Focus Feature on Neuroscience: Intriguing approaches to Parkinson’s disease

In this feature focused on neuroscience and neurology, we look at Parkinson's disease in particular, but also explore Alzheimer's disease, artificial nervous systems, AI-based diagnostics and more

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Focus Feature: Neuroscience/Neurology
Intriguing approaches to Parkinson’s disease
Gene therapy, stem cells, the microbiome and more open up a world of novel approaches to PD
By Jeffrey Bouley
With so many relatively new avenues of potential therapeutics opening up as technologies have improved and novel tech has entered the scene, it’s no longer just small molecule vs. large molecule or similarly limited options for the myriad diseases that vex humanity.
Antibody therapies, antibody-drug conjugates and gene editing are just a handful of the many choices recent years have brought to life-sciences research.
And here in this Focus Feature on Neuroscience, we will explore a few novel arenas that use gene therapy, kinase and protein inhibition, stem cells and microbiome approaches to potentially treat Parkinson’s disease (PD).
A ‘SUNRISE’ to bring light for PD sufferers
Axovant Gene Therapies Ltd., a clinical-stage company developing innovative gene therapies, in June reported six-month follow-up data from the first dose cohort in the open-label, dose-escalation portion of the ongoing SUNRISE-PD Phase 2 trial of AXO-Lenti-PD for the treatment of Parkinson’s disease.
“We continue to be encouraged by the consistency of the data and improvements in quality of life seen at six months in the two low-dose cohort patients, as we enroll additional patients in the second cohort of the SUNRISE-PD study,” said Dr. Gavin Corcoran, Axovant’s chief research and development officer. “Our patient-focused goal of improving motor function, reducing dyskinesia, lowering the requirement for oral levodopa, and improving quality of life is made possible by the continuous dopamine replacement strategy of AXO-Lenti-PD gene therapy. These data at six months highlight the potential for a clinically meaningful improvement over the currently available standard of care for those patients with moderate to advanced Parkinson’s disease.”
AXO-Lenti-PD was observed to be generally well tolerated, with no serious adverse events related to the product or the procedure, and patients showed continued improvement from baseline across multiple measurements.
The Parkinson’s Disease Questionnaire-39 (PDQ-39) Summary Index score, a patient and caregiver reported quality of life measure, was recorded at baseline, month three and month six. The average score at baseline was 50 points, which at month three had improved to an average score of 31 points (a reduction of 19 points from baseline). At month six, the average PDQ-39 Summary Index score was further improved to 18 points (a reduction of 32 points from baseline).
These scores demonstrate an approximate 37-percent improvement from baseline at month three and an approximate 65-percent improvement from baseline at month six.
According to Axovant, “These reductions in total score at both three and six months appear to indicate a substantial clinical benefit in this quality of life measure.”
“Our focus in this first cohort of the SUNRISE-PD study was on the safety and tolerability of AXO-Lenti-PD, as well as the evaluation of efficacy using well-validated, objective measures. These early data support the safety of the lowest dose of AXO-Lenti-PD, similar to what was observed with the earlier generation construct, ProSavin, and also suggest substantially greater biological activity than the highest dose of ProSavin previously tested,” said Dr. Gavin Corcoran, Axovant’s executive vice president of research and development, when the company reported three-month follow-up data for SUNRISE-PD in March. “These findings are highly encouraging, and we look forward to advancing to higher dose cohorts where we will explore the full clinical potential of AXO-Lenti-PD in patients with Parkinson’s disease.”
Also with regard to the March update, Dr. Roger Barker, one of the principal investigators on SUNRISE-PD, noted: “This early data suggests that AXO-Lenti-PD has the potential to significantly improve motor function in patients with advancing Parkinson’s disease. The mechanism of action of AXO-Lenti-PD, which is designed to deliver all three genes necessary for endogenous dopamine biosynthesis, as well as our prior clinical experience with ProSavin, led us to expect that the major benefit would be in improving the ‘off’ state—and the results so far are very encouraging in this regard.”
“Off” times are motor fluctuations when medication—usually levodopa, which is the current gold-standard treatment for PD—is not working optimally and Parkinson’s symptoms (both motor and/or non-motor) return. Off periods are more common as the disease progresses and people take medication for a longer period of time.
French companies team up on new line of research
Servier and Oncodesign announced this spring a strategic partnership for the research and development of potential drug candidates for Parkinson’s disease, particularly around LRRK2 kinase inhibitors. These inhibitors are derived from Oncodesign’s proprietary Nanocyclix platform and are hoped to have potential to act as therapeutic agents against PD.
The partnership draws on the complementary expertise of Servier and Oncodesign in the field of neurodegenerative diseases and macrocyclic kinase inhibitors, the companies say. Oncodesign will be responsible for the research program up to the selection of preclinical candidates, notably at its research site in Les Ulis, France.
The program will be funded in its entirety by Servier, which has been granted an exclusive worldwide licensing option on the program. This can be exercised once IND status is obtained. Oncodesign will receive an initial payment of €3 million upon signing the partnership agreement, followed by other significant milestone payments until the validation of entry into Phase 1. In addition, Oncodesign will receive €3 million in annual funding for research activities related to the project. All in all, Servier could pay Oncodesign up to €320 million (about $360 million) in milestone payments, excluding royalties.
“This partnership is a result of the choices and investments that we have made over the past 18 months to put together a portfolio of promising drug candidates derived from our Nanocyclix platform. The pharmaceutical industry is currently showing a keen interest in new treatments for Parkinson’s disease, particularly around LRRK2 kinase, which is considered as a high-potential target for treating this disease,” said Dr. Philippe Genne, CEO and founder of Oncodesign. “Servier’s expertise will be a key asset in the early stage of this research agreement with regard to successfully carrying out the program which, in the medium term, could lead to the development of new drug candidates. Moreover, this partnership means we can channel our own financial resources into developing our three other proprietary programs: RIPK2, ALK1 and MNK1.”
Added Dr. Jan Hoflack, scientific director and director of operations at Oncodesign: “The only therapies currently available for Parkinson’s patients aim to alleviate the symptoms of the disease. LRRK2 inhibitors have the potential to act directly on the progression of the disease, which would result in improved living standards for patients. This agreement with Servier, a company that is invested in researching neurological conditions and has partnered with Oncodesign in the past, represents an important step towards meeting our goal of offering a real benefit to society through precision medicine.”
Heading PD off at the pass
Also in the theme of inhibition, University of Dundee researchers at the U.K. university’s Drug Discovery Unit (DDU) have partnered with Bukwang Pharmaceutical Co. to tackle a new drug treatment for Parkinson’s disease. In this case, though, the “inhibition” they are looking for is to keep a certain bad actor from accumulating in the brain.
A key biological event in the development of PD is the accumulation and misfolding of a small protein in the brain called α-synuclein, which can kill nerve cells, and research at the University of Oxford has shown that an enzyme, USP8, prevents the natural breakdown of α-synuclein.
Working in collaboration with Dr. George Tofaris at Oxford, the DDU has identified a series of drug-like molecules that block USP8 and could reduce the levels of α-synuclein in the brain, potentially providing a true treatment for Parkinson’s disease.
“Finding treatments that target the alpha-synuclein protein holds promise for one day slowing or stopping the progression of Parkinson’s—something no current treatment can do,” noted Dr. Beckie Port, research manager at Parkinson’s UK. “It’s an exciting time for Parkinson’s research. Our increased understanding of the biology of the condition means we’re now at a stage to turn our wealth of knowledge into much-needed treatments for people with Parkinson’s.”
The partnership with Bukwang Pharm strengthens an existing Dundee-Oxford relationship, which has been supported by the Medical Research Council. Bukwang Pharm will facilitate a further three-year program of work at Dundee and Oxford to advance these drug-like molecules toward clinical development.
The aim is to formulate much-needed therapies for PD and other diseases where α-synuclein pathology is implicated. Bukwang Pharm holds an exclusive option to acquire worldwide development and commercialization rights of resulting novel molecules.
“We are delighted to be announcing this partnership with Bukwang Pharm. Drug discovery for neurological disorders is especially challenging and an area where academia and industry need to be working together,” said Prof. Paul Wyatt, head of the DDU. “This project brings together the clinical and translational research expertise in Oxford with Dundee’s professional drug discovery capabilities allowing us to move one stage further towards a treatment.”
Stem cells vs. Parkinson’s
A paper that appeared in the Journal of Parkinson’s Disease titled “Repairing the Brain: Cell Replacement Using Stem Cell-Based Technologies” suggests that cell replacement therapies in which dopamine-producing stem cells are transplanted into PD patients could improve motor symptoms, reducing or eliminating the need for dopaminergic medicines
Current treatments for PD tend to focus on increasing dopamine levels in the brain in order to relieve motor symptoms, but the effectiveness of these treatments declines the longer they are used, and they come with various side effects.
“We are in desperate need of a better way of helping people with [Parkinson’s disease]. It is on the increase worldwide. There is still no cure, and medications only go part way to fully treat incoordination and movement problems,” said Drs. Claire Henchcliffe and Malin Parmar, co-authors of the paper, in a news release about their study. Their thought is that a better long-term treatment might be to transplant dopamine-producing stem cells into patients’ brains.
“If successful ... a single surgery could potentially provide a transplant that would last throughout a patient’s lifespan, reducing or altogether avoiding the need for dopamine-based medications,” Henchcliffe and Parmar noted.
It will likely be a long road to becoming a routine and successful procedure, though. Data from published studies about such stem cell transplantation using fetal cells have been promising, the authors explain, but concerns have been raised regarding the heterogeneity of clinical outcomes reported. Some of the factors that might cause this lack of heterogeneity include inconsistency in cell preparation, cell number and cell composition, issues related to patient selection, the method used for immunosuppression and duration of said immunosuppression, as well as varying outcome measures and study durations.
Also, ethical concerns exist over using cells from aborted fetuses, and so methods such as shifting to induced pluripotent stem cells are likely to be necessary.
Going for the gut in PD treatment
Axial Biotherapeutics, a biotechnology company dedicated to building a unique class of gut-targeted programs for neurodegenerative and neuropsychiatric diseases, announced earlier this year the completion of a $25-million series B equity financing. The new funding will be used to advance Axial’s programs in PD as well as autism spectrum disorder (ASD)—both programs include small molecules targeting the gut-brain axis.
Axial’s PD program, which evaluates organisms and genes over-represented in the PD gut-microbiome, has resulted in the identification of a pathway that is sufficient to induce motor and GI symptoms and brain pathology in a validated, preclinical PD model, according to the company.
The program includes both AB-4166 and the AB-4000 series. AB-4166 is a first-in-class intervention that is currently being evaluated for safety and tolerability in a subpopulation of PD subjects. Axial’s PD program has also identified multiple novel chemical entities in the AB-4000 series which are being developed to have improved selectivity as potential next-generation drug candidates for PD and other neurodegenerative diseases.
Axial’s program in ASD is focused on research which demonstrates that reducing systemic and brain exposure to problematic microbial metabolites may improve core and non-core ASD symptoms related to behavior and gut health. The company’s lead product, AB-2004, is a drug candidate that has demonstrated, in animal models, the ability to repair leaky gut and improve repetitive behavior, anxiety and ASD-related sensorimotor gating deficits by removing key microbial metabolites. AB-2004 is expected to enter a Phase 1b/2a clinical trial in ASD adolescents in the first quarter of 2019.
Next-gen Parkinson’s therapy
And finally, as a little bonus, since it falls outside the usual chemical, biological and genetic modalities we cover, we have news that researchers at the University of Houston recently found neuro-biomarkers for Parkinson’s disease that they believe can help create the next generation of “smart” deep brain stimulators, able to respond to specific needs of PD patients.
People with  PD sometimes undergo high-frequency brain stimulation, an established therapy for the progressive nervous system disorder that affects movement. However, such therapy has been imprecise.
Currently, stimulators can only be programmed clinically and are not adaptable to the fluctuating symptoms of the disease. They newly identified biomarkers are key to improving the technology to make it responsive—that is, to make it a “smart” system.
“We can now make the closed-loop stimulator adaptive to sense a patient’s symptoms, so it can make the adjustments to the fluctuations in real time, and the patient no longer has to wait for weeks or months until the doctor can adjust the device,” said Nuri Ince, associate professor of biomedical engineering. He and doctoral student Musa Ozturk, lead author of the paper, published their findings in the journal Movement Disorders.

Progress with Alzheimer’s disease
Prior to the July start of the Alzheimer’s Association International Conference in Los Angeles this year, Canaccord Genuity biotechnology analyst Sumant Kulkarni noted that the meeting would be in the shadow of yet another high-profile setback in the area of Alzheimer’s disease (AD) therapy research and development, following the failure of Biogen and Eisai’s aducanumab.
As he noted, though, there remains plenty of activity, with 70 AD products in clinical development, of which 60 percent are small molecules and 40 percent are biologics. He also pointed out that there are almost the same number of molecules that rely on the amyloid-beta, anti-tau and anti-inflammation approaches, with 16, 13 and 13, respectively, while the remainder rely on other approaches (including combinations).
“Separately, the amyloid beta hypothesis is hanging by a thread after some spectacular/expensive failures,” Kulkarni acknowledged, “but it remains the single largest category in terms of the number of products still using that approach. But we are already seeing signs of this changing going forward.”
With that as a backdrop, let’s take a look at some recent news related to the fight to slow or stop disease progression in AD.
Samus launches PU-AD clinical program
BOSTON—Samus Therapeutics Inc. recently initiated its clinical program for PU-AD, an oral, brain-permeable inhibitor of epichaperomes in AD following clearance of its Investigational New Drug application by the U.S. Food and Drug Administration (FDA). Samus is a privately held biopharmaceutical company developing multiple novel therapeutics targeting epichaperomes to induce degradation of aberrant proteins driving the pathology of neurodegenerative disease and cancer.
PU-AD is designed to inhibit epichaperomes, complexes of regulatory networks that nucleate on heat shock protein 90 (Hsp90) in diseased cells and maintain and drive the pathologic cellular phenotype. Epichaperomes protect against the degradation of mutated and aberrant proteins, such as tau, enabling them to stabilize and aggregate. The presence of epichaperomes has been found to contribute to, or possibly initiate, many neurodegenerative diseases, including AD.
“Epichaperomes play a critical role in the pathogenesis and characteristics of neurodegenerative diseases and cancers,” said Dr. Gabriela Chiosis, a co-founder of Samus Therapeutics. “Targeting epichaperomes represents one of the most novel and exciting new pathways toward finding new treatments for these diseases.”
PU-AD specifically inhibits epichaperomes, eliminating aggregation and hyperphosphorylation of tau, affects downstream events associated with the disease, and initiates degradation of mutant tau by a mechanism distinct from other protein degradation platforms. PU-AD reportedly has negligible effect, if any, on housekeeping Hsp90 in normal cells.
Samus’ clinical program will begin with a single ascending dose Phase 1 study to evaluate the safety and tolerability of PU-AD in healthy subjects, with the first subject now dosed, and is expected to be followed by a multiple ascending dose cohort. Assuming the expeditious completion of this study, the company would begin PU-AD clinical testing of Alzheimer’s patients in Phase1b/2a in the first half of 2020.
Better understanding disease progression in familial Alzheimer’s disease
LAUSANNE, Switzerland—AC Immune SA, a clinical-stage biopharmaceutical company with a broad pipeline focused on neurodegenerative diseases, has announced that Genentech, a member of the Roche Group, has initiated a substudy in the ongoing Phase 2 Alzheimer’s Prevention Initiative (API) trial of AC Immune’s investigational candidate, crenezumab. The substudy, which measures tau burden using positron emission tomography, aims to increase the understanding of disease progression in the preclinical stage of autosomal dominantly inherited Alzheimer’s disease (familial AD).
Learning more about the early distribution and severity of amyloid beta- and tau-related pathology in AD is imperative in developing successful Alzheimer’s treatments, says Prof. Andrea Pfeifer, CEO of AC Immune, who added: “This new substudy will provide further evidence on the progression of familial AD by monitoring for changes in tau burden and help examine the potential role of crenezumab as a disease-modifying agent that may prevent the onset or slow progression in people at risk of developing familial AD.”
The substudy will evaluate the effect of crenezumab on the longitudinal tau burden in a subgroup of presymptomatic Presenilin1 (PSEN1) E280A mutation carriers and non-carriers enrolled in API, a landmark study in Colombia to slow or prevent the decline of cognitive and functional abilities in people at risk of developing familial AD. The PSEN1 E280A mutation (or Paisa mutation) is by far the most common cause of familial early-onset Alzheimer’s disease.
The API trial in Colombia, which began in 2013 and for which data are expected in the first quarter of 2022, is in cognitively healthy individuals with an autosomal dominant PSEN1 E280A mutation, which puts them at high risk of developing familial AD. This study will determine whether treating people carrying this mutation with crenezumab prior to the onset of AD symptoms will slow or prevent the decline of cognitive and functional abilities.
“Treating earlier and testing in homogeneous populations are two important elements in AC Immune’s Roadmap to success, and both strategies are being applied in the API trial. Testing therapeutics in a homogeneous group in people carrying the PSEN1 E280A mutation earlier in the preclinical development phase may make it possible to identify successful treatment strategies for treating this debilitating disease,” Pfeifer noted.
Although the amyloid beta hypothesis for AD has taken some hits recently due to high-profile failure of clinical trials targeting amyloid beta, AC Immune points out that many leaders in the field remain convinced that amyloid beta plays an important role in the initiation of AD, with the company saying, “It is widely believed to be possible that studies to date have not intervened early enough or during the period before patients become symptomatic. As such, there may be an opportunity for early intervention with an investigational therapy such as crenezumab.”
Brain wave stimulation may improve AD symptoms
CAMBRIDGE, Mass.—By exposing mice to a unique combination of light and sound, neuroscientists at the Massachusetts Institute of Technology (MIT) have shown that they can improve cognitive and memory impairments similar to those seen in Alzheimer’s patients.
This noninvasive treatment, which works by inducing brain waves known as gamma oscillations, also greatly reduced the number of amyloid plaques found in the brains of these mice. Plaques were cleared in large swaths of the brain, including areas critical for cognitive functions such as learning and memory.
“When we combine visual and auditory stimulation for a week, we see the engagement of the prefrontal cortex and a very dramatic reduction of amyloid,” said Li-Huei Tsai, director of MIT’s Picower Institute for Learning and Memory and the senior author of the study.
Further study will be needed, she says, to determine if this type of treatment will work in human patients. The researchers have already performed some preliminary safety tests of this type of stimulation in healthy human subjects.
The brain’s neurons generate electrical signals that synchronize to form brain waves in several different frequency ranges. Previous studies have suggested that Alzheimer’s patients have impairments of their gamma-frequency oscillations, which range from 25 to 80 hertz (cycles per second) and are believed to contribute to brain functions such as attention, perception and memory.
Creating an ‘artificial nervous system’
SINGAPORE—Researchers at the National University of Singapore (NUS) have developed something called Asynchronous Coded Electronic Skin (ACES), an “e-skin” that could enable robots to have a sophisticated sense of touch for nimbleness and better fine motor movements, but could also be used potentially in prosthetics for humans.
Essentially, what the NUS scientists did was to create an artificial nervous system inspired by the human nervous system that that can detect touch 1,000 times faster than the human nervous system. Also, the system reportedly can accurately identify the shape, texture and hardness of objects within 10 milliseconds, which is 10 times faster than the blinking of an eye.
The e-skin detects signals and differentiates physical contact like a human being. But unlike nerve bundles in human skin, the electronic nervous system is made of a network of sensors, connected with a single electrical conductor.
Pairing ACES with a special transparent and water-resistant sensor layer also recently developed by the team creates an electronic skin that can self-repair like the human skin. This type of electronic skin, NUS notes, could be used to develop more realistic prosthetic limbs that will help disabled individuals restore their sense of touch.  
In addition to looking into such applications as part of the next stage of their research, the NUS team is also keen to explore robotic applications like developing more intelligent robots that can perform disaster recovery tasks or take over mundane operations such as packing of items in warehouses.

Neurodegenerative diseases identified using AI
NEW YORK—Researchers have developed an artificial intelligence (AI) platform to detect a range of neurodegenerative disease in human brain tissue samples, including Alzheimer’s disease and chronic traumatic encephalopathy, according to a study conducted at the Icahn School of Medicine at Mount Sinai and published in the medical journal Laboratory Investigation. Their discovery may help scientists develop targeted biomarkers and therapeutics, resulting in a more accurate diagnosis of complex brain diseases that improve patient outcomes.
The buildup of abnormal tau proteins in the brain in neurofibrillary tangles is a feature of Alzheimer’s disease, but it also accumulates in other neurodegenerative diseases, such as chronic traumatic encephalopathy and additional age-related conditions. Accurate diagnosis of neurodegenerative diseases is challenging and requires a highly-trained specialist.
Researchers at the Center for Computational and Systems Pathology at Mount Sinai developed and used the Precise Informatics Platform to apply powerful machine learning approaches to digitized microscopic slides prepared using tissue samples from patients with a spectrum of neurodegenerative diseases. Applying deep learning, these images were used to create a convolutional neural network capable of identifying neurofibrillary tangles with a high degree of accuracy directly from digitized images.
“Utilizing artificial intelligence has great potential to improve our ability to detect and quantify neurodegenerative diseases, representing a major advance over existing labor-intensive and poorly reproducible approaches,” said lead investigator Dr. John Crary, a professor of pathology and neuroscience at the Icahn School of Medicine. “Ultimately, this project will lead to more efficient and accurate diagnosis of neurodegenerative diseases.”
This is said to be the first framework available for evaluating deep-learning algorithms using large-scale image data in neuropathology. The Precise Informatics Platform allows for data managements, visual exploration, object outlining, multi-user review and evaluation of deep-learning algorithm results.

Emerald Health demonstrates neuroprotective activity of novel CBGA derivatives
SAN DIEGO—Emerald Health Pharmaceuticals Inc. (EHP), a clinical-stage company developing medicines based on cannabinoid science, presented preclinical data for its drug product candidate, EHP-102, an oral formulation of a patented cannabigerol (CBG)-derived new chemical entity (NCE), as well as other novel CBG acid (CBGA) derivatives for the treatment of Huntington’s disease (HD) and Parkinson’s disease (PD) at the 29th Annual Symposium of the International Cannabinoid Research Society (ICRS) in Bethesda, Md.
The data presented compared the in-vivo activity of two of EHP’s novel CBGA derivatives—CBGA-quinone (CBGA-Q) and its water-soluble sodium salt (CBGA-Q-Na Salt) —to EHP-102, the company’s preclinical-stage development candidate, which has previously demonstrated significant benefits in several models of PD and HD.
The preclinical findings demonstrated that oral administration of EHP-102 has potential in PD and HD due to its anti-inflammatory and neuroprotective properties specific to these diseases. The CBGA derivatives also showed anti-inflammatory and neuroprotective effects; however, EHP-102 showed significantly better effects on various parameters compared to the other two molecules. The data were reported in a poster titled “Comparison of the neuroprotective activity of cannabigerol derivatives in Huntington’s and Parkinson’s disease models.”
“Patients with Huntington’s disease and Parkinson’s disease suffer from devastating physical and psychological symptoms,” said Dr. Jim DeMesa, CEO of Emerald Health Pharmaceuticals. “There is currently no cure for these diseases, and so the results of the studies conducted by our scientific team and collaborators, which demonstrate the possible disease-modifying potential of EHP-102 and some of our other CBG-derivatives, are very encouraging as potential therapeutic treatments for these patients in the future.”
Oral EHP-102, CBGA-Q and CBGA-Q-Na Salt all alleviated clinical symptoms and the loss of neurons, as well as inhibited the expression of proinflammatory cytokines in a HD murine model induced by 3-nitropropionic acid. Oral CBGA-Q and EHP-102 also improved the behavioral deficits in a mouse PD model induced by 6-hydroxydopamine and prevented the loss of neurons in the brain. EHP-102, however, showed statistically superior effects compared to both other molecules in several of the parameters measured in each model.
Based on the superior results of EHP-102 as compared to the other two molecules, EHP is currently advancing manufacturing and formulation work on EHP-102 in preparation for initiating the non-clinical studies required to advance to clinical development in both HD and PD.

Stem cell line shows potential in helping recover motor function after a stroke
DURHAM, N.C.—Results of a Phase 1 clinical trial reported recently in STEM CELLS Translational Medicine have identified a specific line of human neural stem cells that shows potential for helping recover motor function in those who suffer a hemiparetic stroke (where one side of the body is left weak or paralyzed).
NSI-566 human neural stem cells were implanted adjacent to the stroke lesion in nine subjects at doses up to 72 million cells per subject, and subjects were followed for 24 months. Cells appeared to survive long-term, and patients in the single-arm trial showed improvements in motor function following cell transplantation. This indicates the procedure is safe and may have potential to provide benefit to patients with motor deficits from stroke.
Strokes are a major cause of prolonged neurological disability worldwide, and no effective therapies currently exist that will reverse the damage. Several different cell types have been proposed and tested in preclinical models and clinical trials to treat neurological conditions, but few have shown significant properties to differentiate into genuine brain cells or the capability to integrate into central nervous system tissue.
One cell type that has been exhibiting some success is the NSI-566 cell line from Neuralstem Inc. NSI-566 is an epigenetically expanded line of primary human neural stem cells isolated from a single fetal spinal cord tissue. Ongoing clinical trials in the United States for treating amyotrophic lateral sclerosis and spinal cord injury have provided evidence that NSI-566 can survive in patients for at least 2.5 years and may have the potential to provide clinical benefit. To date, there have been no major side effects reported.
That information prompted the research team—led by Dr. Karl K. Johe of Neuralstem and Dr. Ruxiang Xu of the Affiliated BaYi Brain Hospital in Beijing—to ponder whether NSI-566 might help stroke patients, too.
“To the best of our knowledge, this is the first study to assess the feasibility and safety of transplanting non-immortalized human neural stem cells into stroke brain in chronic stage. Another objective was to determine the maximum tolerated dose into the peri-infarct sites in these patients,” Johe said.
Nine men and women between the ages of 30 and 65 were selected for the study. All had some level of hemiparesis due to stroke. Eight experienced moderate impairment (they required some help but were able to walk without assistance), while the ninth was moderately severe (unable to walk without assistance and could not self-care). Subjects were given NSI-566 between five and 24 months after the time of stroke.
The patients were divided into three equal groups, with each group administered a different dose of the stem cell line. The patients were then followed for 24 months.
“At the end of that period, we saw that transplantation of the NSI-566 cells was being well tolerated and it suggested preliminary clinical benefits. Results from imaging studies indicate new neural tissue formation in the stem cell implantation area of all nine patients,” noted Xu.
Added Johe: “The results suggest that grafted NSI-566 continue to survive in the stroke lesion long after cessation of immunosuppressant, and that the potential clinical effects persist throughout the 24-month observation period. Although this was a small, one-arm study of feasibility, the results are encouraging to warrant further studies.”

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