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.

Interleukin-17A Augments Mesenchymal Stem Cell Function


One of the biggest problems with organ transplantations is that the immune system can reject the transplanted tissue. Transplant rejection requires the patient to go through another traumatic surgery, and if another organ is not available, then they might very well die. Is there a way to reduce organ rejection?

Our bodies have on our cell surfaces a series of “bar codes” that are the result of “Major Histocompatibility Antigens” or MHC proteins. These proteins are encoded by genes that vary extensively. Therefore, each person has a distinct combination of cell surface proteins that decorate the outside of their cells. If your immune system finds cells that have a different set of MHCs that what you were born with, the immune system, which has been “taught” to accept your own proteins and reject different proteins, will attack and destroy the transplanted tissue. This is known as “Graft vs Host disease” or GvHD. To avoid GvHD, transplant physicians try to find organs that match your own tissue type as closely as possible. However, it is virtually impossible to find organs that perfectly match your own. Even if the patient is given anti-rejection drugs, sometimes the immune system begins to reject the transplanted organ. Is there a way around this?

Mesenchymal stem cells (MSCs) have the ability to suppress unwanted immune responses. If MSCs are pre-treated with cytokines, they can do this even better. Typically, MSCs are pre-treated with a molecule called interferon-γ. This molecule stimulates MSCs and causes then to suppress the immune response, but it also causes MSCs to express proteins that cause them to be rejected by the immune system. Thus interferon-γ seems to cause problems that prevent the MSCs from working properly.

In a really beautiful paper by Kisha Sivanathan in the Coates lab at the School of Medical Sciences, Adelaide, Australia and her colleagues, showed that pre-treating human MSCs with interleukin-17A did a better job at stimulating MSCs without sensitizing the cells to the immune system.

When Sivanathan and her co-workers treated human bone marrow-derived MSC with interleukin-17A, this molecule enhanced the ability of MSCs to suppress the immune response without making the MSCs subjects for rejection by the immune system.  These interleukin-17A-treate MSCs (MSC-17s) showed no induction or upregulation of molecules that the immune system reacts against (MHC class I, MHC class II, and T cell costimulatory molecule CD40), and the the interleukin-17A-treated MSCs maintained normal MSC morphology and made all the common MSC markers.

When MSC-17s were placed in culture with activated human T cells, the MSCs-17s potently suppressed T cell proliferation.  Additionally, MSC-17s prevented activated T-cells from making the whole cocktail of molecules they normally make once they are activated.

Not all T-cells are created equal. There is a group of T-cells called “regulator T-cells” or T-regs for short. T-regs tend to down regulate the immune response. It turns out that MSCs-17s turn on T-regs and stimulate them to potently suppress T-cell activation. They do this without inducing immunogenicity in the MSCs.

Thus, pre-treating MSCs with interleukin-17A represents a superior way for stimulate MSCs to suppress T cell activity in clinical situations.  Dr. Coates and his colleagues are hopeful that this protocol can be the subject of clinical trials in the near future.

Mesenchymal Stem Cells Heal Gastrointestinal Ulcers


Stomach ulcers are a complication of routine use of aspirin, Advil, or other non-steroidal anti-inflammatory drugs. Additionally, radiation therapy, or inflammatory bowel disease can also cause stomach ulcers, and these are painful and potentially dangerous for patients. Trying to get our heads around ulcers is not easy, but a new study by Manieri and colleagues have provided some understanding of ulcer formation and ways that mesenchymal stem cells (MSCs) might help heal these painful lesions.

Manieri and others used prostaglandin-deficient mice as a model system for ulcer formation. In these mice, their stomachs do not produce the prostaglandins that protect the layers of the stomach from being digested by its own acid and enzymes. Consequently, these mice are subject to so-called “penetrating ulcer formation,” or ulcers that penetrate the underlying muscular layer (muscularis propria). When Manieri and his colleagues took biopsies of the colon of these prostaglandin-deficient mice, they observed extensive necrosis of the upper and lower layers of the colon.

When these mice were treated with stable prostaglandin-I2 (PGI2) analogs, Manieri and others showed that they could ameliorate the damage to the colon. However, when this research group analyzed the ulcer beds in these mutant mice, they noticed that CD31+ endothelial cells, which form blood vessels, were found in very low numbers. This suggested that reduced blood vessel formation could be a key driver of penetrating ulcer formation. To confirm their hypothesis, the authors stained the wound sites for vascular endothelial growth factor (VEGF). They saw fewer VEGF+ cells in the mutant mice compared with wild-type animals, which suggests that impaired blood vessel production contributes to ulceration. To further test this hypothesis, Manieri and others treated wild-type mice with tivozanib (a VEGF receptor antagonist), which also caused smooth muscle necrosis in the colon.

Next Manieri and others injected MSCs from the colons of mice that showed increased expression of VEGF into the ulcerated colon of mutant mice. The MSCs dutifully migrated to the ulcer beds, and rescued the muscle necrosis phenotype. These results show that MSC administration can provide a soothing treatment prospect for patients who are dealing with gastrointestinal ulceration.

See N. A. Manieri et al., Mucosally transplanted mesenchymal stem cells stimulate intestinal healing by promoting angiogenesis. J. Clin. Invest. 10.1172/JCI81423 (2015).

So What About Three-Person Embryos?


In 2013, Deiter Egli’s group at Harvard University successfully transferred chromosomes that were in the process of dividing and segregating (known as an incompletely assembled spindle-chromosome complex) from one human egg into another egg whose nucleus had been removed (Nature 493, 632–637 (31 January 2013) doi:10.1038/nature11800). They prevented the eggs from prematurely re-entering meiosis by cooling the chromosome/spindle complex to room temperature. This allowed normal polar body extrusion, efficient development to the blastocyst stage, and, eventually, the derivation of normal stem cells.

3-person-ivf

Egli’s technique allows the genome of one egg to initiate development in the cytoplasm of another egg. Why is this significant? Because within out cells is a bean-shaped vesicle called a mitochondrion. Mitochondria make the energy for our cells. To do this, mitochondria use a variety of proteins encoded on genes found in the nuclear genome. However, mitochondria also have their own genome that encodes some crucial mitochondrial proteins and RNAs. The human mitochondrial genome is a small, circular DNA molecule that encodes 37 different genes.

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Mutations in genes encoded by the mitochondrial genome tend to have rather catastrophic consequences for the fertility of women. When the egg undergoes fertilization, the vast majority of the mitochondria of the sperm are degraded and their mitochondrial DNA is eliminated (Katsumi Kasashima, Yasumitsu Nagao, and Hitoshi Endo. Reprod Med Biol. 2014; 13(1): 11–20). Research has shown that the father’s mitochondrial genome can make some very small contribution to the embryo, a phenomenon known as “paternal leakage,” but it is usually pretty small (Kuijper B1, Lane N, Pomiankowski A. J Evol Biol. 2015 Feb;28(2):468-80). Therefore, if the mother carries a deleterious mutation in her mitochondrial DNA, her eggs will usually not be able to progress through fertilization successfully and support the growth and development of the embryo. Consequently, the mother will be infertile.

This new technique by Egli, however, allows mothers who are infertile because of mutations in their mitochondria DNA, to have children who are genetically related to them. All that is needed are eggs from a healthy donor, and a laboratory that has the know-how and will to do this procedure. The mother’s eggs are harvested by standard IVF technologies, fertilized by the father’s spermatozoa, and after fertilization has ended, the chromosome-spindle complex is lifted from the young embryos and transferred into enucleated donor eggs that contain mitochondria with normal genomes. Development will then ensue without a hitch. Right?

Well not so fast. As it turns out, this procedure has been carried out in several different animal species, and the results are decidedly mixed (see Reinhardt and others, Science 2013;341:1345).

If we begin with insects, we can move new mitochondrial genomes into embryos by standard genetic techniques. If we do so in the fruit fly, Drosophila melanogaster, such mitochondrial transfer produces fly embryos that develop normally, but the animals show altered juvenile viability, adult male animals show accelerated aging and reduced fertility. Genetically, it is clear that transferring new mitochondria into an egg messes up the expression of nuclear genes. Identical experiments in the seed beetle causes altered development and metabolic rates, reduced fertility in males and reduced survival in females. Similar studies in copepods (Tigriopus californicus) causes reduced juvenile viability, and reduced mitochondrial function and energy production in adults.

If mice are subjected to these same experiments, the animals develop normally and survive to adulthood, but these adult mice show reduced growth and exercise ability and reduced learning ability in males.

The above-mentioned experiments used standard genetic breeding techniques to generate animal strains that had a mismatch between the nuclear and mitochondrial genome.  Such techniques are demonstrably non-invasive.  However, the technology applied in Egli’s laboratory were invasive, and included removing chromosome/spindle complexes and transferring them to donor eggs that had been enucleated. Therefore, the effects of these invasive procedures had to be tested as well. If such invasive procedures were tested in cultured mouse cells, the hybrid cells showed altered cellular respiration and growth. In short, their mitochondria worked poorly inside their new homes.

If Egli’s technique was used in non-human primates, macaques in particular, the animals developed to the juvenile stage and appeared normal.

On the strength (or weakness) of these experiments, some reproductive specialists in countries where such techniques can be performed without fear of prosecution have used mitochondrial transfer in human embryos. Again the results are quite mixed. Healthy children have been born by this procedure, but several others have not. Helen Pearson reported in Nature News on the 14th of October, 2005 about two Chinese babies that were made with mitochondrial transfer that died in utero at 24 and 29 weeks. Other outcomes include a miscarriage, an abortion of a fetus that had Turner Syndrome, at least two children with mixed mitochondria that studies linked with cognitive dysfunction and obesity, and a child born with a severe developmental disorder. I do not call these hopeful results.

Another experiment that gives me pause was published in the journal Cell Reports in June of 2014 by Joerg Patrick Burgstaller and others. This paper showed that even small amounts of diseased mitochondrial DNA in an embryo would spread throughout the organism. The amount of spread is wide and varied, but even small amounts of variant mitochondrial DNA did spread. This significance of this is stark for this debate. You see, Egli’s original paper in Nature showed that very small amounts of the original mitochondrial DNA are transferred to the donor egg. Granted it below 1% of the total mitochondrial DNA in the embryo, but it is still detectable. Burgstaller and others have shown that even with this small amount of mitochondrial DNA, it will still spread throughout the developing baby and given them a body with some cells that have most the diseased mitochondrial DNA, and others that have the normal mitochondrial DNA, and other cells that have a mixture of the two. Therefore, Egli’s technique is NOT a cure for conditions linked to mitochondrial DNA mutations. Let me repeat this for every one – Egli’s technique is NOT a cure for conditions linked to mitochondrial DNA mutations.

No vertebrates have yet been studied who have gone through mitochondrial replacement and survived to reproductive age. Given the decidedly mixed record of this technology in a variety of animal models and the paucity of data so far, this technology is clearly not ready for use in humans.

However, that has not stopped scientists and politicians in the United Kingdom from pushing this technology forward as a fertility treatment for infertile women who harbor mitochondrial DNA mutations.  Some in the scientific community warned about the potential dangers of this technology.  Their concerns were largely ignored and in many cases severely criticized.  Even worse, some thought that three-person embryos could grease the slippery slope in which this technology or similar ones like cloning would be applied as generalized treatments for infertility.  That concern was labeled ridiculous. No longer.

Science magazine reported that cloning magnate Shoukhrat Mitalipov has formed a partnership with disgraced fraudster Woo Suk Hwang.  The two are teaming up to form a joint commercial venture to use Mitalipov’s cloning techniques as a way to treat infertility and perhaps other diseases.  Mitalipov’s commercial venture Mitogenome Therapuetics and Hwang along with the company BoyaLife, which will reportedly put up more than $90 million into the effort.  Mitalipov has also generated news reports by asking FDA approval to use so-called 3-person IVF “mitochondrial transfer” technology, which shares some technical elements with cloning, to treat infertility. This surprised some in the UK, including members of Parliament who were hoodwinked into voting to approve the three-person embryo procedure by being told that this technology would only be used to treat mitochondrial diseases.

The slippery slope is real and unless citizens rise up and make noise, we are going to be dragged where angels fear to tread by over-zealous scientists who are willing to sacrifice young children for the sake of their own fame and success.  This technology is not ready for use in humans.  The approval of this technology in the UK is a very bad idea.  It will also spread to the use of cloning in general as a treatment for diseases, and we will then move to fetus farming.  May God give us the strength to say enough is enough.

The United States FDA’s Cellular, Tissue and Gene Therapies Advisory Committee will be holding a public hearing to “discuss considerations for the design of early-phase clinical trials of cellular and gene therapy products” including the three-parent IVF method. The public has until October 15 to send in written comments. If you are interested in making your views known, go here.

Intravenous Administration of Lipitor-treated Stem Cells on the Heart


Hao Zhang and colleagues from the Chinese Academy of Medical Sciences and Peking Union Medical College have published a rather unusual experiment in the American Journal of Translational Research. This experiment, however, could have implications for stem cell therapy in heart attack patients.

When heart attack patients are treated with stem cells, they are either injected directly into the heart muscle or released into the heart through the coronary arteries by means of angioplasty. Injecting stem cells directly into the heart requires special equipment and training. Releasing cells into the coronary arteries causes most cells to end up in the lungs or other organs, and the retention of the stem cells is poor. Introducing cells by means intravenous administration would be supremely simple, but in animal experiments, intravenously administered stem cells almost never get to their target organ.

When the heart undergoes a heart attack, the damaged heart cells release a molecule called SDF1 or stromal cell-derived factor 1. SDF1 summons stem cells to the damaged areas by binding to the surfaces of stem cells and drawing them to the higher concentrations of SDF1. SDF1 binds to a receptor on the surfaces of stem cells called CXCR4. Unfortunately, when stem cells are administered intravenously to animals that have just experienced a heart attack, the stem cells do not have enough CXCR4 on their surfaces to properly respond to the SDF1 being secreted by the damaged heart.

Zhang and his colleagues capitalized on an observation made several years ago. When stem cells are exposed to statin drugs that are normally used to lower serum cholesterol levels, the stem cells increase the number of CXCR4 molecules on their surfaces. Statins have also been shown to increase stem cell survival once the cells get to the heart, but Zhang and his team wanted to know if pre-treating stem cells with statins could increase their migration to the damaged heart.

The Zhang group isolated mesenchymal stem cells from rat bone marrow and treated these cells with increasing concentrations of the drug Lipitor (atorvastatin). Indeed, increasing amounts of Lipitor increased the number of CXCR4 molecules on the surfaces of the mesenchymal stem cells (MSCs), This increase in CXCR4 molecules peaked at 24 hours, after which the number of receptors declined. These Lipitor-treated MSCs also migrated much more robustly in culture when treated with SDF1.

Next, Zhang’s group pre-treated MSCs with Lipitor and labeled them with an innocuous tracking molecule. 24 hours after giving some laboratory rats heart attacks, these MSCs were administered to the rats in their tail veins. Two other groups of similarly treated rats were given either MSCs that had not been pre-treated with Lipitor, or just buffer.

The Lipitor-treated MSCs were found in significantly higher quantities in the hearts of laboratory animals, relative to the other animals. Secondly, these Lipitor pre-treated MSCs cut the size of the heart scar in half, and there was also substantially less inflammation in hearts from animals treated with Lipitor pre-treated MSCs than the other groups. Heart function was also increased in the pre-treated group.

Live MSCs were observed in the hearts of the animals given Lipitor pre-treated MSCs. This is a remarkable finding, because most experiments have shown that MSCs administered to the heart after a heart attack ad usually dead within 21 day after administration. However the Lipitor pre-treated MSCs survive and flourish in the damaged heart, which suggests that SDF1 not only attracts stem cells but also increases their rates of survival.

This is a somewhat off-beat experiment at first glance, but if MSCs could be pre-treated with a drug like Lipitor and then administered to heart patients intravenously, they would survive in the heart, convey greater benefits, and their administration would be safer, and not require special equipment or training. With a little luck, this idea will reach human clinical trials in a few years; provided that further animal and cell culture studies confirm these results, elucidate the mechanism of SDF1-mediated survival, and show that such augmentation of function is also observed in human MSCs.

Rejuvenation Factor Discovered in Human Eggs


When the egg is fertilized by a sperm, it is transformed into a single-celled embryo or zygote that is metabolically active and driven to divide and develop. The egg, on the other hand, is a rather inert cell from a metabolic perspective. What is it in the egg that allows it to transform into something so remarkably different?

A new study by Swea-Ling Khaw and others in the laboratory of Ng Shyh-Chang at the Genome Institute of Singapore (GIS) has elucidated two main factors that help rejuvenate the egg and might also help reprogram adult cells into induced pluripotent stem cells (iPSCs).

Eggs express large amounts of a protein called Tcl1. Tcl1 suppresses the function of old, potentially malfunctioning mitochondria (the structure in cells that makes the energy for the cell). This suppression prevents damaged mitochondria from adversely affecting the egg’s transformation from into an embryo.

Remember also that if an adult cell is fused to an egg, it can cause the egg to divide and form an early embryo. Therefore, the egg cytoplasm is able to reprogram adult cells as well, and Tcl1 seems to play a role in this reprogramming capability as well.

In a screen for genes that are important to the reprogramming process, Shyh-Chang’s laboratory isolated two genes, Tcl1 and Tcl1b1. Further investigation of these two proteins showed that Tcl1 affects mitochondria by inhibiting a mitochondrial protein called polynucleotide phosphorylase (PNP). By locking PNP in the cytoplasm rather than the mitochondria, the growth and function of the mitochondria are inhibited. Tcl1b1 activates the Akt kinase, which stimulate cell growth, survival, and metabolism.

In a review article in the journal Stem Cells and Development, Anaïs Wanet and others explain that energy production in pluripotent stem cells is largely by means of glycolysis, which occurs in the cytoplasm. Mitochondria in pluripotent stem cells are immature subfunctional. When adult cells are reprogrammed into iPSCs, mitochondria function is shut down and energy production is largely derived from glycolysis. When the cells differentiate, the mitochondria are remodeled and become functional once again. Tcl1 is the protein that help shut down the mitochondria so that the pluripotent state can ensue and Tcf1b1 gears up the pluripotent stem cells to grow and divide at will.

Given this remarkable finding, can Tcf1 help make better iPSCs? Almost certainly, but how does one use this important factor to make better iPSCs?  That awaits further experimentation.  Additionally, this finding might also help aging and infertility issues as well. Hopefully this work by Shyh-Chang and her colleagues will lead to many more fruitful and exciting experiments.

Intravenous Bone Marrow For Stroke: Clinical Trial


Akihiko Taguchi from the Institute of Biomedical Research and Innovation in Kobe, Japan, in collaboration with a whole host of colleagues from various places treated stroke with their own bone marrow. This is a Phase 1/2 clinical trial but it is a very small trial that was neither blinded not placebo-controlled. Therefore, while this trial is useful, the results are of limited value.

In this clinical trial, 12 stroke patients were divided into two groups, one of which received 25 milliliters and the other of which received 50 milliliters of bone marrow cells 7-10 days after their strokes. The bone marrow cells were administered intravenously. To isolate bone marrow cells, the so-called “mononuclear fraction” was isolated from whole bone marrow samples that came from bone marrow aspirations. Patients were evaluated by means of brain imaging to measure blood flow in their brains, and a series of neurological tests. The National Institute of Health Stroke Scale or NIHSS scores were used to grade the neurological capabilities of each patient. Patients were examined 1 month and then 6 months after treatment.

All treated patients were compared with the records of other stroke patients in the past who were not treated with bone marrow cells. These comparisons showed that the bone marrow-treated patients showed a trend towards improved neurological outcomes. Statistically, the bone marrow-treated patients had significantly better blood flow and oxygen consumption in their brains 6 months after treatment compared to the historic controls. Also, the NIHSS scores of the bone marrow-treated patients were also significantly better than those of the historic controls. Patients who received the higher doses of bone marrow cells did better than those who received the lower doses.

There were also no apparent adverse effects to administering the bone marrow cells. One patient experienced pneumonia and sepsis 3 months after cell therapy, but data monitoring largely eliminated the cell therapy as being a contributing factor to this issue. Another patient experienced a seconded stroke that was detected the day after the cell therapy. Because the patient had shown signs of a stroke the day before treatment, the association between the cell therapy and the recurrent stroke is rather unclear. None of the other patients showed any worsening of their present strokes, seizures, or other complications.

All in aloe, it seems as though this procedure is safe, and there is a trend towards increased metabolic and neurological recovery. However, this is a very small study and these trends may not hold in a larger study. Secondly, these patients must be followed for an extended period of time in order to determine if these improvements are durable or transient. Finally, these improvements must be compared with a placebo if there are going to convince the FDA.

Bone marrow cells contain a variety of stem cells and other types of cells that may release cocktails of healing molecules that help cells survive, make new blood vessels, and tamp down inflammation. Additionally, bone marrow cells might stimulate resident populations of stem cells to proliferate and make new neurons and glial cells. Until these positive results can be reproduced in larger, better controlled studies, these results will remain interesting and hopeful, but ultimately inconclusive.

These results were published in Stem Cells and Development 2015 DOI: 10.1089/scd.2015.0160.