Study identifies potential drug for treatment of SBMA

In March of last year I mentioned this article:

Study identifies potential drug for treatment of debilitating inherited neurological disease

An excerpt of the article can be found below Dr. Taylor's update.

I wrote Dr. Taylor today and asked for an update on the research. Below is his reply.

We have been working with the group in Vancouver at the University of British Columbia who developed the MEPB compound and have identified analogs that have even better potency and drug properties. UBC owns the rights. My understanding is that UBC is discussing a licensing agreement with a drug company to further develop this – meaning they will run independent preclinical trials in a mouse model using the newer compound, and pending those results will initiate human clinical trials. This typically takes ~ 2years.

The following is an excerpt from the original Medical Press article. To read the entire article follow this link: Potential Drug Treatment. The St. Jude's website also has the article:  Study Identifies PDT

As always, I appreciate Dr. Taylor and his team's support for finding a treatment for Kennedy's Disease.

March 15, 2018

Dr. Paul Taylor of St. Jude Children's Research Hospital ...

"... and his colleagues were led to seek drugs to treat SBMA because of findings from a previous study in his laboratory. The study pinpointed a molecular niche in the mutant androgen receptor protein that appeared to be a key to driving SBMA symptoms. However, that niche did not seem to be essential to the normal function of the androgen receptor. The study started with fruit flies genetically engineered to have the human androgen receptor, giving the scientists a living "test tube" to explore the effects of mutating the receptor.

"This identification of a small patch of this protein that appeared to be functionally important for driving the disease, but is not essential for most androgen receptor functions, gave us a potential drug target," Taylor said.

Pharmaceutical companies have been developing drugs to target this small patch, called the "activator function-2" or "AF2" domain. The companies were testing the drugs as possible treatments for prostate cancer, which also involves the androgen receptor. Taylor obtained a collection of the test drugs to evaluate for use with SBMA.

Using the genetically engineered flies, the researchers identified two drugs—whose long chemical names are abbreviated TA and MEPB—that alleviated SBMA symptoms. Then, using mice, the scientists determined that MEPB more effectively reached target tissues in the brain and spinal cord.

For their trials of TA and MEPB as potential SBMA treatments, the researchers developed a new genetically engineered mouse model to more accurately mimic the mutation found in men with SBMA. The transgenic mice showed many of the symptoms of humans with the disease.

Researchers found that MEPB effectively alleviated symptoms of SBMA in the mice. "Treating the mice with MEPB forestalled muscle atrophy and prevented loss of their motor neurons, with recovery of their testicles to normal size," Taylor said. "The treatment also protected their ability to walk and their muscle strength and endurance." ..."

Swim Training Improves Muscle Function in Mouse Model of ALS, Study Shows

I know of several men with Kennedy's Disease (SBMA) who expressed how good they felt and how much better/safer their exercise routine is in the pool. I never tried it. Below is an article on the benefits of swim training in mouse models with ALS. Clink on the header below to read the entire article or go to the bottom of this page and follow the link to the actual published report.

Swim Training Improves Muscle Function in Mouse Model of ALS

... Findings revealed that ALS mice had reduced muscle strength (70% less between 11 and 15 weeks), and showed significant alterations in energy metabolism (30% less citrate synthase activity, and higher activities of cytochrome c oxidase and malate dehydrogenase), and high levels of oxidative stress markers compared with controls.

However, swim training reduced the loss of muscle strength associated with ALS (5% less between 11 and 15 weeks), and increased citrate synthase activity by 26% compared with ALS mice that did not undergo swim training.

According to previous studies, swim training prolongs the lifespan of ALS mice by 10% to 13%. However, “from a clinical point of view, not only prolongation of lifespan, but also sustained functionality and inhibition of muscle waste are critical elements of therapy,” the study said.

“In agreement with previously published data, swim training significantly decreases the reduction in muscle strength clearly visible at the symptomatic stage of ALS, . . . reduces oxidative stress, and improves muscle energy metabolism at terminal stage of the disease,” the researchers stated.

“Our findings indicate that swim training is a modulator of skeletal muscle energy metabolism with concomitant improvement of skeletal muscle function in ALS mice,” they concluded.

Here is the link to the report on the study:  https://www.mdpi.com/1422-0067/20/2/233/htm

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.

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.

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.