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KD Research

Research Grants

Summer 2024 - KDA Awards Grants to Research Teams

Thanks to generous donations from our members, KDA recently awarded $100,000 grants to two teams of researchers who participated in the 2023 SBMA Research Workshop held at the Banbury Center in New York. The workshop, funded by donations to the 2023 KD Golf Scramble in Magnolia, Texas, brought together participants from 15 labs in the U.S. and three other countries to discuss collaborative approaches between SBMA researchers and experts in other diseases.  

The team of Dr. Al La Spada from the University of California, Irvine, and Mina Gouti, PhD, from the Max Delbruck Center for Molecular Medicine in Berlin will study the question of “How does skeletal muscle expression of mutant AR result in motor neuron degeneration in SBMA?” The team of Helen Miranda, PhD, and Ashleigh Schaffer, PhD, of the Department of Genome Sciences at Case Western Reserve University in Cleveland will investigate “Gene expression, regulation by AR with different CAG repeat sizes in hiPSC-derived neuromuscular junctions." Both projects will use leading-edge research techniques.

KDA congratulates these scientists for their collaborative efforts, and we look forward to the results of their research. We also look forward to this year's Banbury SBMA workshop, again funded by the KD Golf Scramble. Twenty-two participants from six countries will meet to discuss the role of the cellular protein quality control system in SBMA (Kennedy's disease).

Photo courtesy of Banbury Center

KDA Awards $437,000.00 In Research Grants For 2023

As of October 2023, the KDA has awarded $2,453,617.00 in research grants to help find a cure or treatment for Kennedy's Disease. Please scroll down to see the past grant award recipients. 

KDA Waite-Griffen SBMA Fellowship

In 2022, the KDA announced the launch of the first-ever "KDA Waite-Griffen SBMA Fellowship". Because the KDA is relatively small and funding is limited, our focus in recent years has been to provide “seed-money” to post-doc and other young researchers who do not currently have the funding or credentials to receive funding from larger organizations such as the National Institute of Health or the MDA. This “seed-money” normally provides the researcher an opportunity to further his/her research while giving him/her time to apply for other grants.

Grant Award Process

The KDA grant awarding process takes place in the fall. In the late summer, the KDA announces to all known Kennedy’s Disease Researchers that anyone interested should send in their grant requests as outlined in the proposal notification.  The Scientific Review Board reviews all applications with a focus on research projects that are specific to or could be used in finding a treatment or cure for Kennedy’s Disease.  The Scientific Review Board recommends to the Board of Directors which applicant(s) should receive research funding.  The Board of Directors notifies all candidates and awards the grants normally in October.

Grant Award Recipients

2023 Grant & Fellowship Awards.

The KDA rewarded four research grants and one fellowship totaling $437,000. Award recipients are listed below.

  • $100,000 - "Identification and characterization of kinase(s) responsible for androgen receptor phosphorylation at serine 16", Masoud Shekarabi, Thomas Jefferson University.
  • $69,000 - "Connecting SBMA national registries databases: a retrospective study" Davide Pareyson, Besta Institute, Milan, Italy (two-year award) $46,000 (2023) and $23,000 (2024).
  • $91,350 - "Polyglutamine expansion in aggregation AR in cells", Xavier Salvatella Giralt, IRB Barcelona, Spain (two-year award) $49,350 (2023) and $42,000 (2024).
  • $100,000 - "Investigating the role of CD38 in metabolic dysregulation in Kennedy’s Disease", Heather Montie, Philadelphia College of Osteopathic Medicine
  • $75,000 - "Investigating differences in polyQ-AR genomic activity leading to muscle atrophy in SBMA", Anastasia Gromova, University of California, Irvine. Recipient of the 2023 Waite-Griffin SBMA Fellowship

2023 Grant & Fellowship Summaries

Summary - $91,350. Polyglutamine expansion in aggregation AR in cells: The Salvatella laboratory in IRB Barcelona has recently shown that the androgen receptor works by forming nuclear clusters called transcriptional condensates. AR condensation can be beneficial because it facilitates gene expression; however, it can also accelerate protein aggregation, a process in which protein molecules lose their activity by forming insoluble clumps that are harmful to cells. With the support of the KDA the team will investigate whether the polyglutamine expansion associated with Kennedy’s disease causes transcriptional condensates to become dysfunctional due to androgen receptor aggregation. In addition, it will test whether drug-like molecules can accumulate in the transcriptional condensates formed by the mutated receptor and prevent its aggregation. The work will increase our understanding of the molecular basis of the disease and allow us to explore a new therapeutic avenue for Kennedy’s disease.

Bio: Xavier Salvatella studied chemistry at the University of Barcelona (BSc) and Queen Mary College, London (MSc). He completed his PhD at the University of Barcelona, where he studied the interaction between synthetic molecules and hydrophilic surfaces in proteins such as the tumour suppressor P53. He conducted postdoctoral work at the University of Cambridge, combining experiments and simulations to investigate the structural heterogeneity of intrinsically disordered, partially folded and globular proteins. He leads the laboratory of molecular biophysics at IRB Barcelona, where he studies the involvement of intrinsically disordered domains in disease and how to inhibit their functions with drug-like small molecules. Recently, he co-founded the company Nuage Therapeutics, which develops drugs targeting intrinsically disordered targets for oncolog

Summary - $100,000. Investigating the role of CD38 in metabolic dysregulation in Kennedy’s Disease: The energy that skeletal muscles need to function well with strenuous activity is greatly reduced in models of Kennedy’s Disease. Our aim is to identify therapeutic targets that will help fix metabolism in skeletal muscle to help increase this energy and improve muscle function in Kennedy’s Disease.

Heather L. Montie, PhD
Bachelor of Science (BS), Aquinas College, Grand Rapids, MI (Biology) (2000)
PhD Wayne State University, Detroit, MI (Physiology) (2005) (Thesis advisor: Donald DeGracia, PhD)
Postdoctoral Fellowship studying Kennedy’s Disease (SBMA), Thomas Jefferson University (2005-2013) (postdoctoral advisor, Diane E. Merry, PhD)
Prostate Cancer Foundation-Young Investigator, Postdoctoral Fellowship, Thomas Jefferson University, (2011 – 2013) (postdoctoral advisors, Diane E. Merry, PhD and Karen E. Knudsen, PhD)
Assistant Professor, Department of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, (2013-2018)
Associate Professor, Department of Bio-Medical Sciences, Philadelphia College of Osteopathic Medicine, (2018-present)

Summary - $75,000. Investigating differences in polyQ-AR genomic activity leading to muscle atrophy in SBMA: At the heart of Kennedy’s Disease (KD) pathogenesis is the potent reduction of core muscle genes that encode contractile proteins, unsurprisingly leading to muscle loss, but we do not yet fully understand how polyglutamine-expanded AR (polyQ-AR) causes this. We and others have observed that in muscle of KD mouse models, the activity of a transcription factor critically important for sustained muscle gene expression called MEF2 becomes highly defective. MRF4, another muscle transcription factor, is known to repress the activity of MEF2 to prevent uncontrolled muscle growth, and knockdown of MRF4 in muscle cells grown in a dish causes a reduction in polyQ-AR protein levels. This study will determine if MRF4 is involved in KD muscle loss by assessing if disease course is altered in model mice that lack the MRF4 gene. We will also apply cutting-edge genomic techniques to investigate where in the genome of mouse muscle AR and polyQ-AR is binding, and whether those patterns are affected by loss of MRF4. These experiments will provide critical insight into how AR’s interaction with the genome of fully mature, physiological muscle cells is altered by the polyglutamine expansion and whether MRF4 mediates this alteration.

Bio: Anastasia has been studying KD since 2016, when she joined Dr. Albert La Spada’s lab as a first year Biomedical Sciences graduate student at UC San Diego. Coming from a research background in skeletal muscle regeneration and muscular dystrophy, she was instantly awestruck by a 2015 lecture by Dr. Constanza Cortes, then a postdoc in the La Spada lab, in which Dr. Cortes presented their findings on the requirement of polyglutamine-expanded AR expression in skeletal muscle as being necessary for both muscle and motor neuron degeneration. Now a postdoc herself at UC Irvine, she continues to be strongly committed to solving the paradox of KD: despite the well-established pro-hypertrophic effect of androgen signaling and the fact that even polyQ-AR seems to correctly orchestrate male development — including the increased accumulation of muscle mass and strength during male adolescence, why does polyQ-AR instead cause muscle atrophy at older ages? Anastasia hopes to continue working on this critically important question to help the men afflicted with KD and their families in the future in her own lab as an independent investigator, building off the exceptional mentorship and support of Dr. La Spada and the KDA community. Originally from St. Petersburg, Russia, Anastasia has been happy to call SoCal home for over 16 years since starting her undergraduate studies at the University of San Diego. In her free time, she enjoys baking for the lab, supporting the San Diego Zoo Wildlife Alliance, and training to compete in powerlifting.

2022 Grant & Fellowship Awards.

Award recipients are listed below.

In 2022, the KDA awarded two Waite-Griffin SBMA Fellowships, named in honor of the
people who founded the KDA. This is a one-year stipend of $75,000 for a junior PhD or MD
interested in a career in SBMA research and/or patient care. An additional $2,000 is
provided for travel and/or educational expenses. The awardee is expected to devote at least
70% of their time to SBMA research. The fellowship may be extended with demonstrated
progress in SBMA research. Following is a summary of the 2022 Waite-Griffin Fellowships

Developing an imaging biomarker in spinal and bulbar muscular atrophy (SBMA)
Abdullah AlQahtani, MD, MPH
Senior Clinical Research Fellow, NGB, NINDS

Candidate therapeutic strategies have been tested in preclinical models of SBMA, and
potential disease-modifying therapies will soon be evaluated in future clinical trials.
However, without appropriate biomarkers to assess disease progression reliably over a short
period of time, studies would require a large sample size and long duration to evaluate
efficacy. The goal of this study is to identify neuromuscular ultrasound (NMU) parameters
that serve as sensitive, reproducible, and cost-effective disease biomarkers for evaluating
efficacy in future therapeutic studies in spinal and bulbar muscular atrophy (SBMA). In
addition, the project will develop an ultrasound protocol to be used by neuromuscular
specialists in clinical practice to improve diagnostic accuracy and result in an earlier

Using Drosophila exercise for therapeutic discovery in Kennedy’s Disease
Alyson Sujkowski, PhD

Endurance exercise is a potent intervention with widespread benefits proven to reduce
disease incidence across species. While endurance exercise supports neural plasticity,
enhanced memory, and reduced neurodegeneration, less is known about the effect of
chronic exercise on the progression of movement disorders like Kennedy’s Disease (KD).
Initial work has revealed protection of speed and maximal lifespan in exercised KD model
flies. Based on these preliminary observations, there are two specific aims. First, evaluate
the role of endurance exercise on a broad spectrum of KD phenotypes and second,
determine molecular mechanisms of protection from exercise that may be leveraged in the
future toward the development of targeted therapeutics.

In 2021, research grants were awarded totaling $175,000.

Award recipients are listed below as well.

Carlo Rinaldi, Oxford University ($75,000 for one year)
We plan to elucidate polyQ AR transcriptional altered activity and its role in SBMA pathogenesis, filling a fundamental gap in the understanding of this disease, and to unravel the therapeutic mechanism of action of AR45, a naturally-occurring AR isoform able to fine-tune AR transcriptional activity. Ultimately our goal is to bring a gene therapy approach based on therapeutic delivery of AR45 into first-in-man clinical testing for SBMA patients.

Shinichiro Yamada, Nagoya University: ($50,000 per year for two years)
Most patients with SBMA experience cold exposure, a worsening of muscle movement under cold temperature, which is caused by muscle membrane hyperexcitability due to abnormal sodium current alteration. Based on the clinical and basic studies, we carried out a placebo-controlled, randomized, double-blind, multicenter, crossover exploratory clinical study of the efficacy and safety of mexiletine hydrochloride, a sodium channel blocker, in SBMA patients. ALSFRS-R which reflect comprehensive motor function and quantitative muscle strength in SBMA patients were tend to be improved in the mexiletine group. Therefore, we will prepare a confirmatory clinical trial with change of ALSFRS-R as the primary endpoint. This study will be the first trial to confirm the efficacy of mexiletine hydrochloride administration in SBMA patients.

In this proposal, we are also planning a biomarker study in parallel to support the results of the clinical trials. We will measure urine titin and serum neurofilament light chain (NfL) as a biomarker of motor neuron degeneration in the patients with SBMA and female carriers in SBMA that may reflect early pathophysiology of SBMA patients.

2020 - Four research grants were awarded totaling $196,200. Award recipients are listed below. 

Characterizing the high prevalence and founder effects for Kennedy’s disease in Indigenous peoples of western Canada.
Dr. Gerry Pfeffer (University of Calgary)

In this project, we will learn about the prevalence and genetic findings of patients with Kennedy's disease who are of Indigenous descent in western Canada. We have a community engagement plan that will include patients as partners in this research. Participants will be recruited using clinic databases, research assistant contact in our clinics, and contact with family members of recruited participants. We will collect clinical data and family history information. We will also collect DNA samples to identify founder haplotypes. Once we have estimates for the prevalence and genetic origins of Kennedy's disease in these communities, we will communicate results back to participants and communities. This will lead to future study and one of our main goals is to ensure that these communities are receiving the resources they need to support people affected by Kennedy's disease.

Targeting the interaction of poly-Q expanded AR receptor with pVHL to ameliorate SBMA
Antonella Falconieri, PhD (University of Padova)

Spinal and Bulbar Muscular Atrophy (SBMA) is a neuromuscular disease caused by poly-glutamine (poly-Q) expansions in the androgen receptor (AR), which result, upon ligand binding, in misfolding, aggregation and accumulation. A factor contributing to AR aggregation in SBMA cells is inefficient degradation. AR has been shown to interact with the von Hippel-Lindau protein (pVHL), an E3 ubiquitin ligase that I found to associate with MDM2, protein involved in AR degradation. Here, I propose to elucidate the molecular details of AR/pVHL association and investigate its biological effects to demonstrate the role of pVHL in AR degradation. I will also test PROTAC molecules, already used to induce AR degradation in prostate cancer through pVHL, to study their efficacy in pVHL/MDM2-mediated polyQ-AR degradation in SBMA cells. These experiments may ultimately lead to development of a novel therapeutic strategy for SBMA treatment.

A drug repurposing strategy to inhibit AR transcriptional coactivators as a therapeutic approach in SBMA
Manuela Basso, PhD (University of Trento)

Kennedy’s disease is a neuromuscular condition caused by a mutation in the androgen receptor (AR). AR is a transcription factor, which means that it controls what the cells need to transcribe or not to stay healthy. It does that by interacting with other proteins called transcriptional coactivators. The mutation leads to a protein with altered functions; some are lost, others are enhanced. We have collected interesting evidence that by modulating the interaction with two specific AR partners that are increased during the disease, we can reduce the aberrant AR activity and preserve its normal function. We propose to investigate how the enhancement of these two factors contributes to motor neuron and muscle pathology. At the same time, we propose to use safe and well-tolerated drugs that inhibit these two factors to test whether this could be a successful therapeutic approach for the patients.

Unveiling regenerative and metabolic features of SBMA muscle cells to identify new therapeutic targets.
Mariarita Galbiatti, PhD (University of Milan)

Skeletal muscle cells have a primary role in the SBMA pathogenesis. The aim of this project is to clarify how the elongated androgen receptor induces muscle fiber dysfunctions. To achieve this goal, we will take advantage of induced pluripotent stem cells differentiated to skeletal muscle cells, and of skeletal muscle of an SBMA mouse model at different disease stages. We will focus on two different processes: the metabolism and the regenerative ability of SBMA affected muscle cells. Explaining the mechanisms of toxicity of the elongated androgen receptor in muscle will permit us to target therapeutics to key pathological stages, and to identify useful biomarkers for disease diagnosis and the reading of clinical trial results.

2019 - Five research grants were awarded totaling $276,125.

Award recipients are listed below.

Award $51,250
Understanding of early-stage defects in SBMA by allele-targeted therapeutics
Kentaro Sahashi.

Award $50,000
Exploring the contribution of the function of mutant ar in the pathogenesis of sbma 
Eric Anderson and Emanuela Zuccaro

Award $50,000
Investigating disease pathways and novel therapeutic targets in Spinal and Bulbar Muscular Atrophy 
Bilal Malik:

Award $75,000
Generation of a high through putin vivo assayto test potentials therapeutics for SBMA
Heather Montie

Award $50,000
Epigenetic signatures as novel non-invasive blood-based biomarkers for Spinal bulbar muscular atrophy or Kennedy’s disease
Wooi Fang and Catheryn Lim

2018 - Four research grants were awarded totaling $200,000

Award recipients are listed below.

Award $50,000
Using SBMA patient derived stem cells to investigate differential AR gene expression regulation in affected cell types 

Helen Cristina Miranda, Assistant Professor Case Western Reserve University Department of
Genetics and Genome Sciences

Award $50,000
Selective translation of androgen receptor isoform A to prevent polyQ mediated toxicity in Kennedy’s Disease

Riccardo Cristofani, PhD Dipartimento di Scienze Farmacologiche e Biomolecolari (DiSFeB)
Università degli Studi di Milano

Award $50,000
Role of Ser96 phosphorylation in AR pathogenesis

Laura Tosatto, PhD Institute of Biophysics, National Council of Research, Unit of Trento Italy

Award $50,000

Investigating the role of the Excitation‐Contraction‐Coupling machinery in SBMA muscle pathology.

Marco Pirazzini, Ph.D Neurotoxins, Neurodegeneration and Regeneration Lab University of
Padova Dept. of Biomedical Sciences

2017 - 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, PhD.
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 The use of induced stem cells and microfluidics for developing new assays to identify new therapies for Kennedy’s disease

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.

2016 - Three research grants were awarded totaling $150,000. Each grant recipient received $50,000 each. 

Dr Bilal Malik

Professor Linda Greensmith’s Lab, UCL, Institute of Neurology, UK

Targeting pathways of disease in Spinal Bulbar and Muscular Atrophy (SBMA)

Spinal and Bulbar Muscular Atrophy (SBMA), also known as Kennedy’s disease (KD), is adult-onset slowly progressing rare inherited neuromuscular disorder that primarily affects males. As yet there are no effective treatments that can cure the disease or delay its progression. The disease is primarily characterised by muscle weakness and wasting, and degeneration of motor neuron cells within the spinal cord and brain.

Our aim is to establish why motor neurons and muscles degenerate in SBMA by investigating the genes and pathways that underlie disease. The identification of changes that occur early in disease may identify the mechanisms responsible for disease and help establish novel therapeutic targets. This proposal offers the unique opportunity to undertake a comparative study of two platforms that model SBMA, each with its own merits: i) a well-characterised mouse model in which muscle and motor neurons can be examined at various stages of disease, and ii) human cell models, including stem-cell derived motor neurons and patient muscle cells acquired from biopsies. By comparing and contrasting the changes in gene expression in these models of the specific cells affected in SBMA we hope to identify the key changes in gene expression that take place early in disease, identifying a common signature in the pathways of pathology. The results of this study will not only help define novel therapeutic targets with a greater level of confidence by analysing several complimentary models of SBMA, but also allow us to test treatment strategies in a human cell model of the disease.

Dr. Janghoo Lim
Yale University School of Medicine

The role of VCP in the pathogenesis of Kennedy's disease

Spinal and Bulbar Muscular Atrophy (SBMA; Kennedy’s Disease) is a neuromuscular disease that affects motor neurons and skeletal muscles. The symptoms of SBMA include progressive weakness of the limbs and facial muscles, as well as difficulty with speaking and swallowing. SBMA is an X-linked disease that primarily affects men, and is caused by a polyglutamine
expansion in the gene Androgen Receptor (AR). The polyglutamine expansion in AR makes the protein toxic, and can lead to the formation of protein aggregates inside of cells as well as cell death. SBMA is one of nine different polyglutamine expansion disorders that are linked to neurodegeneration. How polyglutamine expanded AR causes SBMA is still being studied, and there are no effective therapeutics available. In order to better understand the mechanisms that cause SBMA and translate these results into the development of effective therapeutics, my proposal aims to assess how the protein Valosin-Containing Protein (VCP) is involved in SBMA. VCP plays a role in breaking down mutant or damaged proteins, and has been studied in other neurodegenerative disorders. Based on our preliminary data, we hypothesize that VCP can regulate the expression and/or the activity of polyglutamine expanded AR. Our proposal will examine how VCP affects the development of protein aggregates and cell death in SBMA. We will use cell culture models and fruit flies, both of which are commonly used to study SBMA. This research will help develop a more thorough understanding of what causes SBMA, and provide important information when developing new therapeutics for this devastating disease.

Manuela Basso, Ph.D.
Assistant Professor
Laboratory of Transcriptional Neurobiology
Centre for Integrative Biology
University of Trento

Insights into the molecular pathology of SBMA: Targeting PRMT6 to attenuate the disease.

In collaboration with the Laboratory of Dr. Pennuto, we have recently discovered that a protein, called PRMT6, exacerbates the toxicity induced by mutant androgen receptor, while its inhibition rescues it in cells and flies. Our strategy is to develop a therapy that preserves AR physiological functions while abolishing the toxicity acquired upon polyglutamine expansion. Thus, we propose to silence PRMT6 both via selective pharmacological inhibitors and via gene-silencing to choose the best system to move our studies in pre-clinical models.

provide important information when developing new therapeutics for this devastating disease.

2015 - Two research grants were awarded totaling $100,000

Project Title - 'Insights into the Molecular Pathology of SBMA'
Miltiadis Paliouras, Ph.D. – Principal Investigator
Assistant Professor, Department of Medicine, McGill University

We have recently undertaken a proteomics study, coupled to a comparative systems biology analysis to characterize the protein composition of polyQ-Androgen receptor (polyQ-AR) complexes vs. wild-type-AR (WT-AR) complexes.  The data shows that AR-interacting partners change dynamically between polyQ-AR and the WT-AR.  Our initial results indicate that the polyQ-AR associates with several RNA-binding proteins that participate in RNA metabolism, presumably through an alternative RNA-splicing pathway.  The possibility that a transcription factor protein like the AR could also bind to RNA is very plausible; and has been previously described by pioneers in the AR field.  

We have employed a unique and powerful genetic approach of using a “humanized” polyQ-AR Drosophila (fly) model that allows us to ectopically express the polyQ-AR in the developing fly embryo. By crossing polyQ-AR flies to RNAi flies of homologous genes encoding candidate polyQ-AR RNA-binding protein interactors, we have been able to identify a number of ligand-dependent enhancers and suppressors.

As neuronal survival has been area of investigation for trinucleotide repeat diseases, and is thought to contribute to disease etiology and pathology, we have specifically focused on mitochondrial dysfunction and apoptosis, and proteasome inhibition.  We will study the impact of overexpressing and silencing selected interactors from our fly genetic interaction screen, on cellular processes associated with SBMA such as androgen ligand- and polyQ-AR-induced mitochondrial dysfunction and proteasome inhibition.  To do so, we will be using mouse motor neuron-derived cell lines expressing 65Q- and 24Q-AR, and transfected HEK-GFPu cells, respectively.

Our approach of combining proteomics and systems biology is extremely well suited to unraveling complex biological systems and has already proven extremely useful.  In the future, we will be interested how polyQ-AR would also impact on the global alternative RNA splicing profile of SBMA patients, and determine the correlation to neuronal survival.  These experiments will enable us to infer potentially new molecular mechanisms of polyQ-AR function and give us insight into the mechanisms underlying neurodegeneration in SBMA. 

Project Title: ‘Characterizing the AR-TFEB Interactome in SBMA’.
Constanza J. Cortes, PhD
University of California, San Diego (UCSD)
Sanford Consortium for Regenerative Medicine

Protein-protein interactions are one of the key regulatory steps to normal protein function. Understanding how these protein complexes are altered with mutant AR versus normal AR is key to uncover new mechanisms of mutant AR toxicity in Kennedy’s Disease. In particular, I have previously shown that in Kennedy’s disease, AR can switch between activating or inhibiting a cellular recycling process known as autophagy by altering its interaction with novel co-regulator Transcription Factor E-B (TFEB). In this project, I will define the interacting partners of the AR-TFEB duplex, with the ultimate goal of identifying novel proteins that regulate this molecular switch and have important therapeutic potential for KD.

2014 - Two research grants were awarded totaling $100,000

Anna Pluciennik, Ph.D., a researcher at Dr. Diane Merry's Lab, Department of Biochemistry and Molecular Biology, Thomas Jefferson University

Amount  Awarded:  $50,000

Project title: Protein interaction networks in the pathogenicity of SBMA
The molecular mechanisms of polyglutamine (polyQ) -induced neuronal cell death that underlies pathogenicity of Kennedy’s disease are poorly understood. Several hypotheses have been put forward to explain the cytotoxic consequences of polyQ expansion in androgen receptor (AR) at the molecular level. These include aberrant protein-protein interactions, altered post-translational modifications, and perturbations to global protein folding homeostasis. The objective of this proposal is to determine the effect of polyQ expansion on the protein-interaction network of the AR. We will test the hypothesis that the protein-interaction network of the AR is significantly altered by the expansion of the polyQ element. Towards this end, we will employ quantitative proteomics tools (SILAC) to identify protein interaction partners of the AR that are differentially affected by polyQ expansion. Using this approach, we will also examine protein –protein interactions broadly with polyQ expanded AR versus interactions that are specific to the soluble aggregated forms of the polyQ expanded AR. This may be significant since there is growing evidence that soluble, aggregated, misfolded polyQ-expanded proteins are likely mediators of neuronal dysfunction and cytotoxicity. Altered AR interactome components discovered in this manner will not only shed light on the pathogenic mechanisms of Kennedy’s disease but also yield attractive pathways and targets for development of therapeutic interventions.

Helen Cristina Miranda, postdoctoral researcher at Al La Spada's Lab, University of California, San Diego

Recent findings from our lab predict that muscle-directed therapies hold great promise as definitive treatments for SBMA motor neuron degeneration. Therefore, our goal in this proposal will be to use our well established human SBMA induced pluripotent stem cell (iPSC) model system to generate a human-based muscle toxicity model and recapitulate the noncell autonomous pathogenesis in SBMA. We will co-culture the iPSC-derived muscles with our iPSC-derived motor neurons cells to determine muscledependent toxicity by assaying motor neuron survival and mitochondrial membrane potential in the respective co-culture conditions. Our iPSC model for SBMA will allow us to use a stem cell approach to evaluate muscle dependent non-cell autonomous motor neuron degeneration for the first

Amount  Awarded:  $50,000

2013 - Two research grants were awarded totaling $100,000

Heather Montie, PhD, Philadelphia College of Osteopathic Medicine

Amount  Awarded:  $50,000

Project Title: Investigating androgen receptor acetyltransferases as therapeutic targets for the treatment of spinal and bulbar muscular atrophy The nature of the nuclear events that transform the polyglutamine(polyQ)-expanded androgen receptor (AR) into a toxic species are a major focus of study in the field of spinal and bulbar muscular atrophy (SBMA). It is unknown at what point in its metabolism the mutant AR becomes toxic to motor neurons and skeletal muscle. However, Dr. Montie's work, along with studies from other laboratories, has begun to dissect a number of potential pathological pathways, with the intention of defining therapeutic targets for SBMA. Dr. Montie has demonstrated that inhibition of mutant AR acetylation decreases its aggregation and toxicity in cell models of SBMA (Montie HL,
et al. SIRT1 modulates aggregation and toxicity through deacetylation of the androgen receptor in cell models of SBMA. J Neurosci. 2011. 31(48):17425-36). She is in the process of generating mouse models that will enable continued investigations into the role of polyQ-expanded AR acetylation in vivo. Dr. Montie is interested in targeting the AR acetyltransferases, Tip60 and ARD1 as potential lines of therapy for SBMA. Support of this project by the Kennedy's Disease Association will enable Dr. Montie to generate preliminary data for grant applications to the National Institutes of Health (NIH) and the Muscular Dystrophy Association to support her new, independent research laboratory at Philadelphia College of Osteopathic Medicine.

Michael Blanar, ARMGO Pharma of Tarrytown, NY

Amount  Awarded:  $50,000

The focus of the research project is to assess the therapeutic effects of orally bioavailable, small molecule modulators of the RyR (known as Rycals) which repair pathophysiologic calcium leak in skeletal muscle disease to reverse chronic muscle weakness. Given recent evidence that Kennedy's Disease may affect muscles directly, causing them to become weak independent of the nervous system, such modulators have the potential to improve motor function in patients affected by KD (SBMA). Rycals restore normal RyR function, improve skeletal muscle biochemical markers and improve function of pathologic muscle in various preclinical models
of skeletal muscle disease. Recent evidence from a mouse model of KD suggests that toxic androgen receptor may cause muscle weakness by impairing the function of RyR, resulting in an elevated concentration of cytosolic calcium and the loss of muscle strength in KD affected men.

"We are very pleased to have been selected by the KDA to receive funding which will support the advancement of our scientific platform against Kennedy’s Disease, complementing our lead Rycal programs for heart failure and Duchenne Muscular Dystrophy" said Dr. Sapan Shah, President and CEO of ARMGO Pharma. "We are
excited at the possibility to expand our Rycal research and development program into skeletal muscle diseases, such as Kennedy's Disease, where new treatment options for patients are desperately needed” remarked Dr. Michael Blanar, Chief Scientific Officer of ARMGO Pharma and Principal Investigator of the KDA-funded
research project.

2012 - One research grant was awarded for $25,000

Jamie A. Johansen, Ph.D., Central Michigan University, Mount Pleasant, MI

Amount  Awarded:  $25,000

Proposal:  "Mechanisms of anti-androgen treatment in SBMA mice muscles"

2011 - Three research grants were awarded totaling $65,000

Thanks to the generosity of its supporters, the Board of Directors of the Kennedy’s Disease Association announced today that they awarded three research grants.  The three recipients and a brief explanation of their research are shown below.

1.  Masahisa Katsuno, M.D. – Ph.D.,  Department of Neurology, Nagoya University Graduate School of Medicine

Amount  Awarded:  $25,000

Proposal:  Elucidation of neuronal death signaling pathways and development of disease-modifying therapies for Kennedy’s disease

Brief Explanation: Their lab has evidence that the synthesis of two proteins are affected by the defective androgen receptor in KD. They wish to determine if neuronal cell death is caused by the alteration in the levels of these proteins and if cell death canbe prevented by the addition of drugs that target the activity of these proteins.

2.  Elise Kikis, Ph. D., Northwestern University

Amount Awarded:  $20,000

Proposal:  Modeling SBMA: from understanding proteotoxicity to identifying therapeutics

Brief Explanation: They believe that the specific cell death is due to the accumulation of misfolded proteins (the androgen receptor) and the inability of cells to handle this accumulation. They propose to use a new model organism (a little worm called C. elegans – a very common and important model system in biology) to examine how different cell types handle the misfolded proteins and genetically look for other proteins that may help the cell get rid of the messed up proteins.

3.  Sara Parodi, Ph.D., Department of Neuroscience and Brain Technologies, Genoa, Italy

Amount Awarded:  $20,000

Proposal:  Identification of PKA signaling as a new therapeutic approach for SBMA

Brief Explanation:  There is evidence that the cell death may involve changes to the androgen receptor (specifically changes in which phosphate is added to the protein, a process called phosphorylation). They hope to determine whether this cell death can be stopped due to the activation of another protein, known as PKA.-

2009 -  3 research grants were awarded totaling $50,000

#1. $25,000 Parsa Kazemi-Esfarjani, B.Sc., Ph.D. is a researcher for the Department of Pediatrics, Division of Genetics, Institute for Genomic Medicine at the School of Medicine, University of California, San Diego

Essentially this research will attempt to determine whether or not, and to what extent, the mutant androgen receptor (AR) in the muscle contributes to both muscle atrophy and motor neuron degeneration in Kennedy’s Disease (KD).  They have produced a mouse model of KD in which they can remove the mutant AR gene just in the muscle cells (this is due to a genetic manipulation), leaving the mutant AR intact in the rest of the cells.  This type of research will hopefully show us which cells and tissues are the most important for the timing of the appearance of KD symptoms (i.e., the onset) and/or the pace of their progression. With this knowledge, we will be able to develop our therapies for KD more effectively and target them to the appropriate tissues.

#2  $20,000  Maria Pennuto,Ph.D. Department of Neuroscience, Italian Institute of Technology, Genova, Italy.

This research is based on results that Maria found when she worked in Dr. Fischbeck's lab at NIH.  She had found that a specific modification of the mutant androgen receptors (AR) results in decreased toxicity and that this modification was due to the activation of an enzyme known as PKA.  She intends to investigate more thoroughly the relationship between PKA and toxicity and to search for drugs that may activate PKA and thus may lessen the effects of the mutant AR.

#3 $10,000 Lenore Beitel, Ph.D. Lady Davis Institute for Medical Research, SMBD-Jewish General Hospital, Montreal, Quebec, Canada

This research is to further study the role of the proteasome and its ability (or lack of ability) to degrade mutant androgen receptors (AR).  She hopes to determine directly if the mutant AR really does 'clog' up the proteasome.  Up to this point, most of the evidence for such an effect is circumstantial.

2008 -  One $ 50,000 research grants was awarded:

At the Kennedy's Disease Association's Annual Conference and Research Symposium in November, Board Member Ed Meyertholen awarded Heather Montie, Ph.D., with a $50,000 check to support her Kennedy's Disease research at Thomas Jefferson University in Philadelphia.  This grant will fund research that will investigate the androgen receptor (AR) - this is the protein that is altered in Kennedy's Disease (KD).  The AR mediates all the effects of testosterone in cells.  Without the AR, testosterone will have no effect. Normally, the AR is activated by testosterone.  Once activated by testosterone, the AR causes changes in the activity of the cell.  It is believed that in cells from those with KD, the cell is not capable of removing the 'old' AR that has been used and this somehow results in the death of the cells.  Preliminary research by Dr. Montie and her colleagues have indicated that the KD form of AR is chemically altered by the cell through a process of hyperacetylation and it is possible that if this process is blocked, the cell may be more capable of removing the AR and thus should not die.  The KDA grant will allow Dr. Montie continue her studies on the role of acetylation of AR  and to determine if blocking this process does reduce the death of cells with mutant KD

2007 -  Two $ 25,000 research grants were awarded:

Two grants just funded by the KDA both attempt to investigate mechanisms to prevent the accumulation of the toxic fragment in cells containing the mutant AR.

Briefly, KD is caused by a genetic mutation to the gene that codes for the Androgen Receptor (AR) protein.  This protein mediates all the actions of the androgen hormones testosterone and dihydrotestosterone, DHT.  In the cells of normal males, the AR is found in the cytoplasm of the cell.  Upon the addition of an androgen hormone (either testosterone or DHT), the hormone binds to the AR and the hormone/AR complex travels to the nucleus of the cell where it initiates the masculine changes that are associated with the presence of androgens (beard growth, for example).  If there is no androgen present, then the AR never enters the nucleus and there are no changes – this is essentially what occurs in females.  Since women do not possess androgens, the AR does nothing in cells and there are no masculine effects.  The AR in the nucleus is ultimately destroyed by a cell structure known as the proteasome.  In individuals with KD, the cell is unable to completely destroy the AR that enters the nucleus - but it can destroy the AR that does not enter the nucleus and this inadequate digestion apparently results in the production of a fragment of the mutant AR that is toxic to the cells – thus the cells die and this leads to the formation of the symptoms of KD.  This appears to explain why women carriers do not show major symptoms.  Since the levels of androgens in women are low, the mutant AR does not enter the nucleus and the cell does not create the toxic fragment.

A $25,000 grant was awarded to Maria Pennuto, Ph.D. from the National Institute of Health. Dr. Pennuto has spent the past few years investigating the molecular switches on the AR that are involved in the movement of the AR into the nucleus upon addition of hormone.  She has discovered that certain chemical changes to the AR seem to reduce the ability of the AR to bind to hormone and thus not enter the nucleus (and cause KD!!).  She has discovered that the exposure of cells to a substance known as IGF-1 can induce these chemical changes to occur to the mutant AR and thus prevent the movement of the AR to the nucleus.  Thus, the addition of IGF-1 to a cell with mutant AR appears to prevent the formation of the toxic fragment and thus the cell stays alive.  Dr. Pennuto will continue this work by determining if any other chemical changes to the AR may alter its movement to the nucleus and  she will also determine if IGF-1 prevents the formation of KD symptoms in a KD mice model (up to this time, the effect of IGF-1 has only been shown to work in cell cultures.  This work could lead to new therapies for KD.

Another $ 25,000 grant was awarded to Udai Bhan Pandey, Ph.D. from the University of Pennsylvania. The proposal by Dr. Pandey and Dr. Paul Taylor continues the work that they did (in part thanks to a previous KDA grant!).  They previously reported that KD symptoms in a fly model of KD could be reduced by activating another mechanism for destroying the KD in the nucleus, by passing the need for the proteasome.  This alternate pathway, known as autophagy, apparently is capable of destroying the toxic fragment.  They did this by making the fly over produce another protein known as HDAC6.  By doing this, they were able to demonstrate that the overproduction of HDAC6 did not show cell death despite the presence of the mutant KD.  They will now try to continue this work as they attempt to find other proteins that may affect this activity of HDAC6 to stimulate autophagy and thus help prevent the cell death associated with KD.

2006 - Two $ 25,000 research grants were awarded:

A $25,000 grant was awarded to Chawnshang Chang Ph.D. from the University of Rochester. His research plans to develop a treatment regimen for Kennedy’s Disease targeting the poly Q-expanded mutant AR.  This concept may be a way to cure the disease.

Another $25,000 grant was awarded to Udai Bhan Pandey Ph.D. from the University of Pennsylvania. Dr. Pandey proposes to use molecular genetic approaches in Drosophila to characterize the mechanism of suppression by HDAC6.  His long-term goal is to contribute to the development of therapeutic interventions for Kennedy’s Disease.

2005 - One $ 25,000 research grant was awarded:

A $25,000 emergency funding grant was awarded to J. Paul Taylor, MD, Ph.D. from the University of Pennsylvania. The grant helped support Dr. Taylor and his team's research using the Drosophila melanogaster (fruitfly) model system to investigate the molecular pathogenesis of Spinal and Bulbar Muscular Atrophy (aka Kennedy's Disease).  In response to the KDA's grant, we received the following email from Dr. Taylor referencing the status of his current Kennedy's Disease research.  "... This (grant) could be a life saver.  We have made great strides with our work, in fact, we have a manuscript on our Kennedy's Disease work that has received good reviews.  This work was largely funded by (the) KDA and I have been anxiously waiting for this work to be accepted for publication before alerting you.  I have also had two graduate students join my lab who are doing their Ph.D. thesis work on Kennedy's Disease.

2004 - One $ 25,000 research grant was awarded:

A $25,000 grant was awarded to Andrew Lieberman, MD, Ph.D., University of Michigan for development of First Ever Kennedy's Disease Knock-In Mouse Model. "Thanks so much for all of your hard work on our behalf!  It sure is inspirational for us to know that the KDA cares enough about this project to launch a difficult fund raising drive to support our work, and it's really gratifying to see that the generosity of the KDA membership made these efforts successful so quickly."  --  Dr. Andrew Lieberman

2003 - One $ 25,000 research grant was awarded:

A $25,000 grant was awarded to J. Paul Taylor, MD, PhD, University of Pennsylvania for developing the Drosophila melanogaster (fruitfly) model system to investigate the molecular pathogenesis of Spinal and Bulbar Muscular Atrophy.