Research at the Day Lab
The Angel Fund for ALS Research supports the ALS (Lou Gehrig’s Disease) 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 Updates
Pilot human study shows novel treatment suppresses mutant ALS gene
The Angel Fund for ALS Research provides major funding
A clinical trial funded by The Angel Fund for ALS Research has shown
significant progress in suppressing expression of the most commonly mutated ALS gene, C9ORF72 (C9). The C9 gene mutation, a lengthy expansion of a repeated segment of six molecules of DNA, causes both familial ALS and frontotemporal dementia. The results of the human trial, initiated and led by Drs. Robert H. Brown and Jonathan Watts at UMass Chan Medical School, were published in Nature Medicine.
This is a major milestone and an exciting breakthrough in the efforts to find a treatment
for this neurodegenerative disease, according to Dr. Brown. The study was conducted on one
patient after being sanctioned by the FDA. Dr. Brown and the study team hope to expand the
study to as many as 10 patients in the coming months with further FDA approval.
To silence the C9 gene, the research team developed antisense oligonucleotides (ASOs)
that target the two RNA transcripts of the gene that contain the toxic, expanded segment of
nucleic acids. When the ASO was delivered into the spinal fluid, the activity of the gene was
substantially suppressed in the participant. The suppression was maintained by repeated doses of
the ASO, which were well tolerated without safety concerns in this pilot study. According to Dr.
Brown, while ASOs against this target region have previously been shown by investigators to attenuate expression of the C9 gene in neurons in cell culture and mouse models, the UMass–led
trial was the first to demonstrate this in a human. A trial of a comparable ASO is now also being
conducted by Biogen, Inc, in Cambridge; results from that study have not yet been reported.
“The Angel Fund for ALS Research has been committed to finding a treatment and a cure
for ALS for nearly three decades,” The Angel Fund said. “This is a giant leap forward on the
road to such a discovery. We are proud to fund this research and are excited with the promising
results of this clinical trial.”
Dr. Jonathan Watts commented, “The research team is excited and encouraged by these
results and we look forward to expanding our trial to include more individuals with C9 ALS and
frontotemporal dementia. We are grateful to The Angel Fund for ALS Research for their
In addition to the lead role taken by Drs. Brown and Watts, key participants included Drs.
Helene Tran and Michael Moazami, as well as an extensive clinical trials team. Beyond the
major funding from the Angel Fund, support was also provided by the National Institutes of
Health and other ALS organizations.
Brief Synopsis – Selected Research Projects conducted with Angel Fund Support
by Brown, Jr., D.Phil., M.D.
August 31, 2021
The last several months have been exciting and productive in the laboratory. In one project, we have been privileged to work with a graduate student, Kit Mocarski and her faculty co-mentor Dr. Paul Greer, to study patterns of a gene expression in ALS. Specifically, we have used a new technique called single cell transcriptomics to study literally thousands of genes that are expressed in spinal cords at different stages in ALS mice. Several patterns of changes are evident both in motor nerves and in other cell types. These changes develop overtime as the disease progresses. Moreover, we have investigated several key signaling molecules that are implicated in these changes in gene expression, some of which have been defined by Dr. Greer. We are optimistic that this study will define new targets for therapy.
In another project using ALS mice, we have been privileged to work with Dr Anastasia Khvorova, a nucleic acid chemist on our faculty, to study a new category of molecule she invented that can suppress gene function. Early data suggeset that Dr. Khvorova’s new platform will provide powerful new compounds to suppress toxic ALS genes. Her molecules, labelled disiRNAs, both bind their targets potently and permeate the brain extremely well. Thus far, they appear to be non-toxic as well.
A third ALS mouse project, funded by the Angel Fund, will examine aspects of head trauma in ALS mice. This investigation, conducted jointly with Dr. Nils Henninger, will test the hypothesis that head trauma is particularly adverse in the presence of mutant ALS genes. A fourth project, spearheaded by Dr. Karin Meijboom, is testing the use of gene editing (CRISPR) technology to correct mutations in ALS genes and thereby reverse the adverse manifestations of the mutant genes.
Jointly with Dr. Jonathan Watts, an Angel Fund awardee, we have extended our investigations of a nucleic acid compound (an antisense oligonucleotide or ASO) that targets the C9orf72 gene. As reported earlier, we have data from multiple animal studies clearly showing that this AS0 (designated afinersen) is effective in suppressing some of the biomarkers generated by mutations in the C9orf72 gene. Our hope is to acquire enough pre-clinical data, including multiple toxicity studies, to be able to test this in a series of patients with ALS or frontotemporal dementia caused by mutant C9orf72. In other studies, again performed jointly with Dr. Watts and also in collaboration with Dr. Kevin Eggan at Harvard, we have been exploring the possible use of a different set of ASOs to target selected genes that are implicated in sporadic ALS.
All of us in the laboratory remain incredibly grateful to the Angel Fund, and all of the Angel Fund supporters, for the continued generous support. The level of funding is remarkable, not only for its marked generosity, but also because it facilitates new lines of investigation and helps support several investigators who have so much to contribute to studies of ALS.
FDA 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.
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.
]br] 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.