Stem Cell Clinic

Researchers Discovers Cell in Zebrafish Critical to Brain Assembly and Function – Technology Networks

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New research from Oregon Health & Science University for the first time documents the presence of astrocytes in zebrafish, a milestone that will open new avenues of research into a star-shaped type of glial cell in the brain that is critical for nearly every aspect of brain assembly and function.

The research was published this week in the journal Nature Neuroscience.

With their transparent bodies, zebrafish larvae provide a unique opportunity to gaze into the inner workings of the central nervous system, including the brain, even in living animals. The identification of astrocytes and the generation of tools to work with them in zebrafish will enable researchers around the world to open new lines of research to advance scientific understanding of how astrocytes function.

Astrocytes, it turns out, are the most abundant and mysterious cell type in the human brain, and OHSU is becoming a hub for research into their roles in development, brain function and disease.

"There is no neurodegenerative disease that I know of where astrocytes are not profoundly affected in some way," said senior author Kelly Monk, Ph.D., professor and co-director of the Vollum Institute at OHSU. "This gives us a powerful tool to get a handle on what these cells do and how they do it."

Monk and co-author Marc Freeman, Ph.D., credit lead author Jiakun Chen, Ph.D., a post-doctoral researcher in the Monk and Freeman labs, with developing a panoply of tools, including a cell-specific approach using the gene editing tool CRISPR to label and manipulate astrocyte precursors and incisively study their development and functions.

"He was able to capture the birth of an astrocyte from a stem cell and its entire development, which has never been visualized before in a vertebrate animal," Monk said.

Freeman said the discovery will dramatically enhance the study of how glia regulate brain development and physiology.

"This opens the door to experiments that you can't do in any other organism," Freeman said. "Zebrafish is the only animal in which you can now live-image all types of vertebrate glial cellsastrocytes, microglia, oligodendrocytes and OPCsalong with any neuron in intact neural circuits, from the earliest stages of development. Zebrafish is also the only vertebrate in which you can image the entire brain in live, behaving animals to figure out how it works. Understanding the role of these cells (astrocytes) in brain development will be key to understanding devastating neurodevelopmental disorders like autism spectrum disorder and schizophrenia.

"It's a major step forward and should power a lot of exciting work in the coming years."

Reference: Jiakun Chen, Kira E. Poskanzer, Marc R. Freeman & Kelly R. Monk. Live-imaging of astrocyte morphogenesis and function in zebrafish neural circuits, Nature Neuroscience,2020. DOI: 10.1038/s41593-020-0703-x

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Researchers Discovers Cell in Zebrafish Critical to Brain Assembly and Function - Technology Networks

Brain Organoids Reveal the Early Stages of Angelman Syndrome – Technology Networks

Image of a human cerebral organoid at 9 weeks of development highlights the location of UBE3A proteins (in green), allowing researchers to track the behavior of UBE3A genes in different cells and at different stages of development. Image credit: Dilara Sen.

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New research from North Carolina State University provides insights into the earliest stages of Angelman syndrome. The work also demonstrates how human cerebral organoids can be used to shed light on genetic disorders that affect human development.

Angelman syndrome is a genetic disorder associated with delayed development, intellectual disability, speech impairment and problems with movement. A great deal of research has been done on Angelman syndrome, primarily involving laboratory studies of mice and natural history studies of humans. However, while researchers have established that the complex disorder is tied to the behavior of a gene called UBE3A, and strong evidence in mice has shown that prenatal time periods may be important in disease development, researchers had yet to find a way of monitoring the earliest stages of the disease in human neural cells.

"Obviously we cannot do studies on developing humans, so we wanted to know whether it was possible to study the molecular dynamics around UBE3A using cerebral organoids," says Albert Keung, corresponding author of a paper on the work and an assistant professor of chemical and biomolecular engineering at NC State. "When is the gene turned on? How do drugs affect gene and neuronal functions? Does the gene behave differently in different types of cells? These are complex questions, but we found that you can learn a lot through the cerebral organoid model."

Human cerebral organoids are millimeter-sized tissues comprised of the cell types typically found in the different regions of the brain. They are made by culturing stem cells. For this study, the researchers monitored the behavior of the organoids for 17 weeks after culturing the cells.

For example, the researchers mapped when UBE3A was turned off or on in different types of cells and at different stages of neurodevelopment - as well as where in each cell the gene was active. This can shed light on things such as the extent to which UBE3A might be regulating the activity of other genes, and when the delivery of therapeutic treatments may be most effective.

One of the things the researchers discovered is that UBE3A appears to be playing an important role in the development of brain tissue earlier than anyone knew - potentially even within three weeks of culturing the organoids.

"We had the ability to see how UBE3A's behavior changed over time in the organoid," says Dilara Sen, first author of the paper and a Ph.D. student at NC State. "We were also able to see how different drugs affected the gene's behavior - and how those changes affected the function of neurons in the organoid."

"This is fundamental, proof-of-concept work," Keung says. "But hopefully it demonstrates how the cerebral organoid model can facilitate the development of therapeutic strategies for people with Angelman syndrome. We believe the model can do this by advancing our understanding of the disease, which can inform research into possible treatments. We also believe that this model could be used to screen drugs that are candidates for therapeutic interventions. Organoid models aren't new. But they may be more powerful tools than we previously anticipated."

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Brain Organoids Reveal the Early Stages of Angelman Syndrome - Technology Networks

New data further reinforce Roche’s OCREVUS (ocrelizumab) as a highly effective treatment for people with multiple sclerosis – GlobeNewswire

September 11, 2020 01:00 ET | Source: F. Hoffmann-La Roche Ltd

Basel, 11 September 2020 Roche (SIX: RO, ROG; OTCQX: RHHBY) today announced new data that show OCREVUS (ocrelizumab) is a highly effective treatment option for people with relapsing-remitting multiple sclerosis (RRMS) who experienced a suboptimal response to their prior disease modifying therapy (DMT). Subgroup analysis from the two-year open-label Phase IIIb CASTING study also demonstrates that patients benefit across a wide range of disease related and demographic subgroups, regardless of prior treatment background. Findings will be presented at MSVirtual2020, the 8th Joint Meeting of the Americas Committee for Treatment and Research in Multiple Sclerosis (ACTRIMS) and the European Committee for Treatment and Research in Multiple Sclerosis (ECTRIMS).

For a wide range of people with MS who experienced a suboptimal response to prior treatment, we continue to see evidence that OCREVUS provides significant benefit in slowing disease progression, said Levi Garraway, M.D., Ph.D., Roche's Chief Medical Officer and Head of Global Product Development. New real-world OCREVUS data show high persistence and adherence to the only B-cell therapy with a twice-yearly dosing schedule, which we know can be very important to both people with MS and their physicians.

Phase IIIb open-label CASTING study Approximately 75% of RRMS patients (492/658) had no evidence of disease activity (NEDA; brain lesions, relapses and worsening of disability) two years after switching to twice-yearly OCREVUS treatment (with prespecified MRI re-baselining at 8 weeks) in the primary analysis of the CASTING study. Patients enrolled in the study had prior suboptimal response to at least six months of treatment with up to two DMTs. The analysis also showed the proportion of patients achieving NEDA remained consistently high across all measured patient subgroups, including baseline MRI activity, relapse activity, disability level, age and the number of prior DMTs. Further, 78% of patients treated with only one prior DMT compared with 70% of patients treated with two prior DMTs achieved NEDA.

Additionally, patients treated with OCREVUS experienced an improvement in the majority of symptoms measured by SymptoMScreen after two years. SymptoMScreen is a patient-reported outcome tool to assess symptom severity across twelve domains. The most pronounced significant improvements (p<0.001) were seen in sensory symptoms, fatigue and vision, which are important for daily living.

CONFIDENCE real-world safety study A 97% treatment persistence for OCREVUS patients at 18 months, and strong adherence to infusions every six months, was seen in an interim analysis of more than 1,600 patients in the ongoing German CONFIDENCE study. Separate data from a U.S. commercial claims database that support high persistence and sustained adherence to OCREVUS treatment will also be presented.

OCREVUS longer-term safety data New safety data as of January 2020 will be presented, representing 5,680 patients with RMS and PPMS and 18,218 patient-years of exposure to OCREVUS, across all OCREVUS clinical trials. These findings further demonstrate the consistently favourable benefit-risk profile of OCREVUS over seven years.

With rapidly growing real-world experience and more than 170,000 people treated globally, OCREVUS has twice-yearly (six-monthly) dosing and is the first and only therapy approved for RMS (including relapsing-remitting MS [RRMS] and active, or relapsing, secondary progressive MS [SPMS], in addition to clinically isolated syndrome [CIS] in the U.S.) and primary progressive MS (PPMS). OCREVUS is approved in 92 countries across North America, South America, the Middle East, Eastern Europe, as well as in Australia, Switzerland and the European Union.

About multiple sclerosis Multiple sclerosis (MS) is a chronic disease that affects nearly 1 million people in the U.S. and more than 2.3 million people worldwide. MS occurs when the immune system abnormally attacks the insulation and support around nerve cells (myelin sheath) in the central nervous system (brain, spinal cord and optic nerves), causing inflammation and consequent damage. This damage can cause a wide range of symptoms, including muscle weakness, fatigue and difficulty seeing, and may eventually lead to disability. Most people with MS experience their first symptom between 20 and 40 years of age, making the disease the leading cause of non-traumatic disability in younger adults.

People with all forms of MS experience disease progression permanent loss of nerve cells in the central nervous system and gradual worsening of disability at the beginning of their disease even if their clinical symptoms arent apparent or dont appear to be getting worse. Delays in diagnosis and treatment can negatively impact people with MS, both in terms of their physical, mental and financial health. An important goal of treating MS is to slow the progression of disability as early as possible.

Relapsing-remitting MS (RRMS) is the most common form of the disease and is characterised by episodes of new or worsening signs or symptoms (relapses) followed by periods of recovery. Approximately 85% of people with MS are initially diagnosed with RRMS. The majority of people who are diagnosed with RRMS will eventually transition to secondary progressive MS (SPMS), in which they experience steadily worsening disability over time. Relapsing forms of MS (RMS) include people with RRMS and people with SPMS who continue to experience relapses. Primary progressive MS (PPMS) is a debilitating form of the disease marked by steadily worsening symptoms but typically without distinct relapses or periods of remission. Approximately 15% of people with MS are diagnosed with the primary progressive form of the disease. Until the FDA approval of OCREVUS, there had been no FDA approved treatments for PPMS.

About OCREVUS (ocrelizumab) OCREVUS is the first and only therapy approved for both RMS (including clinically isolated syndrome, RRMS and active, or relapsing, SPMS, in addition to CIS in the U.S.) and PPMS. OCREVUS is a humanised monoclonal antibody designed to target CD20-positive B cells, a specific type of immune cell thought to be a key contributor to myelin (nerve cell insulation and support) and axonal (nerve cell) damage. This nerve cell damage can lead to disability in people with MS. Based on preclinical studies, OCREVUS binds to CD20 cell surface proteins expressed on certain B cells, but not on stem cells or plasma cells, suggesting that important functions of the immune system may be preserved. OCREVUS is administered by intravenous infusion every six months. The initial dose is given as two 300 mg infusions given two weeks apart. Subsequent doses are given as single 600 mg infusions.

About Roche in multiple sclerosis Roche is following the science in an effort to ultimately stop disease progression and preserve function in people living with multiple sclerosis (MS). As a company, we continue to advance the clinical understanding of MS and progression with the aim of bringing the most benefit to people living with MS.

About Roche in neuroscience Neuroscience is a major focus of research and development at Roche. Our goal is to pursue groundbreaking science to develop new treatments that help improve the lives of people with chronic and potentially devastating diseases.

Roche is investigating more than a dozen medicines for neurological disorders, including multiple sclerosis, neuromyelitis optica spectrum disorder, Alzheimers disease, Huntingtons disease, Parkinsons disease, Duchennes muscular dystrophy and autism spectrum disorder. Together with our partners, we are committed to pushing the boundaries of scientific understanding to solve some of the most difficult challenges in neuroscience today.

About Roche Roche is a global pioneer in pharmaceuticals and diagnostics focused on advancing science to improve peoples lives. The combined strengths of pharmaceuticals and diagnostics under one roof have made Roche the leader in personalised healthcare a strategy that aims to fit the right treatment to each patient in the best way possible.

Roche is the worlds largest biotech company, with truly differentiated medicines in oncology, immunology, infectious diseases, ophthalmology and diseases of the central nervous system. Roche is also the world leader in in vitro diagnostics and tissue-based cancer diagnostics, and a frontrunner in diabetes management.

Founded in 1896, Roche continues to search for better ways to prevent, diagnose and treat diseases and make a sustainable contribution to society. The company also aims to improve patient access to medical innovations by working with all relevant stakeholders. More than thirty medicines developed by Roche are included in the World Health Organization Model Lists of Essential Medicines, among them life-saving antibiotics, antimalarials and cancer medicines. Moreover, for the eleventh consecutive year, Roche has been recognised as one of the most sustainable companies in the Pharmaceuticals Industry by the Dow Jones Sustainability Indices (DJSI).

The Roche Group, headquartered in Basel, Switzerland, is active in over 100 countries and in 2019 employed about 98,000 people worldwide. In 2019, Roche invested CHF 11.7 billion in R&D and posted sales of CHF 61.5 billion. Genentech, in the United States, is a wholly owned member of the Roche Group. Roche is the majority shareholder in Chugai Pharmaceutical, Japan. For more information, please visit http://www.roche.com.

All trademarks used or mentioned in this release are protected by law.

Roche Group Media Relations Phone: +41 61 688 8888 / e-mail: media.relations@roche.com

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New data further reinforce Roche's OCREVUS (ocrelizumab) as a highly effective treatment for people with multiple sclerosis - GlobeNewswire