Mass General

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Nikki J

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PALS
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I received this email from them today summarizing their research accomplishments and plan and programs

As we approach the end of 2019, we want to share our amazing progress and several successes in ALS care and research - made possible by all of you!



Our goal is to accelerate the pace of ALS therapy development by bringing together a global community of the best minds to conquer ALS. We have done this! At the Sean M. Healey & AMG Center for ALS at Mass General, a team of more than 100 affiliated scientists and researchers focus on understanding the cellular and molecular roots of ALS. They made important discoveries about the disease pathway that can be targeted and work closely with our clinical research team to bring treatments from the lab to our patients.



In just one year, our team:





• Brought three companies together for the first time, to meet with us and the FDA in the same room to confirm final approval of the HEALEY ALS Platform trial design. We chose the top five most promising therapies from 27 applications submitted from 10 countries. We have resounding support from the FDA, from patients all over the globe, from our 132 investigators from sites all over North America and from biopharma companies.



• Collaborated across disciplines and disease areas to bring more scientists together to focus on finding cures. This led directly to funding the first study of B cell dysfunction in ALS.



• Discovered a new critical pathway relevant to all forms of ALS.



• Developed new approaches to clinical care and extended our support beyond our clinic through the House Call program, Parenting at a Challenging Time (PACT-ALS), integration of supportive neurology and Palliative Care and Virtual Visits.



• Created the only center to offer multiple expanded access protocols to people with ALS.



We are particularly focused on accelerating efforts to turn off the genetic mutation in every one of the more than 40 different gene mutations that cause ALS.





Gene Therapy Clinical Trials



We are working with Biogen on a Phase I clinical trial measuring the safety of BIIB078, an antisense oligonucleotide (ASO) treatment that specifically targets C9orf72. With approximately 40% of familial ALS cases related to C9orf72, it is the most common ALS gene. The ASO in this trial targets the messenger RNA emerging from the gene and prevents it from being used in the formation of proteins. This approach shows promise in extending survival and in some cases, reversing the loss of muscle function in ALS models.



We are also collaborating with Biogen on a Phase II clinical trial of BIIB067, which targets the SOD1 ALS gene mutation. This study evaluates the appropriate dosing regimen for what we believe is a ground-breaking therapeutic approach to ALS. Mass General was part of the team that brought the first ASO trial forward for any central nervous system disorder. That ASO became the first treatment for an individual with SOD1 ALS.



New Opportunity to Rescue Neurons



A protein called transactive response DNA-binding protein 43 (TDP-43) has emerged as a crucial player in ALS. TDP-43 is involved in both familial and sporadic forms of the disease. TDP-43 is necessary for the processing of over 1,500 RNAs in neurons and its disruption leads to neuronal death. We recently determined that a major consequence of TDP-43 malfunction is the loss of an important protein called stathmin-2, which is involved in axon maintenance and regeneration after injury. With this new knowledge, Healey Center researchers are now developing therapeutic strategies to restore stathmin-2 levels in ALS patients, including those with the C9orf72 gene. Understanding this protein is also providing valuable opportunities to develop treatments for other neurodegenerative diseases affected by a malfunctioning TDP-43, including frontotemporal dementia and Alzheimer’s disease.



Lab-based researchers in the Healey Center work closely with their clinical research colleagues, analyzing patient samples at the molecular level to understand when the genetic malfunction occurs. Team members are generating cellular and mouse models to explore different strategies for silencing or restoring genes that cause ALS earlier in the disease progression, or even before it begins.



Progress in Stem Cell Research



The success of the Phase II clinical trial of Ezogabine to calm the excitability in nerve cells encouraged the Healey Center’s Brian Wainger, MD, PhD, to further explore this ALS pathway to reduce the vulnerability of neurons and slow or stop the degeneration of muscles. Knowing that hyperexcitability of motor neurons leads to exhaustion and dysfunction also encouraged more validation of stem cell models as accurate functional representations of the primary cell types. Dr. Wainger has made great progress in this area, making the use of human pluripotent stem cells to screen treatments a potential, personalized therapy.





Dominant Inherited ALS (DIALS) Network



The DIALS Network is a multicenter study with the goal of developing preventive strategies for ALS. Through the DIALS Network we are gathering information that is critical to identifying the earliest biological and clinical markers of disease among individuals with dominantly inherited ALS. This study has enrolled 81 individuals (60 at Mass General) who are asymptomatic but are at risk for developing ALS because they have a first-degree relative with the disease caused by a genetic mutation.



We are also evaluating these gene carriers over the long term to identify biomarkers of the start of the disease so that we can move up the diagnostic horizon and intervene earlier in the disease progression, including before symptoms manifest. We also want to understand why some people who carry an ALS-related gene do not develop the disease, in an effort understand what naturally protects cells.



A New Focus on Prevention



The DIALS Network research is the first component of our new efforts focusing on prevention. We are determined to develop approaches to prevent C9-related ALS from starting. This effort is one of several strategies to move toward preventing ALS among people at risk as the result of a genetic mutation. Fast-paced lab discoveries in familial ALS have led to a growing list of ideas for translation into therapy, including genetic approaches and small molecules.



A major challenge in ALS drug development is the conventional “parallel group” trial design requiring large patient numbers and long trial duration. We will promote “N-of-1” trials, in which a therapy is tested in just one patient or a small group of targeted patients, to determine potential impact. An experienced team at the Healey Center will lead the design of these small trials conducted in a new familial ALS-focused trial network.



Our work in all these areas is designed to create inclusive programs that provide leading-edge therapies to people with ALS, access to experimental therapies, and building partnerships with industry partners and regulatory agencies to hasten drug development for ALS. Our Healey Center Mass General investigators spoke at conferences around the world and published more than two dozen scholarly articles. Sharing our work and bringing researchers together accelerates our efforts to find the cures.



We are making enormous progress, thanks to your partnership. Every day brings us closer to answers.



Warmly,





Merit Cudkowicz, MD, MSc

Director, Sean M. Healey & AMG Center for ALS at Mass General

Chief, Neurology Department & the Julieanne Dorn Professor of Neurology, Harvard Medical School





Katharine Nicholson, MD

Assistant in Neurology, Multidisciplinary ALS Clinic of the Sean M. Healey and AMG Center for ALS at Mass General

Instructor, Harvard Medical School
 
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