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OSKM stoichiometry determines iPS cell reprogramming

13 hours ago (top) Adding 9 amino acids before Klf4 to switch the isoform from Klf4S to Klf4L subtly lengthens the transgene. (bottom left) This lengthening causes a significant increase in the Klf4 protein expression. (bottom right) It also increases the proportion of reprogrammed cells (green) to partially reprogrammed cells (red). Credit: Dr. Knut Woltjen's Laboratory

Researchers at Kyoto University's Center for iPS Cell Research and Application discover a simple way to increase the production of induced pluripotent stem cells. A major hurdle in reprogramming science is generating a sufficient number of iPS cells to conduct basic research experiments. Yet, a report published in Stem Cell Reports shows that simply adding 9 amino acids to the induction transgene Klf4 dramatically elevates the production of fully reprogrammed mouse iPS cells.

Anyone in the field of cell reprogramming recognizes Oct3/4, Sox2, Klf4, and c-Myc, or "OSKM", as the Yamanaka factors that led to the first iPS cells. Originally, these four genes were delivered as individual (monocistronic) viral vectors. In order to simplify protocols, researchers began to deliver them using single polycistronic vectors, where the OSKM genes are linked as mRNA but still produce four separate proteins to induce reprogramming. However, not all vectors are built the same, and it turns out their subtle variations may influence both reprogramming efficiencies and outcomes. Specifically, the length of Klf4 appears to be a significant factor in determining whether a somatic cell is reprogrammed to the pluripotent state. Klf4 was first reported in 1996 by two independent studies. However, despite investigating the same gene, those two reports predicted different locations of the start codon in the mRNA sequences, which when translated result in proteins that differ by nine amino acids in length. Which isoform is used for reprogramming depends on the lab. "Some labs use short Klf4, some labs use long. Some labs have even switched between the two lengths," says Knut Woltjen, Ph.D., Associate Professor at CiRA.

Curious if these amino acids could explain the diverse reprogramming efficiencies that have been reported by different labs, Woltjen and his team employed piggyBac transposons to deliver various polycistronic reprogramming factors, controlling for the Klf4 length. They found that transfection with polycistronic vectors carrying the shorter Klf4 (Klf4S) resulted in more cells that initiated reprogramming, but failed to complete it, leaving them as partially reprogrammed. In contrast, the majority of cells transfected with vectors carrying the longer Klf4 (Klf4L) became true iPS cells. Deeper investigation found that polycistronic vectors with the Klf4L isoform showed much higher Klf4 protein expression, suggesting that the stoichiometry of the reprogramming factors could be the critical factor underlying reprogramming efficiency. According to Woltjen, "The stoichiometry is so important. No matter what system you use to establish it, the stoichiometry has a major impact on the quality of iPS cells." Other studies have noted stoichiometry effects, but Woltjen's team is the first to propose variation in a single factor's mRNA sequence as a determining factor in establishing stoichiometry. Supporting their hypothesis, appending Klf4S with the missing nine amino acids switched the Klf4 expression and reprogramming dynamics to mirror those seen with Klf4L.

Moreover, these differences in stoichiometry were reflected in gene expression patterns observed during the reprogramming process. Although reprogramming with either Klf4S or Klf4L led to the activation of many hallmark reprogramming genes, the majority of gene regulation was clearly dissimilar. Studying the reprogramming process induced by eight different polycistronic vectors, the team observed that both reprogramming performance and gene expression bifurcated with the Klf4 isoform. This finding may suggest that for popular vectors containing Klf4S, a simple modification of the Klf4 length could augment the number of properly reprogrammed cells. For researchers studying the reprogramming process itself, such vector differences raise caution when directly comparing reprogramming data between labs.

Interestingly, the differences associated with Klf4 length appeared mainly when reprogramming with polycistronic vectors. If instead either Klf4S or Klf4L was induced using a monocistronic vector in combination with an OSM polycistronic vector, the isoform dependency of reprogramming disappeared. These results suggest that the polycistronic design of the vector has some innate effect on the expression level of Klf4, while the protein function itself may not be affected. Nevertheless, inappropriate ratios of monocistronic vectors could also lead to a similar stoichiometry effect. Shin-Il Kim, Ph.D., first author of the study, stresses that just recognizing OSKM is not enough when reprogramming and that one must also be aware of the relative expression of the four genes. "Initially, we had no idea how much of a difference it [the 9 amino acids] would make. It goes to show how important it is to really know the materials you are working with."

Explore further: Carcinogenic mechanism of incomplete cell reprogramming in vivo

More information: Shin-Il Kim, Fabian Oceguera-Yanez, Ryoko Hirohata, Sara Linker, Keisuke Okita, Yasuhiro Yamada, Takuya Yamamoto, Shinya Yamanaka, and Knut Woltjen. KLF4 N-Terminal Variance Modulates Induced Reprogramming to Pluripotency. Stem Cell Reports, 2015.

A research team led by the group of Professor Yasuhiro Yamada, Center for iPS Cell Research and Application (CiRA), Kyoto University, has discovered that when cells are subjected to incomplete reprogramming ...

Austin Smith and his research team at the Centre for Stem Cell Research in Cambridge have just published in the journal Development a new and safer way of generating pluripotent stem cells - the stem cells that can give r ...

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OSKM stoichiometry determines iPS cell reprogramming

Boosting A Natural Protection Against Alzheimer's Disease

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Newswise Researchers at the University of California, San Diego School of Medicine have identified a gene variant that may be used to predict people most likely to respond to an investigational therapy under development for Alzheimers disease (AD). The study, published March 12 in Cell Stem Cell, is based on experiments with cultured neurons derived from adult stem cells.

Our results suggest that certain gene variants allow us to reduce the amount of beta amyloid produced by neurons, said senior author Lawrence Goldstein, PhD, director of UC San Diego Sanford Stem Cell Clinical Center and UC San Diego Stem Cell Program. This is potentially significant for slowing the progression of Alzheimers disease. AD is the most common cause of dementia in the United States, afflicting one in nine people age 65 and older.

The genetic risk factor investigated are variants of the SORL1 gene. The gene codes for a protein that affects the processing and subsequent accumulation of beta amyloid peptides, small bits of sticky protein that build up in the spaces between neurons. These plaques are linked to neuronal death and related dementia.

Previous studies have shown that certain variants of the SORL1 gene confer some protection from AD, while other variants are associated with about a 30 percent higher likelihood of developing the disease. Approximately one-third of the U.S. adult population is believed to carry the non-protective gene variants.

The studys primary finding is that variants in the SORL1 gene may also be associated with how neurons respond to a natural compound in the brain that normally acts to protect nerve cell health. The protective compound, called BDNF, short for brain-derived neurotrophic factor, is currently being investigated as a potential therapy for a number of neurological diseases, including AD, because of its role in promoting neuronal survival.

For the study, UC San Diego researchers took skin cells from 13 people, seven of whom had AD and six of whom were healthy control subjects, and reprogrammed the skin cells into stem cells. These stem cells were coaxed to differentiate into neurons, and the neurons were cultured and then treated with BDNF.

The experiments revealed that neurons that carried disease-protective SORL1 variants responded to the therapy by reducing their baseline rate of beta amyloid peptide production by, on average, 20 percent. In contrast, the neurons carrying the risk variants of the gene, showed no change in baseline beta amyloid production.

BDNF is found in everyones brain, said first author Jessica Young, PhD, a postdoctoral fellow in the Goldstein laboratory. What we found is that if you add more BDNF to neurons that carry a genetic risk factor for the disease, the neurons dont respond. Those with the protective genetic profile do.

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Boosting A Natural Protection Against Alzheimer's Disease

Neuralstem Stock Plunges After Latest Study on ALS Drug

GERMANTOWN, Md. (TheStreet) -- Neuralstem (CUR - Get Report) is providing an overly optimistic picture about its surgical stem-cell therapy for amyotrophic lateral sclerosis (ALS), the degenerative and fatal nerve disease.

Instead of disclosing the results from all 15 ALS patients enrolled in Neuralstem's phase II study of NSI-566, the company decided to only release a comparison between the patients who responded and those who didn't respond. Of course, the seven responders in the study showed more stabilization or improvements in muscle function compared with the eight patients deemed non-responders.

The scientific term for this conclusion is, "Duh."

When you work backwards and do some simple math on the muscle performance of all 15 ALS patients in the Neuralstem study, the results aren't very encouraging. Neuralstem chose to stay mum on this more customary analysis.

Neuralstem shares are down 14% to $3.21 in Thursday trading.

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Neuralstem Stock Plunges After Latest Study on ALS Drug

Hip and shoulder arthritis six months after bone marrow stem cell therapy by Harry Adelson ND – Video


Hip and shoulder arthritis six months after bone marrow stem cell therapy by Harry Adelson ND
Mareen describes her outcome six months after her bone marrow stem cell treatment by Harry Adelson ND for arthritis of her hip and shoulder http://www.docereclinics.com.

By: Harry Adelson, N.D.

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Hip and shoulder arthritis six months after bone marrow stem cell therapy by Harry Adelson ND - Video

Wheelchair Kamikaze: Stem Cell Treatments for Multiple …

As all patients with MS are aware, the currently available treatments do nothing to cure the disease or repair the damage that it does. At their best, todays crop of disease modifying drugs (DMDs) quiet the disease, thereby improving the quality of life for many of the patients taking them, especially those suffering from relapsing remitting multiple sclerosis. However, many of these drugs carry with them risky side effect profiles, and though the newest compounds represent advances over their predecessors, patients are crying out for revolution, not evolution.

Stem cells could represent the revolution patients so fervently desire. Because of their ability to transform into almost any type of cell in the human body, stem cells may hold the key to achieving one of the holy grails of modern medicine, the regeneration and repair of damaged tissues. For MS patients, this could potentially mean the reversal of disability, and with it the long dreamt of disposal of wheelchairs, walkers, and canes. We are still a long way from that lofty goal, however, but the first few steps along the path to that salvation are currently being taken.

Though stem cell research is advancing in laboratories worldwide, the science of using stem cells to treat diseases in humans is still in its infancy. Because multiple sclerosis is a neurodegenerative disease, and its most prominent feature is the damage the disease does to the central nervous system, it is hoped that stem cells may hold the key to reversing the carnage wrought by the disease by facilitating the repair of damaged nerve cells. Furthermore, research has provided hints that stem cells may modulate the abnormal immune response seen in MS patients, and some researchers are even using stem cells to completely reboot the human immune system, a process that in some cases appears to stop the disease dead in its tracks.

Its important to understand that there are two very different approaches to using stem cells in the treatment of multiple sclerosis. One approach hopes to use the cells to repair damaged nervous systems; the other uses stem cells to provide the patient with a brand-new immune system, one that theoretically will not turn against a patients own body. The latter approach is known as hematopoietic stem cell transplant, or HSCT, and has been used on patients in trial settings for almost two decades.

HSCT involves ablating (destroying) a patients existing immune system through the use of powerful chemotherapy drugs, and then intravenously infusing a patients own stem cells back into their body, a process depicted in the below diagram:

As you might imagine, using powerful chemotherapy drugs to destroy a patients immune system is not without its dangers, and early attempts at this therapy had mortality rates as high as 10%. As researchers perfected their methodology and began using less dangerous chemotherapy agents, though, the risks associated with HSCT dropped dramatically. Today, most patients undergoing HSCT are subjected to chemotherapy and immunosuppressive agents that do not completely destroy their bone marrow, and the safety profile of the procedure has improved impressively. The results achieved by this HSCT can be dramatic. In one study (click here) that looked at the long-term outcomes of HSCT, after 11 years 44% of patients who had started out with aggressive relapsing remitting disease were free from disability progression. By comparison, only 10% of those who did not display signs of active inflammation before HSCT remained stable.

One of the primary proponents of HSCT therapy for MS patients, Dr. Richard Burt of Northwestern University, stresses that the proper selection of patients is the key to the success of the treatment. In fact, the title of the paper he recently published (click here) includes the phrase if no inflammation, no response. Its the only therapy to date that has been shown to reverse neurologic deficits, said Dr. Burt, But you have to get the right group of patients. In a study published by Dr. Burt in 2009, 17 out of 21 relapsing remitting patients improved after HSCT, and after three years all patients were free from progression (click here). Dr. Burt is currently heading up the HALT-MS trial for HSCT (click here). There are several centers around the world offering HSCT therapy, and there is a Worldwide HSCT Facebook group (click here) that contains information on all of the legitimate HSCT facilities worldwide. The group is populated by many folks who have undergone HSCT therapy. Be aware that its a private group, and you must request membership before being given access to all of the available information.

While HSCT holds much promise for putting the brakes on very aggressive relapsing remitting multiple sclerosis, it unfortunately has little to offer those with progressive disease, and does nothing to directly repair the damage done to the central nervous system by MS. Fortunately, another form of stem cell therapy proposes to do just that. Researchers in two centers in the US have received FDA approval to use bone marrow derived mesenchymal stem cells (MSCs) to repair nervous system damage, thereby possibly reversing the effects of the disease. There are additional trials using MSCs to treat MS underway internationally. Mesenchymal stem cells have the ability to transform (differentiate) into many different cell types, and could prove to be the building blocks necessary for repairing damage to the central nervous system as well as other organs and tissues. Experiments using MSCs to treat animal models of MS have been very encouraging (click here), demonstrating the cells abilities to modulate the immune system and spur the repair of damaged nervous system tissues. It remains to be seen whether the same effects can be achieved when using the cells to treat human beings.

The two FDA approved studies both use MSCs harvested from a patients own bone marrow, but employ them in very different ways. One study, currently underway at the Cleveland Clinic (click here), infuses mesenchymal stem cells intravenously into the patient, in the expectation that the cells will modulate the immune system and also initiate the regeneration of damaged tissues in the central nervous system. This study, which will eventually use MSCs to treat 24 patients, is proceeding slowly, but as the above linked to article details, one of the first patients treated is already reporting encouraging results.

The second FDA approved trial, to be conducted by the Tisch MS Research Center of New York (which just so happens to be my MS clinic), will use mesenchymal stem cells that have been transformed through a proprietary laboratory process into neural progenitor (NP) cells, injected directly into the spinal fluid (intrathecally)) of the patient (click here). Neural progenitor cells are a specialized type of stem cell specific to the nervous system that have the ability to transform into the various types of tissues damaged and destroyed by the MS disease process. Researchers at the Tisch Center have developed a way to get mesenchymal stem cells to differentiate into neural progenitor cells, and hope that by injecting these cells directly into the spinal fluid the NP cells will directly target the regenerative mechanisms of the central nervous system (click here). The stem cells themselves may act to repair damaged tissues, but theyve also been shown to have the ability to recruit existing stem cells within the brain and spinal cord to jumpstart the bodys own repair mechanisms.

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Wheelchair Kamikaze: Stem Cell Treatments for Multiple ...

Stem cells lurking in tumors can resist treatment

IMAGE:Brain tumor stem cells (orange) in mice express a stem cell marker (green). Researchers at Washington University School of Medicine in St. Louis are studying how cancer stem cells make... view more

Credit: Yi-Hsien Chen

Scientists are eager to make use of stem cells' extraordinary power to transform into nearly any kind of cell, but that ability also is cause for concern in cancer treatment. Malignant tumors contain stem cells, prompting worries among medical experts that the cells' transformative powers help cancers escape treatment.

New research proves that the threat posed by cancer stem cells is more prevalent than previously thought. Until now, stem cells had been identified only in aggressive, fast-growing tumors. But a mouse study at Washington University School of Medicine in St. Louis shows that slow-growing tumors also have treatment-resistant stem cells.

The low-grade brain cancer stem cells identified by the scientists also were less sensitive to anticancer drugs. By comparing healthy stem cells with stem cells from these brain tumors, the researchers discovered the reasons behind treatment resistance, pointing to new therapeutic strategies.

"At the very least, we're going to have to use different drugs and different, likely higher dosages to make sure we kill these tumor stem cells," said senior author David H. Gutmann, MD, PhD, the Donald O. Schnuck Family Professor of Neurology.

The research appears online March 12 in Cell Reports.

First author Yi-Hsien Chen, PhD, a senior postdoctoral research associate in Gutmann's laboratory, used a mouse model of neurofibromatosis type 1 (NF1) low-grade brain tumors to identify cancer stem cells and demonstrate that they could form tumors when transplanted into normal, cancer-free mice.

NF1 is a genetic disorder that affects about 1 in every 2,500 babies. The condition can cause an array of problems, including brain tumors, impaired vision, learning disabilities, behavioral problems, heart defects and bone deformities.

The most common brain tumor in children with NF1 is the optic glioma. Treatment for NF1-related optic gliomas often includes drugs that inhibit a cell growth pathway originally identified by Gutmann. In laboratory tests conducted as part of the new research, it took 10 times the dosage of these drugs to kill the low-grade cancer stem cells.

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Stem cells lurking in tumors can resist treatment

Neuralstem announces topline results of Phase II ALS trial

GERMANTOWN, MD, March 12, 2015 -- Neuralstem, Inc. (NYSE MKT: CUR) announced top line data from the Phase II trial of NSI-566 spinal cord-derived neural stem cells under development for the treatment of amyotrophic lateral sclerosis (ALS). The study met primary safety endpoints. The maximum tolerated dose of 16 million transplanted cells and the surgery was well tolerated.

Secondary efficacy endpoints at nine months post-surgery indicate a 47% response rate to the stem cell treatment, as measured by either near-zero slope of decline or positive slope of ALSFRS score in seven out of 15 patients and by either a near-zero decline, or positive strengthening, of grip strength in seven out of 15 patients. Grip strength is an indicator of direct muscle strength of the lower arm. ALSFRS is a standard clinical test used to evaluate the functional status of ALS patients. The average ALSFRS score for responders at 9 months after treatment was 37. Non-responders scored an average of 14. These scores represent 93%, versus 35%, of the baseline score retained, respectively, by the responders versus non-responders at 9 months, which is a statistically significant difference. As measured by an average slope of decline of ALSFRS, responders' disease progression was -0.007 point per day, while non-responders' disease progression was -0.1 per day, which was again statistically significant. Lung function as measured by Seated Vital Capacity shows that responder patients remained within 94% of their starting scores, versus 71% for non-responder patients. The trial met its primary safety endpoints. Both the surgery and cells were well-tolerated, with one patient experiencing a surgical serious adverse event.

"In this study, cervical intervention was both safe and well-tolerated with up to 8 million cells in 20 bilateral injections," said Karl Johe, PhD, Neuralstem Chief Scientific Officer. "The study also demonstrated biological activity of the cells and stabilization of disease progression in a subset of patients. As in the first trial, there were both responders and non-responders within the same cohort, from patients whose general pre-surgical presentation is fairly similar. However, we believe that through the individual muscle group measurements, we may now be able to differentiate the responders from the non-responders.

"Our therapy involves transplanting NSI-566 cells directly into specific segments of the cord where the cells integrate into the host motor neurons. The cells surround, protect and nurture the patient's remaining motor neurons in those various cord segments. The approximate strength of those remaining motor neuron pools can be measured indirectly through muscle testing of the appropriate areas, such as in the grip strength tests. We believe these types of endpoints, measuring muscle strength, will allow us to effectively predict patients that will respond to treatment, adding a sensitive measure of the therapeutic effects after treatment. Testing this hypothesis will be one of the primary goals of our next trial." The full data is being compiled into a manuscript for publication.

"We believe the top-line data are encouraging," said Eva Feldman MD, PhD, Director of the A. Alfred Taubman Medical Research Institute and Director of Research of the ALS Clinic at the University of Michigan Health System, and an unpaid consultant to Neuralstem. "We were able to dose up to 16 million cells in 40 injections, which we believe to be the maximum tolerated dose. As in the first trial, the top-line data show disease stabilization in a subgroup of patients. Perhaps equally as important, we believe the top-line data may support a method of differentiating responders from non-responders, which we believe will support our efforts as we move into the next, larger controlled trial expected to begin this summer."

"The top-line data look very positive and encouraging. If this proportion of patients doing well after treatment can be corroborated in future therapeutic trials, it will be better than any response seen in any previous ALS trials," said site principal investigator, Jonathan D. Glass, MD, Director of the Emory ALS Center. "Elucidating which factors define a patient who may have a therapeutic response to the stem cell treatment will be the next key challenge. We are hopeful that a set of predictive algorithms can be established to help pre-select the responders in our future trials."

"We were very excited to participate as a site in this clinical trial," said Merit Cudkowicz, MD, Chief of Neurology, Massachusetts General Hospital and Co-Chair of the Northeast ALS Consortium (NEALS). "We are hopeful with respect to the top-line results and we need to move swiftly and safely forward to confirm the responder effect and identify people who might benefit from this treatment approach."

The open-label, dose-escalating trial treated 15 ambulatory patients, divided into 5 dosing cohorts, at three centers, Emory University Hospital in Atlanta, Georgia, the ALS Clinic at the University of Michigan Health System, in Ann Arbor, Michigan, and Massachusetts General Hospital in Boston, Massachusetts, and under the direction of principal investigator (PI), Eva Feldman, MD, PhD, Director of the A. Alfred Taubman Medical Research Institute and Director of Research of the ALS Clinic at the University of Michigan Health System. Dosing increased from 1 million to 8 million cells in the cervical region of the spinal cord. The final trial cohort also received an additional 8 million cells in the lumbar region of the spinal cord.

The company anticipates commencing a later-stage, multicenter trial of NSI-566 for treatment of ALS in 2015. Neuralstem has received orphan designation by the FDA for NSI-566 in ALS.

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Neuralstem announces topline results of Phase II ALS trial

UCLA Research Shows Promising Method For Correcting Genetic Code To Treat Sickle Cell Disease

Posted: Thursday, March 12, 2015 7:08 PM

UCLA stem-cell researchers have shown that a novel stem-cell gene therapy method could one day provide a one-time, lasting treatment for the most common inherited blood disorder in the U.S. sickle cell disease. Publishedin the journal Blood, the study outlines a method that corrects the mutated gene that causes sickle cell disease and shows, for the first time, the gene correction method leads to the production of normal red blood cells. The study was directed by renowned stem cell researcher and UCLA Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research member, Dr. Donald Kohn.

People with sickle cell disease are born with a mutation in their beta-globin gene, which is responsible for delivering oxygen to the body through blood circulation. The mutation causes blood stem cellswhich are made in the bone marrowto produce distorted and rigid red blood cells that resemble a crescent or sickle shape. Consequently, the abnormally shaped red blood cells do not move smoothly through blood vessels, resulting in insufficient oxygen supply to vital organs. Anyone can be born with sickle cell disease, but it occurs more frequently in African Americans and Hispanic Americans.

The stem-cell gene therapy method described in the study seeks to directly correct the mutation in the beta-globin gene so bone marrow stem cells then produce normal, circular-shaped blood cells that do not sickle. The fascinating gene correction technique used specially engineered enzymes, called zinc-finger nucleases, tocut out the mutated genetic code and replace it with a corrected version that repairs the beta-globin mutation.

For the study, bone marrow stem cells donated by people with the sickle cell gene mutation were treated in the laboratory with the zinc-finger nucleases enzyme cutting method.Kohn and his team then demonstrated in mouse models that thecorrected bone-marrow stem cells have the capability to replicate successfully. The research showed that the method holds the potential to permanently treat the disease if a higher level of correction is achieved.

This is a very exciting result,said Dr. Kohn, professor of pediatrics atUCLAs David Geffen School of Medicine, professor of microbiology, immunology and molecular genetics in Life Sciences at UCLA, member of the UCLA Childrens Discovery and Innovation Institute at Mattel Childrens Hospital and senior author on the study. It suggests the future direction for treating genetic diseases will be by correcting the specific mutation in a patients genetic code. Since sickle cell disease was the first human genetic disease where we understood the fundamental gene defect,and since everyone with sickle cell has the exact same mutation in the beta-globin gene, it is a great target for this gene correction method.

To make the cut in the genetic code, Dr. Kohn and his team used zinc-finger nucleases engineered by Sangamo BioSciences, Inc., in Richmond. The enzymes can be designed to recognize a specific and targeted point in the genetic code. For the study, scientists at Sangamo BioSciences engineered the enzymes to create a cut at the site of the mutated genetic code that causes sickle cell disease. This break triggered a natural process of repair in the cell and at the same time, a molecule containing the correct genetic code was inserted to replace the mutated code.

The next steps in this research will involve improving the efficiency of the mutation correction process and performing pre-clinical studies to demonstrate that the method is effective and safe enough to move to clinical trials.

Symptoms of sickle cell disease usually begin in early childhood and include a low number of red blood cells (anemia), repeated infections and periodic episodes of pain. People with sickle cell disease typically have a shortened lifespan of just 36-40 years of age. The disease impacts more than 250,000 new patients worldwide each year. The only cure currently available for sickle cell disease is a transplant of bone marrow stem cells from a matched sibling, but matches are rare or can result in rejection of the transplanted cells.

This is a promising first step in showing that gene correction has the potential to help patients with sickle cell disease, said Megan Hoban, a senior graduate student in microbiology, immunology and molecular genetics and first author on the study. The study data provide the foundational evidence that the method is viable.

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UCLA Research Shows Promising Method For Correcting Genetic Code To Treat Sickle Cell Disease

Repairing the cerebral cortex: It can be done

A team led by Afsaneh Gaillard (Inserm Unit 1084, Experimental and Clinical Neurosciences Laboratory, University of Poitiers), in collaboration with the Institute of Interdisciplinary Research in Human and Molecular Biology (IRIBHM) in Brussels, has just taken an important step in the area of cell therapy: repairing the cerebral cortex of the adult mouse using a graft of cortical neurons derived from embryonic stem cells. These results have just been published in Neuron.

The cerebral cortex is one of the most complex structures in our brain. It is composed of about a hundred types of neurons organised into 6 layers and numerous distinct neuroanatomical and functional areas.

Brain injuries, whether caused by trauma or neurodegeneration, lead to cell death accompanied by considerable functional impairment. In order to overcome the limited ability of the neurons of the adult nervous system to regenerate spontaneously, cell replacement strategies employing embryonic tissue transplantation show attractive potential.

A major challenge in repairing the brain is obtaining cortical neurons from the appropriate layer and area in order to restore the damaged cortical pathways in a specific manner.

The results obtained by Afsaneh Gaillard's team and that Pierre Vanderhaeghen at the Institute of Interdisciplinary Research in Human and Molecular Biology show, for the first time, using mice, that pluripotent stem cells differentiated into cortical neurons make it possible to reestablish damaged adult cortical circuits, both neuroanatomically and functionally.

These results also suggest that damaged circuits can be restored only by using neurons of the same type as the damaged area.

This study constitutes an important step in the development of cell therapy as applied to the cerebral cortex.

This approach is still at the experimental stage (laboratory mice only). Much research will be needed before there is any clinical application in humans. Nonetheless, for the researchers, "The success of our cell engineering experiments, which make it possible to produce nerve cells in a controlled and unlimited manner, and to transplant them, is a world first. These studies open up new approaches for repairing the damaged brain, particularly following stroke or brain trauma," they explain.

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The above story is based on materials provided by INSERM (Institut national de la sant et de la recherche mdicale). Note: Materials may be edited for content and length.

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Repairing the cerebral cortex: It can be done