The Neuro Collaborative: An Engine for ALS Therapeutic Discovery

In 2013, the Golden West Chapter of The ALS Association, led by Advisory Trustees Jim Barber and Linda Della, developed the concept of a novel scientific initiative called the Neuro Collaborative. The idea was to build a synergetic model that brought together complementary expertise within the ALS research community to accelerate scientific discovery and de-risk investment in drug development.

In 2014, this research initiative, spearheaded by the Golden West Chapter, was one of the first to receive ALS Association funding from the global outpouring of support generated by ALS Ice Bucket Challenge.

About the Scientists

The Neuro Collaborative established a formal partnership between the Golden West Chapter, The ALS Association and three leading laboratories in California – including Don Cleveland, PhD at University of California San Diego; Steven Finkbeiner, MD, PhD. at Gladstone Institutes, affiliated with University of California San Francisco; and Clive Svendsen, PhD at Cedars-Sinai Regenerative Medicine Institute in Los Angeles. From sharing information to attracting industry investment, the Neuro Collaborative is a forward looking initiative designed to drive potential therapeutics for ALS quickly toward FDA approval.

Since 2009, these principal investigators have also served on the California ALS Research Network, and help to organize the annual California ALS Research Summit, presented by the Golden West Chapter. The Summit is an annual gathering of researchers, investigators, clinicians, biotech companies, government representatives, partner organizations, and advocates in ALS and related fields. The three scientists have also participated in many of the Golden West Chapter's educational events presented for people with ALS and their families.

Dr. Don Cleveland, professor at the University of California, San Diego’s Ludwig Institute for Cancer Research 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 (ASO). In 1999, The ALS Association and the American Academy of Neurology awarded Dr. Cleveland with the prestigious Sheila Essey Award for ALS Research for his significant contributions. He also received the 2014 Commitment to a Cure Essey Award from the Golden West Chapter, along with Richard Smith, MD, Center for Neurologic Study and C. Frank Bennett, PhD, of Ionis Pharmaceuticals, Inc -- for their ASO research which may lead to a treatment for people with ALS and related diseases. Dr. Cleveland was awarded the $3 million prestigious 2018 Breakthrough Prize in Life Sciences for his numerous accomplishments in neurodegenerative disease research, including establishing ASO in animal models of ALS and demonstrating the promise of ASO drugs for neurodegenerative diseases including ALS. Dr. Cleveland’s efforts have led to ASO drug trials directly targeting genes responsible for the major inherited forms of ALS, as well as one gene implicated in sporadic ALS.

Dr. Steven Finkbeiner is the Director of the Center for Systems and Therapeutics and the Taube/Koret Center for Neurodegenerative Disease Research and Investigator at the Roddenberry Center for Stem Cell Biology and Medicine at Gladstone Institutes. He is also a Professor in Neurology and Physiology at University of California, San Francisco. Dr. Finkbeiner is well known for inventing robotic microscopy, a new form of imaging that has helped illuminate relationships in amyotrophic lateral sclerosis (ALS, or Lou Gehrig’s disease), Huntington’s, Alzheimer’s and other neurodegenerative diseases. Dr. Finkbeiner received the 2017 Commitment to a Cure Essey Award from the Golden West Chapter for his pioneering work with neurodegenerative diseases and urgent focus on bringing effective treatments to the ALS community.

Dr. Clive Svendsen is the Executive Director of the Cedars-Sinai Regenerative Medicine Institute and serves as a Professor In-Residence, at UCLA Medicine. Dr. Svendsen has won numerous scientific awards, including the 2010 Sheila Essey Award for ALS Research from the American Academy of Neurology. He is the principal investigator on multiple research projects studying stem cells and ALS that have been awarded more than $36 million dollars in grant funding from the California Institute of Regenerative Medicine. He is currently working to develop novel ways of using stem cells modified to release powerful growth factors to treat patients with neurological diseases such as ALS, Huntington’s, Alzheimer’s and Parkinson’s. Dr. Svendsen serves as the Co-Director of the Answer ALS program. He is also the Chair for the California ALS Research Network, an initiative that was launched by the Golden West Chapter.

How the Neuro Collaborative accelerates the search for treatments and cures for ALS

The Neuro Collaborative is an initiative designed to drive potential therapeutics for ALS quickly toward FDA approval. The goal of the Collaborative is to efficiently advance ALS drug development together with industry partners. TThis synergetic model leverages open dialogue and the scientific expertise of leading researchers to achieve therapeutic milestones as quickly as possible. It also reduces risk in the drug discovery process and attracts pharmaceutical companies to invest in drug development and clinical trials for ALS. With success, potential therapies for ALS will move more quickly than ever toward FDA approval and the open market.

Some examples of goals of the Neuro Collaborative include:

Each laboratory affiliated with the Neuro Collaborative focuses on different areas of ALS research to maximize shared knowledge and understanding of the complexities of the disease while increasing industry interest and investment in ALS drug development. The Neuro Collaborative partners with prestigious scientific advisors including: Dr. John Dunlop, Ph.D., Vice President of Neuroscience Innovative Medicines at AstraZeneca, Fred Gage, Ph.D., Professor in Laboratory Genetics at the Salk Institute and Harry Orr, Ph.D., Professor of Laboratory Medicine and Pathology at University of Minnesota. In support of their efforts, the Neuro Collaborative was awarded an additional $3 million dollars in support by The ALS Association in 2017.

Laboratories that represent the Neuro Collaborative

The Cleveland lab at the University of California San Diego:

• Focus: Gene therapy and antisense therapy development

• Details: Antisense technology, which The ALS Association has helped fund since 2004, has high potential to become a therapeutic treatment for ALS targeting both SOD1 and C9orf72 – the two leading genetic causes of familial ALS – to slow or even halt ALS progression. A major breakthrough in ALS, antisense technology reduces the production of SOD1 and C9orf72 proteins in the body. Dr. Cleveland’s lab is also developing gene therapy approaches against SOD1 and other targets as they emerge. His lab is collaborating with Martin Marsala, M.D. at University of California San Diego and Brian Kaspar, Ph.D., the founder of Avexis Pharmaceuticals, to develop novel gene therapies for ALS.

• Impact: Antisense technology has high potential to become a therapeutic treatment for ALS targeting both SOD1 and C9orf72 the two leading genetic causes of familial ALS to slow or even halt ALS progression. A major breakthrough in ALS, antisense technology reduces the production of SOD1 and C9orf72 proteins in the body.

• Progress: Dr. Cleveland and Ionis Pharmaceuticals developed the first ever-antisense drug to treat a neurological disorder, ALS. The ALS Association initiated funding for the development of this revolutionary technology and has supported its development through continued funding for over a decade. After a successful Phase I study of the SOD1 antisense drug which demonstrated that it effectively reduced expression of the gene responsible for some instances of inherited ALS, a Phase III trial is underway to test how effective it is in slowing disease progression. A similar trial focused on antisense technology targeting C9orf72, whose mutation causes about half of inherited ALS and 15% of sporadic ALS, initiated in 2018 through partnerships with Ionis Pharmaceuticals and Biogen. In 2019, Dr. Cleveland’s team discovered stathmin-2 as a gene that is silenced in sporadic and C9orf72-mediated ALS. With Ionis, he is now developing ASOs that can restore stathmin-2 as a therapy for ALS.

The Finkbeiner lab at the Gladstone Institutes, which is affiliated with UCSF:

• Focus: High performance drug screening and drug target validation.

• Details: Uses robotic microscope technology, The Brain Bot, which tracks the health of cells (like motor neurons and glia) over many months from healthy to sick to death. It measures millions of individual cells, each tagged with their own signature, derived from people living with ALS and compares them to cells from healthy people.

• Impact: The Brain Bot allows rapid drug screening and validation of potential ALS drugs by measuring whether a potential ALS drug improves or worsens the health of the cells.

• Progress: Dr. Finkbeiner’s Brain Bot drug screening system attracts many industry partnerships. Using the Brain Bot, his team identified potential ALS compounds targeting autophagy, one mechanism the cell uses to get rid of unwanted by-products. His team found that adding potential autophagy compounds to motor neurons derived from people living with ALS was protective. Dr. Finkbeiner is also part of the Answer ALS program and works with the Brain Bot to look for signals of motor neuron health. In addition, Gladstone Institutes, through the leadership of Dr. Finkbeiner, partnered with Biogen in 2016 to discover novel drug targets for the treatment of ALS. Dr. Finkbeiner has partnered with Eli Lilly and Company in 2017 on a multi-year, milestone-driven project using innovative robotic microscope technology to focus on better understanding neurodegenerative diseases, with a large focus on ALS-related therapeutic targets. He has collaborated with Google on developing new ways to apply artificial intelligence to analyze the data generated by the Brain Bot to develop new ways to screen for ALS therapies. He currently is collaborating with Takeda, and Sanofi.

The Svendsen lab at Cedars-Sinai in Los Angeles:

• Focus: iPSC models to be shared globally.

• Details: Creation of clinical-grade iPSC lines from people living with ALS using a standardized, rapid and effective method through the Cedars-Sinai biomanufacturing center. iPSCs are then converted to motor neurons, one type of cell that dies in ALS. iPSCs are like a person’s avatar in a dish, containing the same exact genetic information.

• Impact: iPSCs are used to test drug efficacy and are paired with the clinical data of a person living with ALS. This helps scientists understand the connection between ALS symptoms and cell pathology. Advancements in iPSC development and technology are shared globally and can also help advance understanding of other neurodegenerative diseases.
  

• Progress: The lab has successfully made 24 iPSC lines, derived from 11 healthy controls, 4 C9orf72 mutation carriers, 6 SOD1 mutation carriers and 3 sporadic ALS cases that are available to researchers worldwide. They have also developed new “organ chip” models of ALS, which have now been funded by three large NIH grants, and have detected specific ALS signals in iPSC-derived motor neurons using advanced single cell RNA-seq technologies. The Cedars-Sinai biomanufacturing center has now generated over 700 iPSC lines and motor neuron cultures from patients with ALS as part of the Answer ALS program that Dr. Svendsen Co-Directs.