MDA announces new research grants

Cision published a list of the newest MDA grant recipients today. Click on the link below to read the entire article.

Muscular Dystrophy Association Awards 25 Grants Totaling More Than $6.6 Million for Neuromuscular Disease Research

Critical funding provided by MDA will support studies to further understand disease mechanisms, optimize and build upon existing therapies, and advance drug target identification, especially toward gene-targeted therapies -- research that will have translational and clinical application across many neuromuscular diseases

Spinal-bulbar muscular atrophy (SBMA)

Alireza Mashaghi Tabari, PhD
Leiden University, The Netherlands
Research grant, $300,000
Single molecule folding studies on the mutant androgen receptor underlying SBMA

KENNEDY’S DISEASE RESEARCH NEWSLETTER No. 2

The UCL - London Research Team published their second newsletter. There are several updates on current research and projects. Click on the link below to read the PDF.
https://drive.google.com/file/d/10QzMtIO5kmXIvHQ3isTnODqx-YdGh2Qi/view?usp=sharing

Autophagic and Proteasomal Mediated Removal of Mutant Androgen Receptor in Muscle Models of SBMA

This is way over my head. I need someone to simplify it. Follow the link below to the entire - very long - article in Frontiers in Endocrinology.

Autophagic and Proteasomal Mediated Removal of Mutant Androgen Receptor in Muscle Models of Spinal and Bulbar Muscular Atrophy

Spinal and bulbar muscular atrophy (SBMA) is an X-linked motoneuron disease (MND) caused by a mutant androgen receptor (AR) containing an elongated polyglutamine (polyQ) tract. ARpolyQ toxicity is triggered by androgenic AR ligands, which induce aberrant conformations (misfolding) of the ARpolyQ protein that aggregates. Misfolded proteins perturb the protein quality control (PQC) system leading to cell dysfunction and death. Spinal cord motoneurons, dorsal root ganglia neurons and skeletal muscle cells are affected by ARpolyQ toxicity. Here, we found that, in stabilized skeletal myoblasts (s-myoblasts), ARpolyQ formed testosterone-inducible aggregates resistant to NP-40 solubilization; these aggregates did not affect s-myoblasts survival or viability. Both wild type AR and ARpolyQ were processed via proteasome, but ARpolyQ triggered (and it was also cleared via) autophagy. ARpolyQ reduced two pro-autophagic proteins expression (BAG3 and VCP), leading to decreased autophagic response in ARpolyQ s-myoblasts. Overexpression of two components of the chaperone assisted selective autophagy (CASA) complex (BAG3 and HSPB8), enhanced ARpolyQ clearance, while the treatment with the mTOR independent autophagy activator trehalose induced complete ARpolyQ degradation. Thus, trehalose has beneficial effects in SBMA skeletal muscle models even when autophagy is impaired, possibly by stimulating CASA to assist the removal of ARpolyQ misfolded species/aggregates.

Researchers identify a possible therapeutic target for Kennedy's disease and prostate cancer

https://www.eurekalert.org/pub_releases/2019-08/ifri-ria080819.php

NEWS RELEASE 8-AUG-2019

Researchers identify a possible therapeutic target for Kennedy's disease and prostate cancer

INSTITUTE FOR RESEARCH IN BIOMEDICINE (IRB BARCELONA)

A study led by scientists at the Institute for Research in Biomedicine (IRB Barcelona) and published in Nature Communicationsproposes chaperone protein Hps70 as an attractive therapeutic target for the treatment of Kennedy's disease--a rare neuromuscular condition--and of castration-resistant prostate cancer.

Kennedy´s disease is caused by a mutation in the androgen receptor. This receptor serves as a sensor of testosterone, detecting the levels of this hormone and activating the genes responsible for male traits. But in patients with this disease, the mutated receptor shows an altered structure, as demonstrated by this lab in a previous study recently published in the same journal, and it forms aggregates that damage muscle cells and causes muscular atrophy or wasting.

Chaperone proteins are one of the mechanisms through which the formation of toxic protein aggregates is prevented. These chaperones bind to other proteins in order to facilitate their correct folding, assembly and transport, as well as regulating their degradation. "But we didn't know the role of these chaperones in the regulation of the activity, cell concentration and solubility of the androgen receptor," says ICREA researcher Xavier Salvatella, head of the Laboratory of Molecular Biophysics at IRB Barcelona.

Using a sophisticated biophysics approach, nuclear magnetic resonance (NMR), and experiments with human cell cultures, the scientists discovered that the chaperones Hsp40 and Hsp70 bind strongly to a region of the androgen receptor that is susceptible to forming toxic aggregates. This interaction between the chaperones and the receptor prevents the formation of these deposits and facilitates their clearance.

To confirm whether the increase in the activity of these chaperones decreases the formation of toxic aggregates and whether these proteins are therefore useful for the treatment of Kennedy`s disease, the scientists performed experiments in mouse models. These experiments were done in collaboration with the labs of Professors Jason E. Gestwicki and Andrew P. Lieberman from the University of California San Francisco and the University of Michigan, respectively.

"The results obtain in mice confirm that compounds that activate Hsp70 lead to a decrease in the formation of the aggregates," says Salvatella. "Therefore the chaperone Hsp70 emerges as a possible therapeutic target for Kennedy's disease," he goes on to say.

The results may also be useful in the search for a treatment for castration-resistant prostate cancer, the most advanced stage of this kind of cancer, which causes 30,000 deaths a year in Europe. In cells resistant to current treatments, the binding site of Hsp40 and Hsp70 in the androgen receptor is not altered, and therefore these chaperones may also serve as a therapeutic target in this disease.

Mouse Study Explores Underlying Cause of Motor Neuron Degeneration in SBMA

CHMP7 has shown up twice recently in research on SBMA. The previous article can be found here:

Gene expression analysis reveals early dysregulation of disease pathways and links Chmp7 to pathogenesis of spinal and bulbar muscular atrophy

SMA News published a well written article and excerpts can be found below and the entire article can be read at this link" 

Mouse Study Explores Underlying Cause of Motor Neuron Degeneration in SBMA

"...Results showed that 178 genes were upregulated (overly active), while 287 were downregulated (under-activated) in motor neurons from SBMA mice compared to healthy animals, indicating that transcriptional dysregulation in SBMA starts at an early stage of development.

One of the genes that was donwregulated in motor neurons from animals with SBMA was Chmp7 (Charged Multivesicular Body Protein 7). Interestingly, the expression levels of this gene also were affected in motor neurons from the spinal cord and lower legs of adult SBMA mice before the onset of symptoms. (Of note, gene expression is the process by which information in a gene is synthesized to create a working product, like a protein.)

Similar alterations in the expression levels of CHMP7 (the equivalent gene of Chmp7 in humans) also were found in motor neurons’ precursors derived from SBMA patients’ induced pluripotent stem cells (iPSCs), suggesting that Chmp7 may play an important role in SBMA development. iPSCs are fully matured cells that are reprogrammed back to a stem cell state, where they are able to grow into any type of cell.

Moreover, the research team discovered that other genes involved in multiple signaling cascades essential for cellular function, such as the tumor suppressor (p53), DNA repair and energy metabolism, also were dysregulated in motor neurons from SBMA animals.

In addition, scientists observed that SBMA motor neurons showed signs of mitochondria (the cell compartments responsible for the production of energy) dysfunction and DNA damage, possibly caused by transcriptional dysregulation of genes involved in energy metabolism and/or DNA repair.

“Taken together, these findings indicate that an interplay of multiple pathways contribute to the disease pathogenesis [development] of SBMA. Significantly, the dysregulated genes and pathways, and in particular Chmp7/CHMP7 identified by our transcriptomic profiling may serve as candidate druggable molecular targets for therapy development in SBMA,” the researchers concluded."

CRISPR is Making News Again

Below is an excerpt of a good article on the National Public Radio website. Clink on the title below to read the entire article.

First U.S. Patients Treated With CRISPR As Human Gene-Editing Trials Get Underway

"...scientists have long hoped CRISPR — a technology that allows scientists to make very precise modifications to DNA — could eventually help cure many diseases. And now scientists are taking tangible first steps to make that dream a reality.

For example, NPR has learned that a U.S. CRISPR study that had been approved for cancer at the University of Pennsylvania in Philadelphia has finally started. A university spokesman on Monday confirmed for the first time that two patients had been treated using CRISPR.
The revelation comes as several other human trials of CRISPR are starting or are set to start in the U.S., Canada and Europe to test CRISPR's efficacy in treating various diseases.

"2019 is the year when the training wheels come off and the world gets to see what CRISPR can really do for the world in the most positive sense," says Fyodor Urnov, a gene-editing scientist at the Altius Institute for Biomedical Sciences in Seattle and the University of California, Berkeley.

Here are highlights of the year ahead in CRISPR research, and answers to common questions about the technology..."

So what's happening now with new or planned trials?

"We've finally reached the moment when CRISPR is moving out of the lab and into the clinic around the world..."

"...And yet another study, sponsored by Editas Medicine of Cambridge, Mass., will try to treat an inherited form of blindness known as Leber congenital amaurosis.

That study is noteworthy because it would be the first time scientists try using CRISPR to edit genes while they are inside the human body. The other studies involve removing cells from patients, editing the DNA in those cells in the lab and then infusing the modified cells back into patients' bodies.

Finally, several more U.S. cancer studies may also start this year in Texas, New York and elsewhere to try to treat tumors by genetically modifying immune system cells..."

When might we know whether any of these experimental CRISPR treatments are working?

"...All of these studies are very preliminary and are primarily aimed at first testing whether this is safe. That said, they are also looking for clues to whether they might be helping patients. So there could be at least a hint about that later this year. But it will be many years before any CRISPR treatment could become widely available..."

Gene expression analysis reveals early dysregulation of disease pathways in SBMA

Dr. Al La Spada at Duke University, who many of us know through the KDA, has published in Nature, Scientific Reports some research findings that could prove beneficial in future Kennedy's Disease research. 

Note:  You can read the entire report by clicking on the title (link) above.

Gene expression analysis reveals early dysregulation of disease pathways and links Chmp7 to pathogenesis of spinal and bulbar muscular atrophy

Published: 05 March 2019

Bilal Malik, Helen Devine, Rickie Patani, Albert R. La Spada, Michael G. Hanna & Linda Greensmith

Abstract

Spinal and bulbar muscular atrophy (SBMA) results from a CAG repeat expansion within the androgen receptor gene (AR). It is unclear why motor neurons selectively degenerate and there are currently no treatments for this debilitating disease. To uncover the causative genes and pathways involved in motor neuron dysfunction, we undertook transcriptomic profiling of primary embryonic motor neurons from SBMA mice. We show that transcriptional dysregulation occurs early during development in SBMA motor neurons. One gene found to be dysregulated, Chmp7, was also altered in vivo in spinal cord before symptom onset in SBMA mice, and crucially in motor neuron precursor cells derived from SBMA patient stem cells, suggesting that Chmp7 may play a causal role in disease pathogenesis by disrupting the endosome-lysosome system. Furthermore, genes were enriched in SBMA motor neurons in several key pathways including p53, DNA repair, WNT and mitochondrial function. SBMA embryonic motor neurons also displayed dysfunctional mitochondria along with DNA damage, possibly resulting from DNA repair gene dysregulation and/or mitochondrial dysfunction. This indicates that a coordinated dysregulation of multiple pathways leads to development of SBMA. Importantly, our findings suggest that the identified pathways and genes, in particular Chmp7, may serve as potential therapeutic targets in SBMA.

Results

Transcriptomic profiling of SBMA embryonic motor neurons

To characterise early transcriptional dysregulation and establish disease mechanisms in SBMA, we first performed a global transcriptomic screen of purified cultured spinal cord motor neurons from embryonic AR100 and wild-type (WT) mice treated with dihydrotestosterone (DHT), to reflect the ligand dependency of the disease. We found that 178 genes were upregulated, whilst 287 genes were significantly downregulated in AR100 motor neurons compared with WT cultures (Supplementary Information....

...Despite the ubiquitous expression of the causative AR gene and mutant protein, there is as yet no clear explanation for the selective loss of lower motor neurons in the anterior horn of the spinal cord and specific brainstem motor nuclei in SBMA, although high expression of AR within these cell types may be a possible contributory factor....

...Importantly, as no effective treatment or disease modifying therapies are available, the discovery of targets linked with early motor neuron dysfunction may provide promising therapeutic avenues in alleviating the development and course of the disease....

...There were also signs of DNA damage in spinal cord motor neurons of AR100 mice, which may result from downregulation of DNA repair genes and/or mitochondrial dysfunction. The identified pathways and genes, particularly Chmp7, may therefore represent attractive molecular targets for development of a therapeutic approach for SBMA....

Discussion

...Although our results suggest that several pathways may be associated with SBMA pathogenesis, it is possible that mitochondrial and p53 dysfunction are the key, early drivers of disease (Fig. 5A,B). Mitochondrial deficits and p53 dysfunction may act independently and in parallel, but also synergistically to initiate the early features of disease....

...Finally, mitochondrial and p53 deficits may be early instigators of dysfunction possibly acting independently or also synergistically to initiate the early features of disease in motor neurons. Taken together, these findings indicate that an interplay of multiple pathways contribute to the disease pathogenesis of SBMA. Significantly, the dysregulated genes and pathways, and in particular Chmp7/CHMP7 identified by our transcriptomic profiling may serve as candidate druggable molecular targets for therapy development in SBMA....

Report on the ENMC Conference

I wish to thank the Kennedy's Disease Association (KDA) for sharing this report from the recent European Neuro Muscular Centre Conference (ENMC). 

I feel this is a major step forward in finding a treatment for SBMA.  

Towards a European Unifying Lab for Kennedy's Disease

Twenty-four scientists working in academia, hospitals and industry from 8 different countries (Denmark, France, Germany, Israel, Italy, Spain, United Kingdom, USA) along with three patients’ representatives, (one who was also a representative of the USA patient group, The Kennedy’s Disease Association), met in the Netherlands on the weekend of the 15th- 17th of February 2019. They discussed the recent developments in research and shared the most recent clinical observations in spinal and bulbar muscular atrophy (SBMA). The workshop was conducted under the leadership of Maria Pennuto, Gianni Sorarù, Linda Greensmith and Pierre-Francois Pradat.

Background and Aims of the Workshop

SBMA, also known as Kennedy’s disease, is a rare, adult onset, neuromuscular disease caused by a mutation in the gene encoding for the protein which binds the male hormone androgen. This protein is called the Androgen Receptor (AR). The mutation is carried on the X chromosome and because the effects of the mutation are dependent on the presence of the male hormone androgen, the disease only affects males. However, females can be carriers of the mutation and if they do show symptoms, these tend to be mild.

The Androgen Receptor has an essential role in mediating the effects of the male hormone, androgen, and, when mutated, leads to muscle fatigue, weakness and atrophy of the arm and leg muscles, along with problems in speech, chewing and swallowing. Twitching or cramping of muscles can also occur.

Significant improvements have been made over the last few years in both our understanding of pathological mechanisms underlying the disease as well as in a greater recognition of the varied clinical manifestations of SBMA and in the development of clinical evaluation tools which together are essential to undertake effective therapeutic trials.

The aim of this workshop was to bring together leading clinical and basic scientists working in the field of SBMA to discuss the current understanding of basic disease mechanisms and to share and update the most recent developments in clinical evaluation of patients, with the objective of increasing the prospects of developing and testing new treatments that could effectively slow down disease progression in SBMA patients. ...

... Next Steps

In order to increase scientific and clinical collaborations between groups working in different countries, it was agreed that the First International Conference on SBMA will be organized, to be held in the spring 2020. The researchers and clinicians have underlined the need to collaborate with patients’ associations in the organization of the meeting with the aim of reinforcing the communication of scientific and clinical progress to SBMA patients and families, and providing the community with the possibility to directly collaborate in the research process.

Click here to read the entire report

Leuprorelin Acetate May Reduce Swallowing Dysfunction

The following article was published in SMA News.  The study was 48 weeks long and included 283 patients with Kennedy' Disease.

Leuprorelin Acetate May Reduce Swallowing Dysfunction in SBMA Patients, Study Finds

By Joanna Carvalho

Leuprorelin acetate may be a promising therapy to minimize swallowing dysfunction in patients with spinal and bulbar muscular atrophy (SBMA), a study finds.

The study, “Efficacy and safety of leuprorelin acetate for subjects with spinal and bulbar muscular atrophy: pooled analyses of two randomized-controlled trials,” was published in the Journal of Neurology.

SBMA, also known as Kennedy’s disease, is a type of spinal muscular atrophy (SMA) that starts in adulthood and is characterized by widespread muscle weakness and wasting in the arms, legs, head, and neck (bulbar involvement). For this reason, besides having impaired mobility, SBMA patients may have difficulties swallowing and speaking.

The disorder is caused by mutations in the androgen receptor (AR) gene — located on the X chromosome — which provides instructions for the androgen receptor protein. Although this protein is present everywhere in the body, it is enriched in motor neurons, the nerve cells responsible for controlling voluntary movements that are gradually destroyed in patients with SMA.

Because the the AR gene affects the body’s response to androgens — the male hormones involved in sexual development, such as testosterone — patients may have other symptoms, including infertility and erectile dysfunction (male impotence).


After the discovery of the AR gene, studies in animal models of disease revealed SBMA is triggered by the interaction of androgens with the defective androgen receptors. For this reason, treatment for SBMA has centered on the development of therapies involving androgen deprivation.

“Successful treatment of SBMA in mouse models with castration or administration of leuprorelin acetate, a luteinizing hormone-releasing hormone (LH-RH) agonist that reduces testosterone release from testes, supported the idea that testosterone blockade therapy could be beneficial and enabled subsequent human clinical trials,” the study stated.

In the study, Japanese researchers performed a pooled analysis of two identical randomized, placebo-controlled, double-blind clinical trials — JASMITT-06DB and JASMITT-11DB — to evaluate in more detail the efficacy and safety of leuprorelin acetate in patients with SBMA.


In both trials, patients were randomly assigned to receive either leuprorelin acetate or a placebo (control), once every 12 weeks, for 48 weeks. The primary goal was to assess changes in the amount of barium residues (a contrast agent used to visualize structures in the body) in the pharynx (throat) when patients attempted to swallow. Secondary measures included blood tests to measure testosterone levels, scrotal skin biopsies, and quality of life assessments.

In total, 283 SBMA patients were enrolled, including 142 who were treated with leuprorelin acetate and 141 with placebo.

Patients treated with leuprorelin acetate and those treated with placebo had an average decrease of 4.12% in the amount of barium residues present in the pharynx after initial swallowing. Although differences between the two groups after initial swallowing suggested that leuprorelin acetate might be effective at each assessment point, the changes from the initial visit to the last were not statistically significant between both groups, and the primary objective was not reached.


In general, leuprorelin acetate treatment was well-tolerated. The incidence of side effects (81.7% taking leuprorelin and 80.1% in the placebo group) and drug-related side effects (62.7% taking leuprorelin and 53.9% in the placebo group) were similar between the two groups.

However, some of the side effects, including abnormal liver function, weight gain, skin reactions at the injection site, decreased libido, erectile dysfunction, and excessive sweating, were more severe in patients treated with leuprorelin acetate than in those treated with placebo.

“In conclusion, leuprorelin acetate may be safe and beneficial for improvement of swallowing dysfunction in the patients with SBMA, without increasing the number of serious side effects,” the researachers said. “Further investigations are needed to clarify the efficacy of this therapy for SBMA.”

Muscle Biomarkers Correlate With Severity in SBMA

Neurofilament Light Chain [NfL]

Image: BestPractice

Wikipedia describes Neurofilaments this way: NF are intermediate filaments found in the cytoplasm of neurons. They are protein polymers measuring approximately 10 nm in diameter and many micrometers in length. Together with microtubules and microfilaments, they form the neuronal cytoskeleton. They are believed to function primarily to provide structural support for axons and to regulate axon diameter, which influences nerve conduction velocity. Neurofilaments are found in vertebrate neurons in especially high concentrations in axons, where they are all aligned in parallel along the long axis of the axon forming a continuously overlapping array. In addition to their structural role in axons, neurofilaments are also cargoes of axonal transport. Most of the neurofilament proteins in axons are synthesized in the nerve cell body, where they rapidly assemble into neurofilament polymers within about 30 minutes. These assembled neurofilament polymers are transported along the axon on microtubule tracks powered by microtubule motor proteins. 

Below is a portion of the abstract from a study published February 20th. You can read the entire study (PDF) at Neurology.org . 

Muscle and not neuronal biomarkers correlate with severity in spinal and bulbar muscular atrophy

Objective: To determine whether blood biomarkers of neuronal damage (neurofilament light chain [NfL]), muscle damage (creatine kinase [CK]), and muscle mass (creatinine) are altered in spinal bulbar muscular atrophy (SBMA aka Kennedy's Disease) and can be used as biomarkers for disease severity.

Methods: In this multicenter longitudinal prospective study, plasma and serum were collected from 2 cohorts of patients with SBMA in London, United Kingdom (n = 50), and Padova, Italy (n = 43), along with disease (amyotrophic lateral sclerosis [ALS]) and healthy controls, and levels of plasma and serum NfL, CK, and creatinine were measured. Disease severity was assessed by the SBMA Functional Rating Scale and the Adult Myopathy Assessment Tool at baseline and 12 and 24 months.

Results: Blood NfL concentrations were increased in ALS samples, but were unchanged in both SBMA cohorts, were stable after 12 and 24 months, and were not correlated with clinical severity. Normal NfL levels were also found in a well-established mouse model of SBMA. Conversely, CK concentrations were significantly raised in SBMA compared with ALS samples, and were not correlated to the clinical measures. Creatinine concentrations were significantly reduced in SBMA, and strongly and significantly correlated with disease severity.

Conclusions: While muscle damage and muscle mass biomarkers are abnormal in SBMA, axonal damage markers are unchanged, highlighting the relevant primary role of skeletal muscle in disease pathogenesis. Creatinine, but not CK, correlated with disease severity, confirming its role as a valuable biomarker in SBMA.

Note: The KDA just posted the research on their website. There was also a note from Pietro Fratta, who spoke about his biomarker research at last year's conference:

This work uses blood samples from 93 Kennedy’s patients, alongside controls and samples from models of disease, to look for traces of neuron and muscle damage in Kennedy’s disease. It finds that muscle damage is prominent, whilst neuron damage is below detection levels. This work highlights the role of muscle damage in Kennedy’s disease, which is extremely important for how therapies are designed. Further, this study supports the use of a specific biomarker, creatinine, for Kennedy’s disease clinical trials.

This study was possible only thanks to the incredibly strong participation to research of patients attending the Kennedy’s Clinic at the National Hospital in London and the University of Padova.

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." ..."

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.

Beyond motor neurons

This is a pretty good recap of what we know and what else might be of importance in finding a treatment or cure for Kennedy's Disease.

The entire post can be found here: 

Beyond motor neurons: expanding the clinical spectrum in Kennedy’s disease

The conclusions are shown below:

Conclusions

In SBMA, as in other genetic conditions caused by mutations in ubiquitously expressed genes, the clinical picture is the result of a complex interplay between differentially affected tissues, which struggle to cooperate to maintain homeostasis.

Extra-motor neuron features in SBMA, such as primary muscle atrophy or hormonal abnormalities, are emerging as clinically highly impactful in patients’ quality of life and disease progression. Their thorough investigations are proving critical for a number of reasons. First, they may provide important insights into common mechanisms of pathogenesis. Second, the peripheral abnormalities may offer the opportunity for direct functional assessments and repetitive samplings, therefore representing potentially exploitable biomarkers to track disease progression and/or response to therapy. Lastly, disentangling the underlying molecular mechanisms of this highly integrated inter-tissues cross-talk may offer unparalleled opportunities for therapeutic interventions in the near future.

Gene Editing Fixes Muscular Dystrophy in Dogs

As my readers know, I have been following the development of CRISPR for years. There is a short article written by Alice Park in TIME concerning CRISPR and Duchenne muscular dystrophy. There is also a short video on the page explaining hos CRISPR works. Click on the title below to go to the article.

 What bothers me is that I love beagles.

CRISPR Gene Editing Fixes Muscular Dystrophy in Dogs. Are Humans Next?

The powerful gene editing technology CRISPR is one small step closer to treating a human disease.

In a new paper published in Science, researchers led by Eric Olson, professor and chair of molecular biology at UT Southwestern Medical Center, reported that he and his team successfully used CRISPR to correct the genetic defect responsible for Duchenne muscular dystrophy in four beagles bred with the disease-causing gene. It’s the first use of CRISPR to treat muscular dystrophy in a large animal. (Previous studies had tested the technology on rodents.) In varying degrees, the genetic therapy halted the muscle degradation associated with the disease.

Duchenne is caused by mutations in the dystrophin gene, which codes for a protein essential for normal muscle function. People born with the disease are often eventually confined to wheelchairs as their muscles continue to weaken, and in the later stages, many rely on ventilators to breathe as their diaphragm muscles stop working. Eventually, they develop heart and respiratory failure.

UCL KD Research Newsletter

Below is the first newsletter from the UCL Kennedy's Disease Research Center. Many thanks to all who provide support as well as search for a treatment and a cure.

FYI - Kennedy’s Disease Clinic

This clinic is linked to the National Register for Kennedy’s Disease and is aimed at providing a central referring point for all patients in the UK. Kennedy’s disease (also known as Spinal Bulbar Muscular Atrophy) is a rare disorder and the Clinic will offer the multi-disciplinary approach available for MND and also provide screening for a number of non-neurological conditions that may associate with Kennedy’s Disease.

Coordinator for this clinic is Jan Clarke (jan.clarke1@nhs.net - Telephone: 020 3448 3517); general enquiries Marcia Forde (marcia.forde@nhs.net - Telephone: 020 3448 8251 - Fax: 020 3448 3633).

_______________________

UCL KD Research Newsletter

Hi and welcome to the inaugural research newsletter from the !

We always enjoy letting you know about exciting developments in KD research and care, and a few members of the KD community have asked to know more about the research happening at UCL, Oxford and further afield – so here we are!

We’re planning to update you with research news four times a year. We would really love to hear your feedback on what you like and what doesn’t work so well, so that we can improve what we are sending you. We really want it to be the most useful and interesting for you that it can be. Please do let us know at sbma@ucl.ac.uk.

KD Clinic

It has been wonderful to see so many faces coming through the KD clinic.

From the medical side we have a new consultant, Dr Carlo Rinaldi, who has many years’ experience in KD. Carlo runs a research group at Oxford University studying ways to develop new treatments for KD. Dr Helen Devine, a registrar, has returned from maternity leave and is joining the clinic alongside her PhD using stem cells to study KD.

KD research

There is plenty of ongoing research linked to the clinic, both in UCL and in Oxford. In some cases people with KD have been directly involved, for example: undergoing muscle MRI scans, or donating blood or skin samples that are currently being analysed in the lab. There are also numerous ongoing studies that use disease models to better understand KD and to find ways of changing its course.

We will include updates of these projects in upcoming newsletters.

Results from Japan using testosterone-lowering drug

Many of you have asked us about the results from a clinical trial recently published by colleagues in Japan.

Background: Our bodies naturally produce testosterone. In people with KD, this testosterone binds to faulty androgen receptors – and that causes damage to the nerves and muscles. Gen Sobue’s KD lab in Japan wanted to see if less testosterone would mean less activity of the androgen receptor – and therefore less damage. There is already a drug called Leuroprelin that makes men produce less testosterone. A team lead by the scientist Atsushi Hashizume ran a long-term trial giving Leuroprelin to some people with KD in order to reduce the levels of testosterone in their bodies, to see if they stayed healthier than others who were not given the drug. The scientists chose people who were similar in terms of age, length of disease and CAG repeat length. The first results were published in 2009 and actually showed that there was no clear benefit to people with KD after 18m of treatment.

Results from this study: Treatment was continued with Leuroprelin after the original study end and now the effect of the drug after up to 11.5 years in the longest-term patients has been published. Encouragingly, the researchers found that, over the observed time period, the people who were given Leuroprelin were less likely to develop pneumonia requiring hospitalisation, and they had a slower progression of disease.

Our view: The positive finding of this study is that reducing the action of testosterone can impact on the disease course of KD. On the cautionary side, however, the benefits are modest, and the drug, when taken chronically, has some side-effects.

In summary, although Leuprorelin may not prove to be clearly beneficial for people with KD, these results show that modifying testosterone can have an impact on disease, which brings optimism for future drug therapies.

Symptom management

We thought it would be useful to hear how you deal with KD’s most common and troublesome symptoms to create a resource for all of us to share, review and access.

So our first question is: what are the best strategies you have found to manage laryngospasm?  If you wish to contribute please e-mail Luca at: luca.zampedri@nhs.net

Best wishes,
Pietro, Carlo, Mike, Linda, Helen, Jan and Luca.

Creatinine Biomarker in SBMA

On April 11, SMA News reported the results of a three-year study on biomarkers that can spot neurodegenerative disorders before symptoms appear in conditions like Kennedy's Disease. 

Muscle Waste Product Creatinine Might Be Used as SBMA Biomarker, Study Reports

Yasuhiro Hijikata, Atsushi Hashizume, Shinichiro Yamada, Tomonori Inagaki, Daisuke Ito, Akihiro Hirakawa, Keisuke Suzuki, Naoki Atsuta, Takashi Tsuboi, Makoto Hattori, Akihiro Hori, Haruhiko Banno, Gen Sobue and Masahisa Katsuno
 

“Blood levels of a waste product from muscle metabolism could be used to see how spinal and bulbar muscular atrophy (SBMA) develops before symptoms appear, a Japanese study reports.

The research on the waste product, creatinine, appeared in the journal Neurology. The title of the article is “Biomarker-based analysis of preclinical progression in spinal and bulbar muscular atrophy.”

Scientists have been trying to find biomarkers that can spot neurodegenerative disorders before symptoms appear. The work has led to promising biomarkers for Alzheimer’s and Huntington’s disease.

But little research has been done on biological changes over time that occur before neurodegenerative disease symptoms show up. SBMA is a neurodegenerative disease caused by a mutation of the androgen receptor gene.

The Japanese researchers had previously reported a link between levels of the creatinine that kidneys secrete to the blood and the severity of movement problems once SBMA symptoms appear. But the team had not looked at how creatinine levels change before symptoms show up.

They wondered if tracking changes in biochemical levels and body measurements before SBMA symptoms appeared could shed light on how it develops. They focused on changes before and after the start of patients’ muscle weakness.

The team used statistical methods to predict changes in disease markers. Then they compared the forecasts with changes in healthy men and in ALS and Parkinson’s patients. In addition, they analyzed the link between patients’ creatinine blood levels and the start of their symptoms.

Their study between October 2014 and October 2017 involved 40 men with SBMA, 25 with ALS, 20 with Parkinson’s, and 48 healthy controls. The SBMA patients, whose bulbar and limb muscles had weakened, were followed for a mean of 17.3 years, including 11.4 years before symptoms appeared. …”

Click here to continue reading the rest of the article

Study identifies potential drug for treatment of debilitating inherited neurological disease

The following is an excerpt from a Medical Press article. To read the entire article follow this link: Potential Drug Treatment

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." ..."

Impaired Protein Homeostasis in Neurodegenerative Diseases

Impaired Protein Homeostasis in Neurodegenerative Diseases

The below excerpt is from an article appearing in Select Science. Click on the title above to read the entire article. For a good explanation on autophagy, click on the link below the drawing to watch a video.

https://www.youtube.com/watch?v=PvnqzhtwGZU

“Learn how selective antibodies help decipher an impaired autophagy pathway in spino-bulbar muscular atrophy

Dr. Constanza Cortes, Assistant Professor in the Department of Neurology at Duke University School of Medicine, studies impaired protein homeostasis in polyglutamine diseases such as spino-bulbar muscular atrophy.

SS: What are polyglutamine diseases?

CC: Polyglutamine diseases are a family of inherited neurodegenerative disorders, all caused by expansion of a triplet-nucleotide, CAG, in the coding region of the affected genes. The most notable is Huntington’s Disease, caused by a CAG expansion in the huntingtin gene. Another polyglutamine disease is spino-bulbar muscular atrophy (SBMA), caused by a CAG expansion in the androgen receptor (AR) gene. As the CAG codon encodes for the amino acid glutamine, the resulting proteins all carry extended polyglutamine tracts, giving the name to this family of diseases.

I study SBMA, a neuromuscular condition that targets the skeletal muscle and motor neurons in the lower spinal cord. These express high levels of the mutant AR, that result in protein inclusions, accumulating in the nuclei of affected tissues. This suggests that impaired protein quality control may form the basis of the neurodegenerative phenotypes observed in SBMA.

SS: What is the focus of your research in spino-bulbar muscular atrophy (SBMA)?

CC: I focus on protein quality control mechanisms and investigate the role they may play in the pathogenesis of SBMA. Protein homeostasis (also known as proteostasis), is fundamental for the survival of neurons, and proteostasis dysfunction is a feature of many neurodegenerative diseases, including Alzheimer’s and Parkinson’s disease. Understanding the mechanisms underlying proteostasis dysfunction and uncovering novel targets for rescuing these defects may yield important therapeutic targets for diseases associated with proteostasis failure.

SS: How does impaired protein homeostasis contribute to neurodegeneration in SBMA?

CC: I have uncovered a previously unreported periphery-to-CNS signaling network originating in skeletal muscle. Using a transgenic mouse model for a gene that’s a master regulator of cellular clearance and metabolism, conditionally expressed in the skeletal muscle, I have shown improved proteostasis in the CNS during normal aging. This suggests that maintaining skeletal muscle proteostasis during aging may yield important neuroprotective benefits in the aging brain.

In agreement with this, these muscle-specific proteostasis-activated mice perform significantly better in neurocognitive testing at 18 months of age compared to their age-matched control littermates. This suggests the existence of secreted signals originating in skeletal muscle and targeting the CNS, resulting in improved proteostasis control in the brain. My current work focuses on identifying those signals and testing their ability to rescue neurodegenerative ‘proteinopathies’, including Alzheimer’s disease….” For more, click on the heading at the top of this page.

Kennedy's Disease - Beyond Motor Neurons

The link below opens a recent study published in the Journal of Neurology, Neurosurgery & Psychiatry. It explains SBMA (Kennedy’s Disease) very well. The report is not just focused on the motor neurons. It goes into detail explaining other aspects of the condition and other potential opportunities for a treatment.

Beyondmotor neurons: expanding the clinical spectrum in Kennedy’s disease

Raquel Manzano, Gianni Sorarú, Christopher Grunseich, Pietro Fratta, Emanuela Zuccaro, Maria Pennuto, Carlo Rinaldi

“…Compared with other motor neuron diseases, such as amyotrophic lateral sclerosis (ALS), disease progression is relatively slow, with muscle strength declining by 2% per year. Recent evidence has shown that the muscle atrophy in SBMA is not solely secondary to the motor neuron degeneration but also consequence of a primary myopathic process. In addition, SBMA is frequently complicated by other signs and symptoms such as gynaecomastia, impotence, testicular atrophy and metabolic changes, suggesting a multisystem involvement in the disease. These features frequently manifest early in the disease course and can contribute substantially to the morbidity. In this review, we discuss the non-motor neuron abnormalities underlining SBMA symptomatology. We propose that an improved understanding of these features not only could result in better management of the patients SBMA, but also has the potential to shed new light into the disease pathogenesis, lead to the discovery of biomarkers for disease progression and open new treatment avenues. …”

“… Motor neurons are particularly sensitive to alterations in the proteostasis network, likely due to their extreme polarisation and post-mitotic nature. On the other side, alterations of protein quality control in muscle, by tilting the balance towards increased protein degradation, are likely the underlying cause of the muscle atrophy observed in this disease. …”

I feel this information should be shared with your primary care doctors. It might help explain other symptoms not normally associated with Kennedy’s Disease.

SBMA and Fatty Liver Disease - Follow up

This is a follow-up to an earlier article on this research. This article in Neurology Advisor has an important message for your doctor.

___________

“… Patients with spinal-bulbar muscular atrophy (SBMA) are at high risk for nonalcoholic liver disease as well as elevated glucose, serum triglycerides, and insulin, according to study findings published in Neurology.”

“… Although the researchers indicate that previous research has demonstrated elevations of serum cholesterol in patients with SBMA, the small sample size of 14 in the second group limits the study's detection power for this variable.

Because of the liver's prominent role in drug metabolism, the investigators suggest healthcare practitioners "prescribing medications or evaluating candidate therapeutics for patients with SBMA should be aware of the risk for fatty liver disease and monitor hepatic function." …”