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2010 - 2002 Research Updates


2010 Research

Microarray Analysis of Gene Expression by Skeletal Muscle of Three Mouse Models of Kennedy Disease/Spinal Bulbar Muscular Atrophy


Emerging evidence implicates altered gene expression within skeletal muscle in the pathogenesis of Kennedy disease/spinal bulbar muscular atrophy (KD/SBMA). We therefore broadly characterized gene expression in skeletal muscle of three independently generated mouse models of this disease. The mouse models included a polyglutamine expanded (polyQ) AR knock-in model (AR113Q), a polyQ AR transgenic model (AR97Q), and a transgenic mouse that overexpresses wild type AR solely in skeletal muscle (HSA-AR). HSA-AR mice were included because they substantially reproduce the KD/SBMA phenotype despite the absence of polyQ AR.

Methodology/Principal Findings

We performed microarray analysis of lower hindlimb muscles taken from these three models relative to wild type controls using high density oligonucleotide arrays. All microarray comparisons were made with at least 3 animals in each condition, and only those genes having at least 2-fold difference and whose coefficient of variance was less than 100% were considered to be differentially expressed. When considered globally, there was a similar overlap in gene changes between the 3 models: 19% between HSA-AR and AR97Q, 21% between AR97Q and AR113Q, and 17% between HSA-AR and AR113Q, with 8% shared by all models. Several patterns of gene expression relevant to the disease process were observed. Notably, patterns of gene expression typical of loss of AR function were observed in all three models, as were alterations in genes involved in cell adhesion, energy balance, muscle atrophy and myogenesis. We additionally measured changes similar to those observed in skeletal muscle of a mouse model of Huntington’s Disease, and to those common to muscle atrophy from diverse causes.


By comparing patterns of gene expression in three independent models of KD/SBMA, we have been able to identify candidate genes that might mediate the core myogenic features of KD/SBMA.

Study links normal function of protein, not its build up inside cells, to death of neurons

A new study led by St. Jude Children's Research Hospital scientists signals hope for treatment of a neurodegenerative disease and a new model for understanding the mechanism at work in other more common neurodegenerative disorders. A study led by St. Jude Children's Research Hospital investigators links the muscle weakness and other symptoms of a rare neurodegenerative disease to a misstep in functioning of a normal protein, rather than its build-up inside cells. The finding offers insight into the mechanism driving common nervous system disorders like Parkinson's and Alzheimer's diseases. The work advances understanding of how the inherited mistake at the heart of spinobulbar muscular atrophy (SBMA) leads to the death of neurons in the brain and spinal cord. Investigators showed that the underlying mutation caused an amplification of the protein's normal function. The work appears in the September 23 online edition of the scientific journal Neuron.

"The idea that toxicity is mediated by the native, or normal, function of the protein itself is a departure from conventional wisdom. This research adds to growing evidence the principle applies very broadly in other neurodegenerative disorders, including Alzheimer's and Parkinson's diseases," said J. Paul Taylor, M.D., Ph.D., an associate member in the St. Jude Department of Developmental Neurobiology and the paper's senior author. The current neurodegenerative disease model links the disorders to a toxic build-up of improperly folded proteins inside cells. Taylor said: "Our findings suggest the focus on protein aggregation inside cells may be misplaced." Developing therapies that target the normal protein function will likely be easier and more effective, he added. Medications are already available to block the androgen receptor (AR) protein, which is mutated in SBMA. Work is now underway in Taylor's laboratory to identify drugs that more selectively block AR functioning.

SBMA belongs to a family of eight disorders, including Huntington's disease, which stem from an overabundance of the same small, repeated sequence of DNA known as a trinucleotide. Such repetitions are common throughout the genome, but problems arise when they occur too frequently. That is what happens in the estimated 1 in 50,000 males with SBMA. 
In the case of SBMA, the repeated sequence occurs in the gene for the androgen receptor. The repeated nucleotide sequence CAG is protein-production shorthand for an amino acid called glutamine. The resulting androgen receptor (AR) protein includes surplus glutamine. After earlier work by other investigators showed that blocking testosterone prevented male mice with the SBMA mutation from developing the disease, Taylor and his colleagues set out to track what happened inside cells after the hormone bound to the mutated AR protein.

Working in a Drosophila fruit fly model of the disease, the scientists identified a small region of the AR protein, known as the AF-2 domain, which played a pivotal role. Using a variety of techniques, researchers demonstrated they could rescue the cells by preventing certain members of a family of proteins called coregulators from binding to the AF-2 domain. Coregulators partner with AR and other transcription factors to regulate gene expression. "In this study, we showed the ability of the mutant protein to interact with the normal binding partners is an essential step in the cascade of degeneration. By blocking it, we block degeneration," Taylor said. He added that the AF-2 domain is far from the mutated region of the AR protein. "That would be unexpected if the mechanism of toxicity were related to the protein aggregating," he explained.

Meanwhile, investigators are still studying why the protein's change in function is so deadly to cells. Taylor noted that research into inherited diseases like SBMA has historically provided important clues into the mechanisms at work in other more common neurodegenerative disorders, including Alzheimer's. The findings also hold hope that treating or preventing SBMA by selectively disrupting AF-2 binding will soon be possible, Taylor said. "Selectively blocking the hormone will be key if we hope to prevent the side effects associated with androgen ablation in males," he said. The side effects include bone thinning, infertility or blocked sexual maturation. The study also suggests the need to begin treatment earlier. If the damage to motor neurons begins with the hormone surge of puberty rather than the accumulation of mis-folded proteins, therapies must begin in childhood, Taylor said.

Natalia Nedelsky, of St. Jude and the University of Pennsylvania, is the study's first author. The co-authors are Maria Pennuto, Italian Institute of Technology, Genoa, Italy; Isabella Palazzolo, National Institute of Neurological Disorders and Stroke; Zhiping Nie, University of Pennsylvania; and Rebecca Smith, Jennifer Moore and Geoffrey Neale, all of St. Jude. 
The study was funded in part by the Muscular Dystrophy Association, the Kennedy's Disease Association, the National Institutes of Health and ALSAC.

Efficacy and safety of leuprorelin in patients with spinal and bulbar muscular atrophy (JASMITT study): a multicentre, randomised, double-blind, placebo-controlled trial.

Katsuno M, Banno H, Suzuki K, Takeuchi Y, Kawashima M, Yabe I, Sasaki H, Aoki M, Morita M, Nakano I, Kanai K, Ito S, Ishikawa K, Mizusawa H, Yamamoto T, Tsuji S,Hasegawa K, Shimohata T, Nishizawa M, Miyajima H, Kanda F, Watanabe Y, Nakashima K, Tsujino A, Yamashita T, Uchino M, Fujimoto Y, Tanaka F, Sobue G; for the Japan SBMA Interventional Trial for TAP-144-SR (JASMITT) study group.

Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Institute for Advanced Research, Nagoya University, Nagoya, Japan.


BACKGROUND: Spinal and bulbar muscular atrophy is a hereditary motor neuron disease caused by the expansion of a polyglutamine tract in the androgen receptor. At present there are no treatments for spinal and bulbar muscular atrophy, although leuprorelin suppressed the accumulation of pathogenic androgen receptors in a phase 2 trial. We aimed to assess the efficacy and safety of leuprorelin for spinal and bulbar muscular atrophy. METHODS: The Japan SBMA Interventional Trial for TAP-144-SR (JASMITT) was a 48-week, randomised, double-blind, placebo-controlled trial done at 14 hospitals between August, 2006, and March, 2008. Patients with spinal and bulbar muscular atrophy were randomly assigned (1:1) by minimisation to subcutaneous 11.25 mg leuprorelin or identical placebo every 12 weeks. Patients and investigators were masked to treatment allocation. The primary endpoint was pharyngeal barium residue, which indicates incomplete bolus clearance, measured at week 48 by videofluorography. All patients who were randomly assigned and who were assessed with videofluorography at least once were included in the analyses. This study is registered with the JMACCT clinical trials registry, number JMA-IIA00009, and the UMIN clinical trials registry, number UMIN000000465. FINDINGS: 204 patients were randomly assigned and 199 started treatment: 100 with leuprorelin and 99 with placebo. At week 48, the pharyngeal barium residue after initial swallowing had changed by -5.1% (SD 21.0) in the leuprorelin group and by 0.2% (18.2) in the placebo group (difference between groups -5.3%; 95% CI -10.8 to 0.3; p=0.063). The mean difference in pharyngeal barium residue after piecemeal deglutition at week 48 was -3.2% (-6.4 to 0.0; p=0.049), but there was no significant difference between the groups after covariate adjustment for the baseline data (-4.1 to 1.6; p=0.392). In a predefined subgroup analysis, leuprorelin treatment was associated with a greater reduction in barium residue after initial swallowing than was placebo in patients with a disease duration less than 10 years (difference between groups -9.8, -17.1 to -2.5; p=0.009). There were no significant differences in the number of drug-related adverse events between groups (57 of 100 in the leuprorelin group and 54 of 99 in the placebo group; p=0.727).

INTERPRETATION: 48 weeks of treatment with leuprorelin did not show significant effects on swallowing function in patients with spinal and bulbar muscular atrophy, although it was well tolerated. Disease duration might influence the efficacy of leuprorelin and thus further clinical trials with sensitive outcome measures should be done in subpopulations of patients. FUNDI

NG: Large Scale Clinical Trial Network Project, Japan and Takeda Pharmaceuticals. Copyright © 2010 Elsevier Ltd. All rights reserved.

 2009 Research

Few Benefits Seen With Androgen Reduction for Spinal and Bulbar Muscular Atrophy

BALTIMORE (EGMN) –Long-term dutasteride therapy in men with spinal and bulbar muscular atrophy does not appear to improve muscle strength or fatigue and might actually lower mental quality of life, according to the results of a phase II, randomized, double-blind, placebo-controlled trial. Patients derived some benefit from treatment with the 5-alpha reductase inhibitor, which converts testosterone into more potent dihydrotestosterone, as a result of a significant reduction in their number of falls and improvement in their physical quality of life.

Spinal and bulbar muscular atrophy (SBMA) is characterized by a toxic buildup of mutant androgen receptors with an excessively long string of glutamine residues in motor neurons. This buildup weakens bulbar and extremity muscles, causing difficulty with gait and dysphagia, and also might lead to gynecomastia, infertility, and other manifestations of androgen insensitivity. Dutasteride has been thought to be a potential therapy for SBMA because experiments in mice that were bred to express the mutant androgen receptor showed that reducing androgen levels could mitigate the toxicity of the mutant phenotype. To evaluate the efficacy and safety of dutasteride, Dr. Kenneth H. Fischbeck, chief of the Neurogenetics Branch of the U.S. National Institute of Neurological Diseases and Stroke (NINDS) and his colleagues randomized 50 men with SBMA to either 0.5 mg/day of dutasteride or placebo. That dose of dutasteride is the same as that approved for treating symptomatic benign prostatic hyperplasia.

The men in each group were an average age of about 53 years, and had an average CAG repeat length of 4 codons (compared with wild-type human repeat length of 36 codons or less, a mean duration of weakness of about 12 years, and an average body mass index of about 28 kg/m2. After 2 years, patients treated with dutasteride had virtually no appreciable increase in weight-scaled quantitative muscle assessment scores from baseline – the primary efficacy measure – whereas the scores in patients taking placebo declined by 5% from baseline. This difference was not significant, according to the investigators, who reported their results in a poster session at the annual meeting of the American Neurological Association.

On the Short Form-36 quality of life questionnaire (version 2), the physical component summary improved by about 14% from baseline for dutasteride-treated patients, which was significantly different from the 10% drop recorded in placebo-treated patients. Significantly fewer falls occurred among patients who were treated with dutasteride than among those who received placebo (9 patients reporting 40 falls vs. 16 subjects reporting 63 falls).

However, patients who took dutasteride fared more poorly than those who took placebo on the mental component summary of the questionnaire, in which patients on placebo had a 10% improvement and patients on dutasteride worsened by about 7%. Modified barium swallow scores, a measurement for dysphagia severity, worsened by a similar amount in subsets of patients from both arms. Dutasteride did not have an effect on total and free testosterone levels after 2 years, but dihydrotestosterone levels declined during that period from 46 ng/dL at baseline to 5 ng/dL.A total of two patients in the placebo arm and two in the dutasteride arm dropped out of the trial before the 2-year end point. One death in the dutasteride arm was caused by a cardiac event (confirmed by autopsy). One patient on dutasteride left the trial because of respiratory distress.

The muscle strength of men who were taking placebo declined by only 2% per year. “With such slow progression, longer trial duration or a more sensitive outcome measure may be needed to show therapeutic benefit,” the investigators wrote on their poster. They also suggested that in future trials, it might be useful to conduct functional muscle testing with the Adult Myopathy Assessment Tool, which registered nearly a 5% rate of decline in placebo-treated patients, and other testing methods, such as physical quality of life and electrophysiological measures. The trial was funded by the NINDS. None of the investigators had relevant disclosures.

Therapy Investigated for ALS May Find New Role in Kennedy's 

IGF1 might work better and more specifically in Kennedy's disease than in ALS says ... Kennedy's disease also called spinal and bulbar muscular atrophy (SBMA)

Rescuing SBMA-Affected Muscles - Maria Pennuto

Effect of aerobic training in patients with spinal and bulbar muscular atrophy (Kennedy disease)

N. Preisler, MD, G. Andersen, BSc, F. Thøgersen, BSc, C. Crone, MD, PhD, T. D. Jeppesen, MD, F. Wibrand, PhD and J. Vissing, MD, PhD

From the Neuromuscular Research Unit, Department of Neurology and Copenhagen Muscle Research Center (N.P., G.A., F.T., T.D.J., J.V.), Department of Clinical Neurophysiology (C.C.), and Department of Clinical Genetics (F.W.), University of Copenhagen, Rigshospitalet, Denmark.

Address correspondence and reprint requests to Dr. Nicolai Preisler, Neuromuscular Research Unit 3342, University of Copenhagen, Rigshospitalet, Blegdamsvej 9, DK-2100 Copenhagen, Denmark npreisler{at}

Objective: We examined the effect of aerobic exercise in patients with spinal and bulbar muscular atrophy (SBMA). SBMA is caused by a defect androgen receptor. This defect causes motor neuron death, but considering the important function of androgens in muscle, it is possible that muscle damage in SBMA also occurs independently of motor neuron damage.

Methods: Eight patients with SBMA engaged in regular cycling exercise for 12 weeks. Maximum oxygen uptake (Vo2max), maximal work capacity (Wmax), muscle morphology, citrate synthase (CS) activity, body composition, EMG, static strength measurements, lung function, plasma proteins, and hormones were evaluated before and after training. Evaluation of improvements in activities of daily living (ADL) was conducted after training.

Results: Wmax increased by 18%, and CS activity increased by 35%. There was no significant change in Vo2max or any of the other variables examined before and after training, and the patients with SBMA did not feel improvements in ADL.

Conclusions: Frequent, moderate-intensity aerobic conditioning is of little beneficial effect in patients with spinal and bulbar muscular atrophy (SBMA). High levels of plasma creatine kinase and muscle regeneration indicate a primary myopathic affection, which, in parallel with the motor neuron deficiency, may attenuate the response to exercise training in patients with SBMA.

Abbreviations: ADL = activities of daily living; AR = androgen receptor; ASI = androgen sensitivity index; BMI = body mass index; CK = creatine kinase; CS = citrate synthase; FSH = follicle-stimulating hormone; LH = luteinizing hormone; MU = motor unit; SBMA = spinal and bulbar muscular atrophy; Vo2max = maximum oxygen uptake; Wmax = maximal work capacity.

Clinical features of spinal and bulbar muscular atrophy


Spinal and bulbar muscular atrophy is an X-linked motor neuron disease caused by a CAG repeat expansion in the androgen receptor gene. To characterize the natural history and define outcome measures for clinical trials, we assessed the clinical history, laboratory findings and muscle strength and function in 57 patients with genetically confirmed disease. We also administered self-assessment questionnaires for activities of daily living, quality of life and erectile function. We found an average delay of over 5 years from onset of weakness to diagnosis. Muscle strength and function correlated directly with serum testosterone levels and inversely with CAG repeat length, age and duration of weakness. Motor unit number estimation was decreased by about half compared to healthy controls. Sensory nerve action potentials were reduced in nearly all subjects. Quantitative muscle assessment and timed 2 min walk may be useful as meaningful indicators of disease status. The direct correlation of testosterone levels with muscle strength indicates that androgens may have a positive effect on muscle function in spinal and bulbar muscular atrophy patients, in addition to the toxic effects described in animal models.

Full Transcript:

2008 Research

The National Institute of Health finished a two year clinical trial in 2008.  A summary of the results of the study follows:

A trial of dutasteride in spinal and bulbar muscular atrophy

Lindsay Rhodes, Angela Kokkinis, Michelle White, Charlotte Watts, Sungyoung Auh, Neal Jeffries, Joseph Shrader, Tanya Lehky, Li Li, Jennifer Ryder, Ellen Levy, Beth Solomon, Alison La Pean, Alice Schindler, Cheunju Chen, Nicholas Di Prospero and Kenneth Fischbeck


Spinal and bulbar muscular atrophy (SBMA) is caused by polyglutamine expansion in the androgen receptor, which results in ligand-dependent toxicity. SBMA animal models have a neuromuscular deficit that is mitigated by anti-androgen treatment. We explored the efficacy and safety of the anti-androgen drug dutasteride in a two year double-blind, placebo-controlled clinical trial. Physical, neurophysiological, quality of life, and biochemical outcomes were assessed in 50 SBMA subjects randomized to receive dutasteride or placebo. There was no significant difference in the primary outcome measure, change in strength as indicated by quantitative muscle assessment (QMA). Of the secondary outcome measures, only quality of life as measured by change in the SF-36v2 physical component summary showed a significant benefit (p=0.004), and this was balanced by a negative effect on the SF-36v2 mental component summary. In the placebo group the QMA showed an average decrease in muscle strength of 2% per year, indicating that SBMA patients may need to be studied over a longer period to show a significant effect on disease progression. These observations provide a basis for future therapeutic trials in SBMA, and indicate counter-balancing effects of androgens in this disease.

In a conference call with Dr. Kenneth Fischbeck, Angela Kokkinis, Ke-lian Chen, Alice Schindler and George Harrison in June of 2008 is summarized below:

The dutasteride trial did not show a significant effect on the progression of muscle weakness.  Those patients on a placebo lost, on average, 2% of their strength per year (two-year study).  Patients on Dutasteride showed a slight increase in strength, but statistically the difference was not significant.  Dr. Fischbeck surmised that the trial needed to be longer (at least three years) to better determine any benefits.  A few patients on Dutasteride did show significant improvement, while others did not.  Dr. Fischbeck felt that this could mean that the drug reacts differently in certain patients.

The full report is available for download in PDF:  Dutasteride Trial

Efficacy and safety of leuprorelin in patients with spinal and bulbar muscular atrophy (JASMITT study): a multicentre, randomised, double-blind, placebo-controlled trial

Katsuno M, Banno H, Suzuki K, Takeuchi Y, Kawashima M, Yabe I, Sasaki H, Aoki M, Morita M, Nakano I, Kanai K, Ito S, Ishikawa K, Mizusawa H, Yamamoto T, Tsuji S,Hasegawa K, Shimohata T, Nishizawa M, Miyajima H, Kanda F, Watanabe Y, Nakashima K, Tsujino A, Yamashita T, Uchino M, Fujimoto Y, Tanaka F, Sobue G; for the Japan SBMA Interventional Trial for TAP-144-SR (JASMITT) study group.

Department of Neurology, Nagoya University Graduate School of Medicine, Nagoya, Japan; Institute for Advanced Research, Nagoya University, Nagoya, Japan.

INTERPRETATION: 48 weeks of treatment with leuprorelin did not show significant effects on swallowing function in patients with spinal and bulbar muscular atrophy, although it was well tolerated. Disease duration might influence the efficacy of leuprorelin and thus further clinical trials with sensitive outcome measures should be done in subpopulations of patients.


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.

Androgen receptor and Kennedy disease/spinal bulbar muscular atrophy

Kennedy  Disease/Spinal  Bulbar Muscular Atrophy (KD/SBMA) is a progressive  neurodegenerative  disease caused by genetic polyglutamine expansion of  the androgen  receptor. We have recently found that overexpression of  wildtype  androgen receptor in skeletal muscle of transgenic mice  results in a  KD/SBMA phenotype. This surprising result challenges the  orthodox view  that KD/SBMA requires expression of polyglutamine  expanded androgen  receptor within motoneurons. Theories relating to the  etiology of this  disease drawn from studies of human patients,  cellular and mouse models  are considered with a special emphasis on  potential myogenic  contributions to as well as the molecular etiology  of KD/SBMA.

 2007 Research

Effectiveness of Anti-androgen Therapy for Spinobulbar Muscular Atrophy (SBMA): An Open Study of 4 Cases for 3 Years

Yusuke Niimi, Kinya Ishikawa, Masanaga Yamawaki, Hidehiro Mizusawa, Tokyo, Japan

OBJECTIVE: To clarify the effect of anti-androgen therapy in patients with SBMA.

BACKGROUND: Spinobulbar muscular atrophy (SBMA) is an adult-onset, X-linked recessive motor neuron disease caused by an expansion of a trinucleotide CAG repeat that encode polyglutamine tract in the androgen receptor (AR) gene. The pathogenic mechanism of this disease is recapitulated in mice by overexpressing the human AR gene with expanded CAG repeat. In addition, disease progression as well as formation of polyglutamine inclusion in vivo was suppressed in the transgenic mice by administering leutenizing hormone-releasing hormone (LH-RH) analog, which interferes mutant AR protein to accumulate in the nucleus of cells. DESIGN/METHODS: After approved by the institutional review board, we prospectively studied clinical efficacy of goserelin (Zoladex LA), a LH-RH analog, in 4 patients with SBMA with an open study manner. The study was undertaken for four years from, September, 2002 to October, 2006. Goserelin was subcutaneously injected every 3 month regularly to maintain the drug concentration. We evaluated the clinical manifestations by manual muscle testing (MMT), micro-FET, serum CK and ALT, and nerve conduction study. Changes of polyglutamine inclusion densities in the epidermis of the scrotum were assessed by immunohsitochemistry using anti-polyglutamine antibody 1C2, before and after the therapy. Clinically, effect of goserelin was seen by strength. The muscle strength showed 28% increase after the therapy. In nerve conduction study, median nerve CMAP improved 23%. Three out of four patients showed improvement in any of the parameters. In relationship with the disease severity, the goserelin was the most effective in patients with early stage of illness. The density of polyglutamine-inclusion in the epidermis of the scrotum did not change significantly.

CONCLUSIONS/RELEVANCE: Anti-androgen therapy with LH-RH analog may inhibit disease progression especially in the early stage. A study recruiting a larger number of patients is needed to confirm the efficacy of this agent.
Category - Neurogenetics and Gene Therapy
SubCategory - Therapeutics

 KDA Funded Research Update

Chawnshang Chang, Ph.D. and a team of researchers at the University of Rochester Medical Center have published the attached news release concerning their research that could potentially lead to a treatment for Kennedy's Disease.  The article was published in the March 6 issue of the journal Nature Medicine.

Read More

 2006 Research

Muscle pathology in mice with Kennedy's Disease

Announcing the results of a University of Michigan research study that is related to Kennedy's Disease.  The research project was partially funded by the KDA through the generous donations of our associates, their family, and friends.

Click here to read the report - PDF Document

Neurons Grown from Embryonic Stem Cells Restore Function in Paralyzed Rats

For the first time, researchers have enticed transplants of embryonic stem cell-derived motor neurons in the spinal cord to connect with muscles and partially restore function in paralyzed animals. The study suggests that similar techniques may be useful for treating such disorders as spinal cord injury, transverse myelitis, amyotrophic lateral sclerosis (ALS), and spinal muscular atrophy.

The study was funded in part by the NIH’s National Institute of Neurological Disorders and Stroke (NINDS).  

Natural history of  spinal and bulbar muscular atrophy (SBMA): a study of  223 Japanese  patients

Note:  A  PDF copy can be downloaded at:


Spinal  and bulbar muscular atrophy (SBMA) is an adult-onset motoneuron  disease  caused by a CAG-repeat expansion in the androgen receptor  (AR) gene  and for which no curative therapy exists. However,  since recent  research may provide opportunities for medical  treatment, information  concerning the natural history of SBMA  would be beneficial in planning  future clinical trials. We  investigated the natural course of SBMA as  assessed by nine activities  of daily living (ADL) milestones in 223  Japanese SBMA  patients (mean age at data collection = 55.2 years; range  =  30–87 years) followed from 1 to 20 years. All the patients were   diagnosed by genetic analysis. Hand tremor was an early event  that was  noticed at a median age of 33 years. Muscular weakness  occurred  predominantly in the lower limbs, and was noticed  at a median age of 44  years, followed by the requirement of a  handrail to ascend stairs at  49, dysarthria at 50, dysphagia at  54, use of a cane at 59 and a  wheelchair at 61 years. Twenty-one of  the patients developed pneumonia  at a median age of 62 and 15  of them died at a median age of 65 years.  The most common cause  of death in these cases was pneumonia and  respiratory failure.  The ages at onset of each ADL milestone were  strongly correlated  with the length of CAG repeats in the AR gene.  However CAG-repeat  length did not correlate with the time intervals  between  each ADL milestone, suggesting that although the onset age of   each ADL milestone depends on the CAG-repeat length in the AR  gene, the  rate of disease progression does not. The levels of  serum  testosterone, an important triggering factor for  polyglutamine-mediated  motoneuron degeneration, were  maintained at relatively high levels  even at advanced ages.  These results provide beneficial information for  future  clinical therapeutic trials, although further detailed   prospective studies are also needed.

 2005 - 2004 Research

Drosophila melanogaster (fruitfly) model system

KDA funded research grant update - The KDA funded a grant to J. Paul Taylor, MD PhD at University of Pennsylvania for $25,000 in November 2003 for a Drosophila melanogaster (fruitfly) model system to investigate the molecular pathogenesis of Spinal and Bulbar Muscular Atrophy.  Dr. Taylor has provided us with an update as to how their research is coming along.

Research update as of June 2004, J. Paul Taylor, MD, PhD University of Pennsylvania

$25,000 Grant Awarded November 2003: Drosophila melanogaster (fruitfly) model system to investigate the molecular pathogenesis of Spinal and Bulbar Muscular Atrophy

I'd like to provide an update on our Kennedy's disease research.  We've made substantial headway in our characterization of the phenotype as reflected by locomotor activity and lifespan.  We're now getting set to examine the histopathology using several different techniques.  In addition, we have started creating a series of new transgenic Drosophila lines to extend the utility of the model.  Specifically, we think that the Drosophila model provides a good system to test ideas raised by Dr. Lisa Ellerby of the Buck Institute and Dr. Andy Lieberman of the University of Michigan.

First, in collaboration with Dr. Ellerby, we will  investigate the role of androgen receptor cleavage in the process of motor neuron toxicity.  As you may recall her describing at past KDA meetings, Dr. Ellerby's work suggests that polyglutamine-expanded androgen receptor becomes toxic only after cleavage (cutting the protein into fragments).  It is hypothesized that this cleavage event results in the formation of a toxic protein fragment.  If it can be verified that cleavage is a requisite step in pathogenesis, preventing this cleavage may be a useful therapeutic strategy.  Dr. Ellerby will be providing several "non-cleavable" forms of androgen receptor that we will use to make transgenic flies.  If the cleavage hypothesis is correct, these flies may not show as much degeneration as the flies we are working with currently.

Second, in collaboration with Dr. Lieberman, we will investigate the role of chemical modification of the androgen receptor in the process of motor neuron toxicity.  Dr. Lieberman recently published an excellent article describing a role for acetylation in aggregation of the androgen receptor (Thomas et al. J. Biol. Chem., Vol. 279, Issue 9, 8389-8395).  Similar to the work by Dr. Ellerby,  this suggests that features of the androgen receptor other than the polyglutamine repeat may be important determinants of toxicity.  If it can be verified that acetylation of the androgen receptor (a chemical modification) influences toxicity, this may also provide a therapeutic strategy.  Dr. Lieberman will be providing a "non-acetylatable" form of the androgen receptor that we will use to make transgenic flies.  If this acetylation is an important step in pathogenesis, this should be reflected in the severity of degeneration in these flies.

-- J. Paul Taylor, MD, PhD

2003 Research

2003 Kennedys Disease Conference Presentations

J. Paul Taylor, M.D., Ph.D. NIH, Transitioning to University of Pennsylvania, Philadelphia (USA). Drosophila (fruit fly) Models
Andrew Lieberman, M.D., Ph.D. - University of Michigan (USA). Creation of a KD Knock-in Mouse Model
Nicholas Di Prospero, M.D., Ph.D. National Institutes of Health, NINDS (Bethesda, MD) Kennedy's Disease Clinical Trials
Jean-Marc Gallo, Ph.D. King's College, London (England). Common ground between KD & other neurological diseases

2002 Research

Recent Studies Indicate Testosterone may Aggrevate Kennedy's Disease

Studies indicate that ligand, i.e. testosterone, is responsible for setting in action the toxic effects of the expanded repeat androgen receptor in KD mouse models.  This is an important finding that indicates that testosterone may NOT be a good therapy for KD. A reduction of testosterone in this mouse model of Dr. Sobue's reduced the toxic effects of the mutant androgen receptor.

However, the use of antagonists (drugs that counter the effect of testosterone) to the androgen receptor are not warranted either, as the accompanying paper on a fly model of SBMA shows that the use of antagonists that promote the transfer of the receptor into the nucleus of the cell (which testosterone does), also promotes disease symptoms. Please see the links to the files below.  They are fairly large files and may take a few minutes to download depending on your connection speed so please be patient.

PDF File #1

PDF File #2