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2014 Research Updates

2014 Research

BVS857 clinical trial results are in.

The results of Novartis Pharmaceuticals drug BVS857 study involving patients with Spinal and Bulbar Muscular Atrophy has been published. For more information, click here.

Scientists show bad androgen receptor impairs body's ability to dispose of damaged cells

Researchers at University of California, San Diego School of Medicine have identified the mechanism by which a rare, inherited neurodegenerative disease causes often crippling muscle weakness in men, in addition to reduced fertility.

The study, published August 10 in the journal Nature Neuroscience, shows that a gene mutation long recognized as a key to the development of Kennedy's disease impairs the body's ability to degrade, remove and recycle clumps of "trash" proteins that may otherwise build up on neurons, progressively impairing their ability to control muscle contraction. This mechanism, called autophagy, is akin to a garbage disposal system and is the only way for the body to purge itself of non-working, misshapen trash proteins.

"We've known since the mid-1990s that Alzheimer's disease, Parkinson's disease and Huntington's disease are caused by the accumulation of misfolded proteins that should have been degraded, but cannot be turned over," said senior author Albert La Spada, MD, PhD and professor of pediatrics, cellular and molecular medicine, and neurosciences. "The value of this study is that it identifies a target for halting the progression of protein build-up, not just in this rare disease, but in many other diseases that are associated with impaired autophagy pathway function."

Of the 400 to 500 men in the U.S. with Kennedy's disease, the slow but progressive loss of motor function results in about 15 to 20 percent of those with the disease becoming wheel-chair bound during later stages of the disease.

Kennedy's disease, also known as spinal and bulbar muscular atrophy, is a recessive X-linked disease men inherit from their mother. Women don't get the disease because they have two copies of the X chromosome. The genetic abnormality causes men to produce a mutant androgen receptor protein, which impairs the body's sensitivity and response to male sex hormones, sometimes resulting in testicular atrophy and enlargement of male breasts.

In experiments with mice, scientists discovered that the mutant androgen receptor protein besides disrupting male reproductive biology also deactivates a protein called transcription factor EB (TFEB) that is believed to be a master regulator of autophagy in nerve and other cell types.

Specifically, the mutant androgen receptor protein in Kennedy's disease binds to TFEB and blocks its ability to mediate the break-down and removal of non-working proteins and aggregated proteins.

"Our study tells us that if we can find a way to keep TFEB working, we likely can prevent this disease and others like it from progressing," La Spada said. "We now have a target for new therapies to treat not only Kennedy's disease, but also many more common neurological disorders."

September 08, 2014 - The following research paper was published in Science Direct this month. The highlights, abstract and conclusion are shown below. You can read the entire article by following the link above.


Stem cell-derived motor neurons from spinal and bulbar muscular atrophy patients

Christopher Grunseicha, , Kristen Zukoskya, 1, , Ilona R. Katsa, 1, , Laboni Ghosha, , George G. Harmisona, , Laura C. Botta, b, , Carlo Rinaldia, , Ke-lian Chena, , Guibin Chenc, , Manfred Boehmc, , Kenneth H. Fischbecka,


  • We characterized stem cells and motor neuron derivatives from patients with SBMA.
  • Variation in the repeat expansion mutation was observed in the cultured cells.
  • Reduced HDAC6 levels were found in the derived motor neurons.
  • Motor neurons from 2 patients with long repeats had increased acetylated α-tubulin.


Our study demonstrates several findings in the SBMA iPSCs that warrant additional investigation. The finding that CAG repeat length is unstable in specific iPSC lines allows additional study of factors that may be involved in the expansion or contraction of the repeat. It is possible that genetic factors in some lines make them more susceptible to instability, or that factors intrinsic to the reprogramming strategy modify the instability. SBMA iPSCs appear to have motor neuron differentiation capacity equivalent to controls, and although no changes in cell survival could be appreciated it is possible that treatment with additional stressors would induce a selective vulnerability. Although increased acetylated α-tubulin was observed predominantly in cells from two patients with particularly long repeats, the HDAC6 decrease was also observed in motor neurons cultured from several others. Decreased HDAC6 and increased acetylated α-tubulin levels were also seen in an MN1 cell model of SBMA, and in the spinal cord of an SBMA patient. Since HDAC6 has been shown to be important for trafficking misfolded protein to the aggresome, a deficiency in HDAC6 may produce a reduction in autophagic flux, with changes in mitochondrial activity, protein trafficking, and lysosomal function. Changes in lysosomal localization were observed in the SBMA motor neurons, and the lysosomal marker LAMP1 was found to have increased glycosylation. The significance of this glycosylation is not clear at this time, but it appears to indicate abnormal function of the lysosomal compartment. Further studies may help to determine how HDAC6 levels are reduced in SBMA and to characterize the consequence of these changes in the disease mechanism.

Study of Hepatic Function in Patients With Spinal and Bulbar Muscular Atrophy

NIH has scheduled another study and is currently recruiting patients.  Link to NIH website.


  • Spinal and bulbar muscular atrophy (SBMA) is an inherited disease. It causes weakness in muscles used for swallowing, breathing, and speaking. SBMA mainly affects men, but women can carry the gene for it. Researchers think there may be a link between SBMA and excess fat in the liver.


  • To look for fatty liver and liver injury in people with SBMA, people with motor neuron disease, and people who carry the gene for SBMA.


  • Adults 18 years and older who have SBMA, have motor neuron disease, or are carriers of SBMA.
  • Healthy adult volunteers.


  • Participants will be screened with medical history, physical exam, and blood tests.
  • Participants will have 1 outpatient visit of 1-2 days. Women will have a urine pregnancy test. All participants will have:
  • Blood tests.
  • Liver ultrasound. A probe is placed on the abdomen at certain locations and angles and takes pictures. The painless procedure takes 20-30 minutes.
  • Liver magnetic resonance imaging (MRI) scan. The MRI scanner is a metal cylinder with a magnetic field. Participants will lie on a table that slides in and out of it. They will be in the scanner for about 30 minutes. They will get earplugs for loud noises.
  • Some participants with abnormal liver testing will have a biopsy (small piece) of the liver taken. The biopsy site will be located with ultrasound, then cleaned and numbed. The physician will quickly pass a needle in and out of the liver while the participants holds their breath. Afterward, participants will be monitored in bed for 6 hours.
  • Participants may return for follow-up and another 1-2 day outpatient visit yearly for up to 2 years.

May 08, 2014 -Two recent reports by Cortes et al. and Lieberman et al. reveal a novel role of skeletal muscle on SBMA pathology and opens new avenues for alternative therapies against motor neuron disorders.  Dr. Lieberman was a Chat Room guest in September.  He explained the recent findings and the possible implications on Kennedy's Disease Research.  Below is the highlights and summary of Science Direct reported study.

Peripheral Androgen Receptor Gene Suppression Rescues Disease in Mouse Models of Spinal and Bulbar Muscular Atrophy


  • AR-targeted antisense oligonucleotides suppressed gene expression in mice
  • Subcutaneous delivery suppressed AR gene expression in the periphery but not the CNS
  • Subcutaneous administration rescued disease in two mouse models of SBMA
  • Peripherally expressed polyQ AR contributes to disease and is a therapeutic target


Spinal and bulbar muscular atrophy (SBMA) is caused by the polyglutamine androgen receptor (polyQ-AR), a protein expressed by both lower motor neurons and skeletal muscle. Although viewed as a motor neuronopathy, data from patients and mouse models suggest that muscle contributes to disease pathogenesis. Here, we tested this hypothesis using AR113Q knockin and human bacterial artificial chromosome/clone (BAC) transgenic mice that express the full-length polyQ-AR and display androgen-dependent weakness, muscle atrophy, and early death. We developed antisense oligonucleotides that suppressed AR gene expression in the periphery but not the CNS after subcutaneous administration. Suppression of polyQ-AR in the periphery rescued deficits in muscle weight, fiber size, and grip strength, reversed changes in muscle gene expression, and extended the lifespan of mutant males. We conclude that polyQ-AR expression in the periphery is an important contributor to pathology in SBMA mice and that peripheral administration of therapeutics should be explored for SBMA patients.

April 16, 2014 - The following is the top section of a study lead by Dr. LaSpada a UC-San Diego.

Mutant Protein in Muscle Linked to Neuromuscular Disorder 

A new therapeutic target for Kennedy’s disease and a potential treatment  Sometimes known as Kennedy’s disease, spinal and bulbar muscular atrophy (SBMA) is a rare inherited neuromuscular disorder characterized by slowly progressive muscle weakness and atrophy. Researchers have long considered it to be essentially an affliction of primary motor neurons – the cells in the spinal cord and brainstem that control muscle movement.

But in a new study published in the April 16, 2014 online issue of Neuron, a team of scientists at the University of California, San Diego School of Medicine say novel mouse studies indicate that mutant protein levels in muscle cells, not motor neurons, are fundamentally involved in SBMA, suggesting an alternative and promising new avenue of treatment for a condition that is currently incurable.  [Follow the link above to read the entire report]