Precise ALS Worm Model Gives Insight into How Motor Neurons Die

Why motor neurons die in ALS largely remains a mystery. In a study funded by The ALS Association, Dr. Anne Hart, professor of neuroscience at the Carney Institute for Brain Science at Brown University, and her colleagues gained insight into why some types of motor neurons die, while other don’t. A paper about the study was recently published in PLOS Genetics.

Interestingly, Dr. Hart and her team used microscopic worms, called C. elegans, which maintain conserved ALS genes seen in humans to create the first precise worm models for SOD1 ALS, the second most common genetic cause of inherited ALS, using gene editing.

Motor neurons are the cells that die in ALS. Basically, a person has two types of motor neurons. Upper motor neurons (UMNs) connect the primary motor cortex in the brain (area of the brain that controls voluntary movement) to the spinal cord. UMNs use glutamate, a type of neurotransmitter, to send signals and communicate with each other.

Lower motor neurons (LMNs) connect the spinal cord to muscle and use acetylcholine as a neurotransmitter. (See diagram below.) It is not clear why, in some people with ALS, one or both types of motor neurons die.

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Meet Dr. James Shorter: ALS Researcher Dedicated to Understanding What Causes ALS

Meet Dr. James Shorter, professor of Biochemistry and Biophysics at the Perelman School of Medicine at the University of Pennsylvania in Philadelphia. He and his team work tirelessly in the lab to better understand the causes of ALS, so those causes can be translated into potential therapeutic targets. The ALS Association has proudly funded him since 2014.

Dr. Shorter’s work focuses on protein homeostasis, which is how proteins in the cells of the body fold into specialized structures to perform specific functions. Sometimes protein misfolding occurs, which allows the formation of protein aggregates (clumps of protein).

When protein aggregates are in the form of fibrils and oligomers, they can be harmful to cells. Dr. Shorter and his team’s goal is to understand how protein misfolding occurs and how cells can prevent it from happening.

In ALS disease, it is known that certain RNA-binding proteins, such as TDP-43, FUS, hnRNPA1, and hnRNPA2, mis-localize from the cell’s nucleus into the cytoplasm and accumulate in cytoplasmic aggregates (protein clumps). Mutations in a specific area of these proteins, called prion-like domains, play a part in accelerating fibrillization that causes toxicity in cells.

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MediciNova Announces Positive FDA Feedback to Start Phase III Plan for MN-166 (ibudilast) to Treat ALS

Yesterday, MediciNova, Inc. announced that the U.S. Food and Drug Administration (FDA) relayed positive feedback regarding its phase III clinical trial plan to test MN-166 (ibudilast) in a broad population of people with ALS. No safety issues were raised by the FDA and safety will be revisited when results are available in the phase III trial.

The ALS Association helped support the phase II trial through funding the PBR28 PET (positron emission tomography) imaging biomarker study that was conducted by Dr. Nazem Atassi at Massachusetts General Hospital in parallel to the trial. PBR28 is a biomarker that measures inflammation in the brain, which can track inflammation over time and evaluate the effects of ibudilast on brain inflammation.

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Members of ALS Community Gather with Representatives from FDA and Industry to Inform FDA Draft Guidance on ALS

The ALS community recently presented its recommendations to the U.S. Food and Drug Administration (FDA) regarding the Amyotrophic Lateral Sclerosis: Developing Drugs for Treatment Guidance for Industry at a day-long event, called ALS Community Workshop: Therapy Development and Regulatory Pathways, which was held in Washington, D.C., on July 12. Over 90 people attended in person, with many more tuning in online.

Throughout the day, there were opportunities to make comments to the FDA and industry representatives, both in-person and online. The Association was proud to host the day to bring many ALS stakeholders together to provide targeted feedback and information to further inform the FDA’s Draft Guidance on ALS Drug Development.

The FDA’s Draft Guidance provides drug developers with recommendations for all aspects of clinical trials for ALS, from study design to risk-benefit considerations to patient selection. For many years, The ALS Association has worked closely with the FDA and members of the ALS community in the development of a comprehensive ALS Guidance to make clinical trials faster, shorter, and more responsive to special considerations inherent to people with ALS and their caregivers.

The Workshop was an opportunity to provide targeted feedback and information from the ALS community to further inform the FDA’s Draft Guidance on ALS Drug Development. After the Workshop, the Association composed a report to the FDA to address key points discussed at the Workshop and to make recommendations on how to improve the FDA’s final Guidance (listed below).

“The purpose today is to build a strong guidance together,” said Calaneet Balas, president and CEO of The ALS Association. “We will be taking the great ideas from this meeting and presenting them to the FDA for their consideration in developing the final Guidance document. We look forward to that document, and to seeing it used widely for making clinical trials faster, more effective, and more aligned with the needs of patients and caregivers. We believe that is the route to the fastest development of new treatments for ALS.”

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Meet Dr. Don Cleveland: Prominent ALS Researcher Who Pioneered Antisense Technology

Our Every Drop Adds Up campaign builds on the idea that people coming together for a common goal can make the impossible happen, just as it did four summers ago when the ALS Ice Bucket Challenge soaked the world. Every person helped, research project funded, story shared, discovery made, piece of legislation passed, and auction bid placed – it all adds up!

By the beginning of 2019, three trials are slated to be underway to help develop antisense therapy for people with ALS, dividends on a bold investment The ALS Association made in 2004, when the technology was new. We sat down with Dr. Don Cleveland, a pioneer in the field, for the second part of our series highlighting antisense technology.

Dr. Cleveland, professor at the University of California, San Diego’s Ludwig Institute for Cancer Research, is a long-time funded ALS researcher. He has been working with The ALS Association since 2004 to develop DNA-based designer drugs to silence ALS genes, called antisense gene silencing or antisense technology.

In 1999, The ALS Association, along with the American Academy of Neurology, awarded Dr. Cleveland with the prestigious Sheila Essey Award for his significant contributions to research. He was recently awarded the $3 million prestigious 2018 Breakthrough Prize in Life Sciences for his numerous accomplishments in neurodegenerative disease research, including establishing antisense therapy in animal models of ALS.

He talked with us to discuss this important gene silencing technology that currently targets inherited ALS genes and could be potentially applied to non-inherited (sporadic) ALS in the future.

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The ALS Association’s Early Investment in Antisense Technology Is Having a Real Impact

Our Every Drop Adds Up campaign builds on the idea that people coming together for a common goal can make the impossible happen, just as it did four summers ago when the ALS Ice Bucket Challenge soaked the world. Every person helped, research project funded, story shared, discovery made, piece of legislation passed, and auction bid placed – it all adds up!

When Dr. Timothy Miller and his colleagues from Washington University in St. Louis published preclinical data in The Journal of Clinical Investigation last month, showing how second-generation antisense drugs were effective in ALS mouse and rat models, it served as a vivid reminder that every research investment and discovery adds up.

Antisense technology, which The ALS Association has supported from the beginning, represents one of the most promising potential treatments for ALS. The goal is to prevent the production of the toxic proteins by preventing them from being created in the first place. Toxic proteins kill motor neurons, the cells that primarily die in ALS, leading to muscle weakness and, eventually, paralysis.

Doing so could slow or stop disease progression in people living with ALS. Specifically, an antisense drug selectively targets and binds to the mutated messenger RNA linked with ALS and prevents toxic proteins from being made.

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The ALS Association and Teva Grant Two Awards as part of Teva CNS Target Identification Crowdsourcing Challenge

The ALS Association and Teva Pharmaceutical Industries Ltd. (“Teva”) have announced the recipients of the TEVA CNS Target Identification Crowdsourcing Challenge awards for their outstanding proposals to identify novel ALS targets. The two awards will be granted to Dr. Philip Wong, along with Dr. Jonathan C. Grima and Dr. Jeffrey D. Rothstein, all from Johns Hopkins University School of Medicine in Baltimore, Maryland.

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