Cecil B. Day Laboratory for Neuromuscular Research
The Cecil B. Day Laboratory for Neuromuscular Research was founded in 1983 to investigate genetic defects that cause neuromuscular paralysis. The focus of the initial investigations was a rare form of muscular dystrophy known as Miyoshi myopathy. A second disease that has been extensively studied in the Day Lab is Lou Gehrig’s Disease, or amyotrophic lateral sclerosis (ALS). Other research topics include periodic paralysis, a sensory-motor neuropathy (HSN1) and a form of adrenoleukodystrophy (Lorenzo’s Oil Disease). In each disease category, the initial research goal has been to identify primary gene defects that can cause these disorders. In each case, investigators in the Day Laboratory have been fortunate to participate in the discovery of underlying gene defects. The laboratory is now generating animal and Petri dish models of each disease as a first step toward developing treatments.
Research update from Dr. Robert H. Brown, Jr. – June 2016
Summary of Recent ALS Research
University of Massachusetts Medical School
by Dr. Robert H. Brown, Jr.
June 14, 2016
We are delighted that ALS continues to be a major research focus at the University of Massachusetts Medical School (UMMS). The program is supported enthusiastically from the highest levels of leadership, including both the Chancellor (Dr. Michael Collins) and the Dean (Dr. Terry Flotte). More than twenty principle investigators at UMMS pursue ALS research projects.
We are particularly excited that the Angel Fund has supported two new junior faculty investigators: Dr. Sandra Almeida in the laboratory of Dr. Fen-Biao Gao and Dr. Claudia Fallini in the laboratory of Dr. John Landers (a former Angel Fund fellow). As described in detail elsewhere, Dr. Almeida is an expert in using human stem cells to study how motor neurons die in ALS and the related disorder ALS with fronto-temporal dementia. Dr. Fallini employs petri dish models of motor neurons to investigate how defects in selected ALS genes impair the viability of motor neurons.
There continue to be exciting developments along several fronts in the UMMS ALS labs.
ALS Genetics: Remarkably, there are now upwards of 50 ALS genes, depending on how they are categorized and counted. Each new ALS gene is important because it defines new targets both for understanding and treating the disease. The UMass ALS genetics group, led by Dr. Landers, has recently reported three new ALS genes: profilin-1, tubulinA4, and NEK1. These genes were identified using different strategies. For example, profilin-1 was found using an older method, called gene linkage, applied to a large family that Dr. Brown had been studying, with branches in the U.S., France and Israel. By contrast, the tubulinA4 and NEK1 genes were discovered using newer, high throughput DNA sequencing techniques. It is encouraging that so many potential ALS genes are now known; that said, it is clear that many remain to be discovered.
ALS Models: The critical element in using genetics to devise therapies for ALS is understanding how gene defects lead to motor neuron degeneration. Members of the team have approached this using both in vitro, Petri dish models and animal models. Dr. Brown has investigated SOD1 mutations in transgenic ALS mice (with mutant SOD1) since 1995. The Brown lab, working with Drs. Marc Freeman and Jemeen Sreedharan, has also generated a new mouse model based on the gene known as TDP43. In 2015, Dr. Brown published a mouse model based on the common ALS gene C9orf72. Drs. Landers and Zuoshang Xu have recently developed mouse models for ALS caused by profilin-1 mutations. These mice will be invaluable in analyzing the events in motor neuron disease and in testing possible therapies.
ALS Biology: Several investigators at UMMS focus on disturbances of basic neuronal biology in ALS. Dr. Daryl Bosco continues her pioneering work in understanding how mutant ALS genes trigger cell death, with a focus on protein instability, protein aggregation and the formation of cellular structures known as stress granules. UMMS is extremely fortunate to have recruited Dr. Fen-Biao Gao, who has used the power of fruit fly genetics to discover how gene defects can trigger neuron-death in both ALS and fronto‐temporal dementia. As one example, Dr. Gao has recently published high profile reports on a mechanism whereby mutant C9orf72 impairs export of proteins from the nucleus of cells, with dire consequences for cell function and viability.
ALS Therapies: The broadest ALS treatment program uses RNA molecules to turn off the offending ALS genes. A principle strategy uses microRNA (miR) to silence genes, with delivery of the miR to nervous system with a virus known as adeno-associated virus (AAV). Dr. Miguel SenaEsteves and his doctoral student, Lorelei Stoica, have achieved outstanding silencing of SOD1 in the SOD1 mouse model, starting with injections into the brain at birth. Dr. Chris Mueller and a doctoral student Gaby Toro, have documented that intravenous infusion of the virus-miR can partially silence SOD1 in adult mice. Moreover, with Dr. Brown, this team has shown that the same approach clearly can silence SOD1 in non-human primates. A central, pivotal goal of the laboratory now is to bridge this treatment platform to urgently needed human trials.
In another program, Dr. Anastasia Khvorova has patented several chemical modifications that allow gene silencing reagents to permeate the nervous system and silence diseasecausing mutant genes, without depending on viral delivery. She has a new post-doctoral fellow who will test the efficacy of these compounds in ALS mice.
ALS Clinical Trials: Dr. Brown remains active in ALS therapy development. In addition to the mouse studies above, in collaboration with the Mass General Hospital and the Mayo Clinic he has just completed a trial of stem cells in ALS. This was done with the company Brainstorm Therapeutics from Israel. We should know by mid-summer if this therapy was effective.
Respectfully submitted With gratitude to the Angel Fund,
Robert Brown, Jr., D.Phil., M.D.
We will find the cure!!