidity of the membranes of our cells, serves as a precursor for the synthesis of steroid hormones (such as estrogen, testosterone, cortisol and others), and is an important signaling molecule for several biological processes. Therefore. cholesterol is not all bad. Cholesterol when we get too much of it and our bodies handle the excess cholesterol poorly. Then wandering cells called macrophages have to mop up the excess cholesterol, but it makes them sick, and they get lost underneath the inner layers of blood vessels. That, however, is for another blog post.

In the present study, scientist from Karolinska Institutet in Sweden have identified two molecules, both of which are derivatives of cholesterol, that can help turn brain cells into the kind of cells that die during Parkinson’s disease. This finding might be useful for producing large quantities of neurons in the laboratory for therapeutic purposes.

As I have blogged before Parkinson’s disease results from the death of midbrain neurons that use the neurotransmitter dopamine. Because these midbrain neurons project to, in part, regions of the brain involved in voluntary movement, the death of the dopamine-using neurons in the midbain produces pronounced defects in voluntary movement and resting stability. Several experiment in humans and laboratory animals have definitively shown that cell transplantation experiments can improve the symptoms of patients with Parkinson’s disease. Therefore, cultivating and growing dopamine-using neurons in the laboratory is of cardinal importance in the treatment of this devastating disease.

Workers in the laboratory of Ernest Arenas investigated molecules known to play a role in the differentiation of midbrain neurons. They discovered that a group of receptors collectively known as “liver X receptors” or LXRs are necessary for making ventral midbrain neurons from neural stem cells. However, they were unsure what molecules bound to the LXRs in order to activate them.

Enter cholesterol stage right. By subjecting LXRs to a cocktail of molecules from living organisms and analyzing by means of mass spectrometry, they discovered that two molecules, cholic acid (a bile salt), and 24,25-EC, both of which are derivatives of cholesterol, bind to LXR and activate it.

Cholesterol
Cholesterol
Cholic Acid
Cholic Acid

24,25-Epoxycholesterol24,25-Epoxycholesterol

Cholic acid binds to LXR and stimulates the neural stem cells to form a group of midbrain cells known as the “red nucleus.” The red nucleus receives signals from several different parts of the brain to coordinate the movements of several different parts of the body. The other molecule, 24,25-EC binds to LXR and induces the formation of dopamine-using midbrain neurons – the ones that die off during Parkinson’s disease.

These data could open the possibility that cholesterol derivatives can be used to produce dopamine-using neurons from neural stem cells to treat Parkinson’s disease.

Ernest Arenas, professor of stem cell neurobiology in the department of biochemistry and biophysics, who led this study said: “We are familiar with the idea of cholesterol as a fuel for cells, and we know that it is harmful for humans to consume too much cholesterol. What we have shown now is that cholesterol has several functions, and that it is involved in extremely important decisions for neurons. Derivatives of cholesterol control the production of new neurons in the developing brain. When such a decision has been taken, cholesterol aids in the construction of these new cells, and in their survival. Thus cholesterol is extremely important for the body, and in particular for the development and function of the brain.”

Bone Marrow-Mesenchymal Stem Cells Rescue Motor Defects in Parkinson’s Macaques


A research group from Kobe, Japan at the RIKEN Center for Molecular Imaging Science and collaborators from Osaka, Kyoto, and Tokyo have successfully differentiated bone marrow mesenchymal stem cells (MSCs) into dopamine-making neurons (the kind that die off during Parkinson’s disease), and transplanted them into macaques (a type of monkey shown below) that have Parkinson’s disease. The implanted cells relieved the motor symptoms of Parkinson’s disease. This is a remarkable proof-of-priniciple publication.

Macaque

Parkinson’s disease causes a variety of motor (motor simply means associated with voluntary movement) problems. Parkinson’s disease patients have tremors, rigidity, slowness of movement, and difficulty walking. These symptoms result from the death of neurons in the midbrain that make a neurotransmitter called dopamine. Dopamine-making neurons in the midbrain are connected to regions in the cerebral cortex that help coordinate voluntary movement. Without these dopamine-making neurons, voluntary movement suffers and the characteristic symptoms of Parkinson’s disease ensue.

Several experiments have shown that replacing the dead dopamine-making neurons with manufactured neurons is feasible, but finding the right stem cell to do this has been laborious. In this new publication, a collaborative research team from Japan, led by Takuya Hayashi at the RIKEN center for Molecular Imaging Science in Kobe used a very versatile stem cell from bone marrow called the mesenchymal stem cell (also known as a stromal stem cell) for this experiment. MSCs, particularly those from bone marrow, have been used in many different regenerative medical experiments and clinical trials. However, the ability of MSCs to form neurons remains rather controversial. Even though researchers could get MSCs to form cells that looked like neurons in culture, several labs have presented observations that challenge this notion. Nevertheless, several groups have used genetic engineering techniques to place specific genes into MSCs, and these introduced genes do push MSCs to become not only neurons, but dopamine-making neurons (for papers, see Dezawa M, et al. J Clin Invest. 2004 113(12):1701‚Äď10, and Nagane K, et al., Tissue Eng Part A. 2009;15(7):1655‚Äď65).

Once it was confirmed that Hayashi and his co-workers had indeed made dopamine-making neurons from the MSCs, they were surgically transplanted into the brains of macaques that had been given a drug-induced form of Parkinson’s disease. Those animals that received the dopamine-making neurons made from bone marrow MSCs showed significant improvement in motor defects.

Did the cells integrate into the brain? Clearly they did. PET scans of the animal’s brains showed that the implanted cells were metabolically active and making dopamine. Further postmortem examination of the macaque brains confirmed that the implanted cells were still in the brains after seven months. Also, the PET scans and postmortem examination also confirmed that none of the implanted animals had any tumors or showed changes in blood chemistry. Thus the implanted cells improved symptoms, integrated into the brain. and did not produce any significant side effects or tumors.

This paper nicely illustrates that it is entirely possible to treat a patient’s Parkinson’s disease with cells from their own bone marrow in a manner that is safe and relatively effective.

Stem Cells from Your Nose to Treat Parkinson’s Disease?


Parkinson’s disease (PD) is a neurodegenerative disease that is a global problem and the incidence of PD increases as the population lives longer and longer. PD results from the loss of dopamine-making neurons in the midbrain. The main treatment for PD is a drug called L-DOPA, which can cross the blood-brain barrier, but this drug decreases in effectiveness as time progresses because the neurons become less sensitive to the drug and L-DOPA does not prevent dopamine-making neurons in the midbrain from dying.

substantia nigra

Experimental stem cell treatments of PD have used embryonic stem cells and induced pluripotent stem cells that were differentiated into dopamine-making neurons and transplanted into the midbrain of rodents that suffered from drug-induced PD. Unfortunately, even though symptom relief was observed, tumors were formed in many of these animals in these experiments. Until a more sure-fire way is discovered to identify and isolated dopamine-secreting neurons from other cells types, this approach will always seem too dangerous for clinical trials. References: Embryonic stem cells – Brederlau, et al., Stem Cells 2006 24:1433-40; Sonntag KC, et al. (2007) Stem Cells 25:411‚Äď418. and Roy, et al., Nature Medicine 2006 12:1259-68. Induced Pluripotent Stem Cells – Chang, et al., Cell Transplant 2012 21:313-32.

A paper that used induced pluripotent stem cells and differentiated them into dopamine-producing neurons which were transplanted into the brains of PD rodents did not produce tumors (see Hargus, et al., Proceedings of the National Academy of Sciences USA 2010 107:15921-6). It is likely that the stringent isolation procedures employed in this paper decreased tumor incidence (48 different cell lines were generated in this paper and none of them produced detectable tumors).

These experiments show that stem cell-based treatments for PD are feasible. The key is to find the right cell. Well, an old bromide says that “your nose knows.” Maybe this is true in the case of PD treatments. In the nose resides a tissue known as the “olfactory epithelium,” (OE) which is a source of stem cells that can form neurons. OEs can be harvested with minimally invasive nasal surgery (see Winstead W, et al., American Journal of Rhinology 2005 19:83-90). In fact, more than 150 different patient-specific cell lines of “human olfactory neural progenitor” (hONPs) cells have been established from cultures of adult olfactory epithelial cells taken from cadavers (see Roisen FJ, et al., Brain Research 2001 890:11-22).

 The olfactory epithelium lines the posterodorsal nasal cavity immediately inferior to the cranial cavity. The normal epithelium is composed of a handful of cell types: sustentacular cells (Sus), microvillar cells (a supporting cell variant), olfactory sensory neurons ‚Äď both mature and immature (OSNs), globose basal cells (GBCs), horizontal basal cells (HBCs), Bowman‚Äôs duct and gland cells. Deep to the basal lamina, the fascicles of the olfactory axons are ensheathed by the specialized glia of the olfactory nerve, the olfactory ensheathing cells (OECs). In addition, stromal cells (fibroblasts) of the lamina propria secrete signals that regulate epithelial assembly and turnover.
The olfactory epithelium lines the posterodorsal nasal cavity immediately inferior to the cranial cavity. The normal epithelium is composed of a handful of cell types: sustentacular cells (Sus), microvillar cells (a supporting cell variant), olfactory sensory neurons ‚Äď both mature and immature (OSNs), globose basal cells (GBCs), horizontal basal cells (HBCs), Bowman‚Äôs duct and gland cells. Deep to the basal lamina, the fascicles of the olfactory axons are ensheathed by the specialized glia of the olfactory nerve, the olfactory ensheathing cells (OECs). In addition, stromal cells (fibroblasts) of the lamina propria secrete signals that regulate epithelial assembly and turnover.

Human ONPs can also be differentiated into dopamine-making neurons in culture (Zhang X., et al., Stem Cells 2006 24:434-442). Therefore, these cells should be candidate stem cells for making treatments for PD.

Fred Roisen and his cohorts from the University of Louisville, Kentucky, has used hONPs to treat rats with drug-induced PD.  In their paper, Roisen and others used cultures of hONPs and then proceeded to differentiate them into dopamine-making neurons. Then they transplanted these cells into the midbrains of rats that had been treated with 6-hydroxydopamine, which is a drug that kills off dopamine-making neurons in the midbrain and induces PD. However, it is important to understand that the dopamine-producing neurons were only destroyed on the right side of the brain, thus leaving the left side intact. When they stem cells were injected into the midbrains of these rats, they were only injected into the right side, the side that had been damaged by the drugs. Therefore, the right side of the midbrain served as a control throughout these experiments.

The behavioral tests on these PD rats determined if the transplanted hONPs helped decrease the effects of PD. In all three behavioral tests, the hONP-injected rats showed significant improvements over the untreated rats. Were these improvements due to the formation of new dopamine-making neurons? The answer is a clear yes, since postmortem analyses of the brains of these rats showed that the hONP-injected rats not only showed the presence of dopamine-making neurons on the injected side, but the levels of dopamine production in the right side of the brain as compared to the left side of the brain were higher in the hONP-injected animals, even though they were three times lower than those dopamine levels found in the left side of the midbrain.

This experiment shows that hONPs should be considered serious players in the treatment of PD. In none of the transplanted animals were tumors found. Therefore, hONPs seem to be safe, they are easily acquired, and they have the capacity to form dopamine-making neurons. The goal should be to jack up the dopamine levels in the transplanted cells.

See Meng Wang, Chengliang Lu, Fred Roisen, “Adult human olfactory epithelial-derived progenitors: A potential autologous source for cell-based treatment for Parkinson’s disease,” Stem Cells Translational Medicine 2012 1:492-502.

BrainStorm Announces that There Are No Dangerous Side Effects Observed in NurOwn Trial


A developer of innovative stem cell technologies, BrainStorm Cell Therapeutics Inc. has developed a stem cell treatment called NurOwn for central nervous system-based disorders. NurOwn‚ĄĘ is a product derived from human bone marrow mesenchymal stem cells. After these cells are collected from a patient by means of a bone marrow aspiration (which not nearly as invasive as a bone marrow biopsy), they are differentiated into nerve-like cells that can release the neurotransmitter dopamine and a nervous system-specific growth factor called glial-derived neurotrophic factor (GDNF). Dopamine cell damage and death is the hallmark of Parkinson‚Äôs Disease (PD), and GDNF-producing cells can protect healthy dopamine-producing cells and repair degenerated cells. This halts the progression of PD and other neurodegenerative diseases. BrainStorm‚Äôs NurOwn‚ĄĘ therapy for PD replaces degenerated dopamine-producing nerve cells and strengthens them with GDNF.

BrainStorm has just announced patient data from its ALS combined phase I & II human clinical trial. ALS patients who were treated with NurOwn, a stem cell-based product that BrainStorm had developed, did not show any significant side effects to the NurOwn treatment. Therefore, so far, NurOwn seems to be safe.

The leader of this clinical trial at Hadassah Medical Center, Prof. Dimitrios Karussis, stated, ‚ÄúThere have been no significant side effects in the initial patients we have treated with BrainStorm‚Äôs NurOwn technology. In addition, even though we are conducting a safety trial, the early clinical follow-up of the patients treated with the stem cells shows indications of beneficial clinical effects, such as an improvement in breathing and swallowing ability as well as in muscular power. I am very excited about the safety results, as well as these indications of efficacy, we are seeing. This may represent the biggest hope in this field of degenerative diseases, like ALS.‚ÄĚ

The Hadassah Medical Center ethics committee reviewed the safety data from the first four patients who were implanted with NurOwnTM, and concluded that the clinical trial should proceed with implanting the next group of ALS patients.

BrainStorm‚Äôs President, Chaim Lebovits, remarked: ‚ÄúWe are happy to report that the first patients treated with our NurOwn technology did not present any significant side effects. This supports and strengthens our belief and trust in our technology. Based on the interim safety report, the hospital ethical and safety committee granted the company approval to proceed with treating the next patients. We are pleased with the progress we are making and look forward to continuing to demonstrate the safety of NurOwn in the future.‚ÄĚ

This study is headed by Prof. Karussis, MD, PhD, head of Hadassah’s Multiple Sclerosis Center and a member of the International Steering Committees for Bone Marrow and Mesenchymal Stem Cells Transplantation in Multiple Sclerosis (MS), and a scientific team from BrainStorm headed by Prof. Eldad Melamed. This clinical trial is being conducted at Hadassah Medical Center in Israel in collaboration with BrainStorm and utilizes BrainStorm‚Äôs NurOwn technology for growing and modifying autologous adult human stem cells to treat ALS, which is often referred to as Lou Gehrig’s Disease. The initial phase of the study is designed to establish the safety of NurOwn, but will also be expanded later to assess efficacy of the treatment.