Monday, January 21, 2019

Impaired Nuclear Export of Polyglutamine-Expanded Androgen Receptor in SBMA

The link below is to a very detailed report on a recent Kennedy's Disease (SBMA) research study. It is too detailed for me to summarize.

Impaired Nuclear Export of Polyglutamine-Expanded Androgen Receptor in Spinal and Bulbar Muscular Atrophy


... It has been widely reported that the ligand-dependent nuclear accumulation of mutant AR is required for SBMA pathogenesis17,18,46. This mechanistic insight into the toxicity of polyQ-expanded AR ultimately led to clinical studies that tested the effect of the androgen suppressors leuprorelin acetate and dutasteride on disease progression in SBMA patients81,82,83. Despite recent evidence that long-term treatment with leuprorelin acetate modestly slows disease progression84, overall the protective effects of androgen suppressors observed in SBMA animal models have not had a substantial impact on disease progression in symptomatic patients. The lack of an effective treatment for SBMA underscores the need for a better mechanistic understanding of aspects of mutant AR metabolism that can be targeted to ameliorate its toxic effects. To this end, the goal of this study was to determine if nuclear export, a poorly understood step in the metabolism of AR, plays a role in SBMA pathogenesis and whether reducing nuclear AR by enhancing its export can reduce its aggregation and toxicity.

The results of our study demonstrate (1) that the nuclear export of polyQ-expanded AR is impaired, (2) that enhancing the nuclear export of polyQ-expanded AR with an exogenous NES decreases its aggregation and toxicity by promoting its proteasomal degradation, (3) that polyQ-expanded AR exhibits reduced phosphorylation at S650 and that blocking S650 phosphorylation further exacerbates its nuclear export deficiency, and (4) that global disruption of nucleo/cytoplasmic transport is not a common feature of SBMA models.  ...

...  This study offers the first evidence that the nuclear export of polyQ-expanded AR is impaired, highlighting a novel aspect of AR metabolism that may contribute to the pathogenesis of SBMA. Furthermore, our data support a model in which the mutant AR is rapidly degraded by the proteasome once exported from the nucleus, thereby decreasing its stability, aggregation, and toxicity. Although additional work will be required to fully elucidate the mechanism underlying deficient nuclear export of polyQ-expanded AR, our results provide a new direction for investigations into therapeutic manipulation of the mutant, polyQ-expanded AR in SBMA.

Monday, January 14, 2019

Using Exercise and Other Physical Therapy Interventions to Optimize Functional Mobility

Below is a link to a PDF that was used for a presentation at the KDA annual conference. Anyone who follows my blog knows that I highly recommend developing a frequent and sustainable "smart" exercise program for those of us living with Kennedy's Disease (SBMA). The presentation expounds upon the benefits of a regular exercise program as well as provides warnings and tips.

As always, I recommend three things:
1. Consult with your doctor and a physical therapist before beginning any exercise program.
2. A PT familiar with KD or ALS is essential in the design of a sustainable program.
3. Don't overdo. Listen to your body.

Using Exercise and Other Physical Therapy Interventions to Optimize Functional Mobility

Joseph Shrader, PT, CPed

Click on this link to see some other presentations that given at the annual conference.

Friday, January 11, 2019

Patient trial shows impressive clinical results

The following article is from The Florey. A few people have commented that this might be helpful for Kennedy's Disease, SBMA. I am not an expert, but KD impacts the lower motor neurons. Lung function and cognitive ability are not normally affected. ALS is both an upper and lower motor neurons disorder. Lungs are affected. The drug trial mentioned appears to help upper motor neurons.

Motor neurone disease breakthrough: Patient trial shows impressive clinical results

A new drug delays motor neurone disease progression and improves cognitive and clinical symptoms. The latest trial results were announced by a spin-out company from the Florey and University of Melbourne, Collaborative Medicinal Developments.

Research at a glance:

The copper-delivery drug CuATSM improved symptoms in MND patients over six months
Improvements were seen in lung function and cognition. Decline in motor disability was reduced in treated patients compared to standard-of-care patients. The researchers will begin a larger Phase 2 trial to confirm CuATSM’s effectiveness in motor neurone disease. 

A new drug developed by scientists at the Florey Institute of Neuroscience, and the School of Chemistry and Bio21 Institute at the University of Melbourne has dramatically improved clinical and cognitive symptoms of motor neurone disease, also called amyotrophic lateral sclerosis.

This is the first human evidence for a disease-modifying drug for motor neurone disease. It is a huge breakthrough, and we look forward to confirming the positive results in a larger study soon

Motor neurone disease is a progressive, fatal neurodegenerative disease. Its key hallmark is the death of the brain cells that control muscle movements. This results in muscle weakness and eventually paralysis. Patients usually die of respiratory failure within three years of diagnosis, and there are no treatments or disease-modifying therapies available.

In this dose-finding trial involving 32 patients, the group given the highest amount of the CuATSM compound showed improved lung function and cognitive ability, compared to the predicted declines observed in standard-of-care patients. Further, treated patients showed a much slower overall disease progression as measured by a global disability score.

Professor Ashley Bush, Chief Scientific Officer of Collaborative Medicinal Development and director of the Melbourne Dementia Research Centre, said “This is the first human evidence for a disease-modifying drug for motor neurone disease. It is a huge breakthrough, and we look forward to confirming the positive results in a larger study soon.” 

Associate Professor Kevin Barnham of the Florey, Associate Professor Anthony White at the Queensland Institute of Medical Research, and Professor Paul Donnelly and Associate Professor Peter Crouch from the University of Melbourne, developed and tested CuATSM over a 15-year period. After showing its therapeutic potential for motor neurone disease in pre-clinical models, the researchers founded a company, Collaborative Medicinal Development, to take the drug into human studies. 

Professor Donnelly said, “It is gratifying to see such promising results made possible by collaborative fundamental research at the interface between chemistry and biology.” The results were reported at the 29th International Symposium on ALS/MND in Glasgow by Dr Craig Rosenfeld, CEO of Collaborative Medicinal Development.

The researchers plan to begin enrollment for a larger, randomised, placebo-controlled double-blind Phase 2 trial in mid- to late 2019. This trial will test CuATSM’s effectiveness in motor neurone disease / amyotrophic lateral sclerosis in a larger patient sample.