Research at the Day Lab
Cecil B. Day Laboratory for Neuromuscular Research
The Angel Fund for ALS Research supports the ALS research at the Cecil B. Day Laboratory for Neuromuscular Research at UMass Medical School in Worcester, MA. The lab is under the direction of Dr. Robert H. Brown, Jr.
Dept of Neurology at UMass Medical School
ALS Research UpdateFDA clears investigational new drug application for ALS gene therapy candidate
UMass Medical School Communications
April 21, 2021
Apic Bio, a gene therapy company developing treatment options for patients with rare genetic diseases and co-founded by UMass Medical School’s Robert H. Brown Jr., DPhil, MD, announced that the FDA has cleared its investigational new drug (IND) application for APB-102, a gene therapy candidate designed to treat a common cause of familial amyotrophic lateral sclerosis.
“The clinical development of APB-102 is rooted in nearly 30 years of gene therapy research demonstrating the link between the SOD1 gene mutation and ALS and the strong potential of AAV-delivered SOD1 targeting miRNA to slow down or reverse the progression of ALS in patients with SOD1 mutations,” said Dr. Brown, the Leo P. and Theresa M. LaChance Chair in Medical Research, professor of neurology and scientific co-founder of Apic Bio.
Brown was a lead member of the team that discovered SOD1 as the first genetic mutation linked to ALS.
“Despite SOD1 gene mutations being well understood as a cause of genetic ALS for decades, we don’t yet have an approved treatment option that targets the disorder at the source,” said Brown. “I am pleased to see APB-102 progress as Apic Bio aims to develop a meaningful, long-term disease-modifying gene therapy option for patients.”
APB-102 is designed to slow or reverse progression of SOD1 ALS through a recombinant adeno-associated virus (AAV) capsid and micro ribonucleic acid (miRNA) vector construct, which has been shown in preclinical proof of concept studies to suppress activity of the mutated SOD1 gene.
The Phase I/II clinical trial will be initiated in late 2021 or early 2022 as a multi-center, three-part study to evaluate the safety, tolerability and efficacy of APB-102 in patients with SOD1 ALS mutations.
ALS is a fatal neurodegenerative disorder characterized by loss of motor neurons, leading to muscle weakness and eventual paralysis. Most patients face mortality within five years of disease onset due to respiratory failure. ALS can be caused by multiple genetic mutations and can be sporadic or familial. Approximately 10 percent of ALS cases have a known genetic driver; of those, approximately 20 percent are linked to a mutation in the SOD1 gene that codes for the enzyme superoxide dismutase 1. Current approved ALS treatments only delay disease progression without addressing the underlying genetic causes of the disease.
23-November-2020By Dr. Robert H. Brown, Jr. It is a pleasure to provide this year end research update on the Angel Fund’s ALS research program at UMass Medical School, which continues along several fronts.
- First, we are continuing our investigations of the compound we call afinersen for ALS arising from mutations in the C9orf72 This compound, an antisense oligonucleotide (ASO), has continued to look promising in the initial pilot trials in a single individual. We have engaged the FDA regarding opportunities to expand our trial; these efforts are underway.
- Second, we are continuing to pursue our program to suppress the SOD1 gene using a different type of compound, known as a microRNA, delivered into the spinal fluid using an adeno-associated virus (AAV). Some aspects of this program are being studied in detail in our laboratories; at the same time, an expanded human trial is being planned by a company (ApicBio) in Cambridge. Our initial report of our pilot study of this modality was published as a Brief Report in the New England Journal of Medicine last summer (Mueller CM et al., New Engl J Medicine, 383(2):151-158). It is particularly exciting that in the same issue, the Cambridge company, Biogen, reported that an ASO that they are investigating, called tofersen, suppresses SOD1 gene in many patients with SOD1 gene mutations.
- Third, in parallel studies we have explored the use of an ASO to suppress the ALS gene known as FUS, which unfortunately often causes devastatingly rapid ALS in young adults (and even children). We have been deeply grateful in this project initially to work with a California company (Ionis) with expertise in this area. We have extensively tested an ASO from Ionis that suppresses the FUS gene effectively in patient motor neurons in culture. A collaborator in the program, Dr. Neil Shneider at Columbia University, has now used this anti-FUS ASO in pilot studies in several FUS patients.
- Read more.
Silencing of an ALS gene safely delivered to patients in UMass Medical School study
Synthetic microRNA treatment targets mutant SOD1 gene that causes ALS
Year in Review 2019 – 2020
Dr. Robert Brown, Jr. UMass Medical School
The last year has seen unprecedented progress in clinical trials in ALS. A collaborative team involving UMass Medical School, the Mayo Clinic and the Massachusetts General Hospital reported the first-ever, placebo controlled study of stem cell therapy in ALS. The trial involved harvesting bone marrow stem cells and then returning them to each participant. The study, not only documented safety but showed a benefit in a sub-group of more rapidly progressing patients. This has led to a much larger controlled trial now underway. At UMass, three programs to suppress activity of mutant genes were initiated.
• One entails using a virus to deliver the gene-suppressing agent (a microRNA) to the spinal cords of two patients with familial ALS caused by SOD1 gene mutations.
• Another involved using different approach, known as an anti-sense oligonucleotide (ASO), to target the gene C9orf72.
• And a third, undertaken collaboratively with Columbia University and a company in California, Ionis, targeted the FUS gene. In these pilot programs, safety has been documented. Close follow-up and monitoring are underway to determine if these therapies are beneficial.
Outside these academic programs, two other achievements this year have been noteworthy.
• One was the demonstration by the Cambridge company Biogen that an ASO it developed with Ionis to target the SOD1 gene appeared to be slowing disease progression, at least in some rapidly progressing individuals.
• Another was a preliminary report by the company Amylyx that a two compound therapy it developed for sporadic ALS also appeared to be beneficial. The UMass ALS team was one of several sites involved in the Amylyx study.
Beyond these trial programs, the UMass ALS group had a banner year in ALS discovery.
We have completed trials of two different ALS drugs in ALS mice, with a third now underway. We have nearly completed an extensive study of how DNA mutations in the ALS gene C9orf72 alter chromosome folding and function in motor neurons of patients. And, we have continued efforts to develop new biomarkers for ALS.
• One involves a method of imaging of spinal cord that permits a quantitative measure of how effectively motor nerves transport materials from the muscle up to the spinal cord (axonal transport).
• Another, undertaken in collaboration with a team headed by Dr. Eran Hornstein at the Weizmann Institute in Israel, involves quantifying levels of a critical type of RNA (“microRNA”) in the spinal fluid. A junior faculty fellow supported in part by the Angel Fund, Dr. Claudia Fallini, demonstrated that a drug therapy could correct an ALS-related defect in the nuclear membrane of ALS neurons in cell culture; this work was co-led by Dr. John Landers (a former Angel Fund fellow). Another junior faculty member supported partially by the Angel Fund, Dr. Sandra Almeida, has collaborated with Dr. Fen-Biao Gao to study and publish mechanisms of toxicity of adverse proteins made by the C9orf72 gene.
All of us on the UMass ALS Team remain profoundly grateful to the Angel Fund, and the scores of supporters for their continuing generosity and support of our research program.
Robert Brown, Jr., D.Phil., M.D.