New Funding for SBMA Research

The MDA announced the funding of $9.9 million dollars in research grants. The grant below is for the study of Kennedy's Disease.

Carlo Rinaldi, Ph.D., associate professor and clinician scientist at the University of Oxford in England, was awarded an MDA Development Grant to study how variants in the gene of the androgen receptor (AR) protein cause spinal-bulbar muscular atrophy (SBMA) and investigate whether a novel antisense oligonucleotide therapy approach can target these toxic variants. The results of the study will provide a better understanding of SBMA disease mechanisms, as well as develop a new therapy potentially capable of treating the disease.

This work has potential implications for other diseases of the motor unit as well, including spinal muscular atrophy (SMA) and ALS. This grant is co-funded by the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM).

Additional information was provided on another page:

“Better understanding of the underlying disease mechanisms, coupled with improvement of gene vector design, therapeutic gene selection, and methods of delivery, have made gene therapy a realistic option for neuromuscular conditions — and neurological diseases in general — for which no treatment option was available until few years ago. Many challenges still lie ahead, but we have good reasons to be very optimistic for the future.”

Carlo Rinaldi, associate professor and clinician scientist at the University of Oxford in England, was awarded an MDA Development Grant totaling $120,000 over 3 years to study the role of androgen receptor isoforms in SBMA pathogenesis and the potential as therapeutic targets. This grant is co-funded by the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM).

Mutations in the gene encoding the androgen receptor (AR) protein cause spinal and bulbar muscular atrophy (SBMA). SBMA is an adult-onset neuromuscular condition affecting males with unmet clinical need. It is not undestood how mutations in AR lead to primary degeneration of motor neurons and muscle in patients. The activity of AR and other hormone receptors can be modulated in human cells by isoforms and/or splice variants, which may block or enhance their functions.

Dr. Rinaldi and colleagues plan to investigate the role of AR alternative isoforms in mediating SBMA toxicity. By revealing how these isoforms regulate AR activity in health and disease, researchers expect to better understand the mechanisms of disease in SBMA and provide a novel rational therapeutic target. If successful, the work could pinpoint tissue-specific targets for therapy development, with implications not only for SBMA but for other diseases of the motor unit as well, including spinal muscular atrophy and amyotrophoic lateral sclerosis.

KDA Awards Five Research Grants

Five research grants were awarded totaling $199,000. Award recipients and summaries are listed below.

Award $50,000
Targeting AR toxicity in SBMA by modulation of USP7 activity.
Anna Pluciennik, Ph.D.
Department of Biochemistry and Molecular Biology
Thomas Jefferson University

Summary: PolyQ-expanded androgen receptor-dependent cellular toxicity in the neuromuscular system is a characteristic feature of SBMA pathogenesis, although the molecular mechanisms for these effects are poorly understood. However, because cellular toxicity in SBMA is likely to arise, at least in part, from the polyQ-expanded-dependent dysregulation of protein-protein interactions that sustain normal cellular function, we reasoned that identification of such dysregulated interactions might help reveal potential therapeutic targets for disease modification. Therefore, as part of a KDA-funded project (2014), we used a quantitative proteomics approach and identified a deubiquitinating enzyme, USP7, that preferentially interacts with polyQ-expanded AR and contributes to toxicity. In fact, we have demonstrated that not only does partial knockdown of USP7 protein expression decrease mutant AR-dependent aggregation and dihydrotestosterone-dependent cytotoxicity, but also that overexpression of the protein aggravates these cellular effects. These results establish the need for further investigation into the role of the deubiquitinating function of USP7 in SBMA pathogenesis. The objective of this -research is to investigate the functional consequence of pharmacological inhibition of USP7 deubiquitinase activity in cellular and mouse models of SBMA. These studies will extend our previous KDA-funded proteomics work and, if successful, will establish the validity of inhibition of USP7 activity as a therapeutic approach for the treatment of SBMA.

Award $50,000
Identification of New Polyglutamine-Specific Mutant AR-Interacting Proteins in SBMA Motor Neurons
Xia Feng
Postdoctoral Fellow, Neurogenetics Branch
National Institute of Neurological Disorders and Stroke, National Institute of Health

Summary: Spinal and bulbar muscular atrophy (SBMA) is a slowly progressive neuromuscular disease. As the disease proceeds, nerve cells in the spinal cord (called motor neurons) start to die and muscle cells will waste away. The causative mutation of SBMA is the mutant androgen receptor (AR) with an abnormal expansion in the certain region. Such aberrant expansion in the mutant protein (called a polyglutamine tract) damages the normal function of the protein as well as obtains toxicity. Thus, it is important to understand how the mutant AR is regulated via other proteins in the disease. Here, I propose to use a human induced pluripotent stem cell model to generate disease-relevant motor neuron-like cells, and use these cells to identify specific interacting proteins of the mutant androgen receptor. I am hoping that my research will help provide a motor neuron-specific basis for designing and developing novel therapeutics for the treatment of SBMA.

Award $33,000
Transcellular regulation of the proteostasis network in Kennedy’s disease
Laura Bott, Ph.D.
Postdoctoral Fellow
Molecular Biosciences, Northwestern University

Summary: Misfolding and abnormal accumulation of the mutant androgen receptor in Kennedy’s disease indicates that the cellular machinery controlling protein abundance, folding, and transport (proteostasis) may be defective in the disease. We are planning to study molecular mechanisms of Kennedy’s disease in the worm Caenorhabditis elegans. For this, we will genetically engineer worms to express the mutant androgen receptor in the neuromuscular system and assess effects of the polyglutamine expansion on proteostasis regulation in this model organism. Insights into cell type-specific effects and regulation across tissues may lead to new therapeutic approaches for this disease.

Award $33,000
One gene, many proteins: investigating the role of AR isoform 2 as a therapeutic target for SBMA
Carlo Rinaldi, MD, PhD
Department of Physiology, Anatomy and Genetics
University of Oxford

Summary: The activity of steroid hormone receptors, such as progesterone and oestrogen receptors, is modulated by a number of isoforms and splice variants in a tissue-specific manner, in both health and disease. Androgen receptor may be no exception. AR isoform 2, or AR45 by the molecular weight of its encoded widely-expressed protein, is the only naturally occurring AR isoform, arising from use of an alternative transcriptional start site in intron 1 of the AR gene and containing a short, unique seven amino-acid-long N-terminal stretch instead of the long N-terminal domain found in the full length AR. Overarching aim of this proposal is to unravel the contribution of AR isoform 2 to SBMA pathogenesis and provide a novel therapeutic target for this disease, suitable for oligonucleotide antisense targeting without running the risks associated with silencing of the only available copy of the AR gene in males.

Award $33,000
The use of induced stem cells and microfluidics for developing new assays to identify new therapies for Kennedy’s disease
Thomas M Durcan, Ph.D., Assistant Professor,
Montreal Neurological Institute, McGill University

Summary: It is important to explore new avenues in the search for treatments for Kennedy’s disease (KD). Our overall goal is to develop disease-relevant assays that use human motor neurons made from stem cells of both men with Kennedy’s disease and healthy individuals. Using special silicone microfluidic devices to grow motor neurons, we will measure the function of neurons upon exposure to different compounds. First, we will develop assays to measure the survival and growth of the motor neurons. Next, we will look at the how well mitochondria work and move within the neurons. Finally, we aim to set up an assay to test the ability of the normal and KD motor neurons to form synapses (junctions). Taken together, these innovative assays will provide a foundation to build a KD drug discovery platform to screen for promising compounds and targets to treat KD.

Another call for action - NIH Budget Cuts

Take action to prevent cuts to federal research funding

We need your help to urge Congress to reject proposed cuts to National Institutes of Health (NIH) research funding. Support for NIH is critical as it is the largest funding source of biomedical research in the United States, and why ensuring adequate funding for NIH is one of MDA's policy priorities. While research funding from organizations like MDA - which has invested more than $1 billion in research - is significant and is moving the needle, robust federal funding is essential to finding treatments and cures. Congress has come together in a bipartisan effort to support NIH funding in recent years, and it is up to all advocates to ensure that the bipartisan support continues. NIH fuding was increased in fiscal year (FY) 2016, and increases were proposed for FY17, though a final budget agreement for FY17 has not yet been enacted. It is a concern that there is no final budget in place for the current fiscal year, but of greater concern are the NIH budget cuts outlined in the President's budget blueprint (a $5.8 billion cut to NIH equivalent to 18% of the overall budget).

We must work together to ensure that research funding is not cut, and that NIH support continues to grow through strong bipartisan support in Congress. To deliver this message in person, researchers from leading institutions around the country visited Capitol Hill on March 22 in conjunction with MDA's 2017 Scientific Conference to urge Congress to reject any proposed funding cuts and to instead enact sustained and robust funding increases for the National Institutes of Health (NIH).

Now it is your turn to amplify this message. Please take a moment today to urge your members of Congress to maintain the bipartisan support for research and to reject any proposed cuts that would harm quest for the development of treatments and cures. 

We need to be heard! 

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