Tuesday, October 16, 2018

IGF-1 Clinical Trial for Kennedy's Disease



The Lancet – Neurology published the following article yesterday on the IGF-1 clinical trial for Kennedy’s Disease (SBMA). Below are excerpts of the Summary. The full Summary can be read at the link below and the article can also be purchased on the website.

Safety, tolerability, and preliminary efficacy of an IGF-1 mimetic in patients with spinal and bulbar muscular atrophy: a randomised, placebo-controlled trial


Summary


Background


“Spinal and bulbar muscular atrophy is an X-linked neuromuscular disease caused by CAG repeat expansion in the androgen receptor gene. Patients with this disease have low concentrations of insulin-like growth factor-1 (IGF-1), and studies of overexpression and administration of IGF-1 showed benefit in a transgenic model; thus the IGF-1 pathway presents as a potential treatment target. We assessed safety, tolerability, and preliminary efficacy of BVS857, an IGF-1 mimetic, in patients with spinal and bulbar muscular atrophy. …”

Methods


“In this randomised, double-blind, placebo-controlled trial, we recruited patients from neuromuscular centres in Denmark (Copenhagen), Germany (Ulm), Italy (Padova), and three sites within the USA (Bethesda, MD; Irvine, CA; and Columbus, OH). …”

Findings


“31 patients were assessed for eligibility, 27 of whom were randomly assigned to either BVS857 treatment (n=18) or placebo (n=9), and 24 were included in the preliminary efficacy analysis (BVS857 group, n=15; placebo group, n=9). BVS857 was generally safe with no serious adverse events. No significant differences were found in adverse events between the BVS857 and placebo groups. …”

Interpretation


“TMV (thigh muscle volume) remained stable in patients with spinal and bulbar muscular atrophy after being given BVS857 for 12 weeks. The intervention was associated with high incidence of immunogenicity and did not improve muscle strength or function. Additional studies might be needed to assess the efficacy of activating the IGF-1 pathway in this disease. …”

Note:  There is an accompanying article also noted:


Image:  http://www.hgh-pro.com/igf-1.html

Saturday, October 13, 2018

Biomarkers of Spinal and Bulbar Muscle Atrophy

This report was published in Frontiers of Neurology three days ago. Excerpts are below and the entire report ban be read by following the link.


Biomarkers of Spinal and Bulbar Muscle Atrophy (SBMA): A Comprehensive Review

Biomarkers in SBMA


A biomarker is a parameter that can be measured accurately and reproducibly and used as an indicator of normal biological processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention (WHO definition, 1998). An ideal biomarker should have a predictive value and capture subtle changes over relatively short periods of time. Additional requirements to biomarkers include cost-effectiveness, non-invasiveness, and reproducibility. It is generally agreed that no single biomarker is suitable for diagnostic, prognostic and monitoring roles and a panel of several markers may be better suited as multirole indicators. SBMA is a rare and slowly progressing condition, therefore the development of sensitive outcome measures would enable smaller sample-size and shorter duration of pharmaceutical trials.

Biomarkers of Neurological Involvement in SBMA


In recent years, an unprecedented interest has developed in the standardized assessment of neuromuscular performance in SBMA, evaluation of novel therapeutic strategies and in the launch of national SBMA registries. Many of the commonly used instruments, such as the MRC score, respiratory function parameters, the modified Norris scale, ALSFRS-r, Quantitative Myasthenia Gravis Score etc. are non-specific to SBMA, yet remain widely utilized. As these tools have been developed for other conditions, new batteries of tests have been recently proposed to specifically appraise disability in SBMA.


Discussion and Future Perspectives


Interest in SBMA biomarkers has grown steadily in recent years, fuelled both by accruing knowledge about pathogenesis and novel therapeutic strategies. SBMA is now widely recognized as a multisystem syndrome. A multitude of studies focus on multi-organ involvement, and the systemic phenotype is now considered just as relevant as the neurological manifestations. It is increasingly recognized that non-neurological features of the disease have an equally important impact on the patients' quality of life. Until now, clinical trials on SBMA focused almost exclusively on the treatment of motor symptoms, but a shift to targeted molecular therapies and focus on systemic processes are likely to be witnessed in the near future. From a clinical trial perspective, ideal biomarkers should undergo robust validation, sensitivity and specificity profiling, and sampling and measurement harmonization across different centers. Crucially, candidate markers should be able to detect the subtle changes expected after the administration of a specific treatment. Given the particularly slow progression rates observed in SBMA, the definition of an effective outcome measures is challenging. The integration of neurological, metabolic, and endocrine indicators seems essential into composite biomarker panels in addition to functional scales. Serum creatinine levels appear to correlate strongly with motor impairment and HOMA-IR index with disease duration. The convincing validation of these parameters and their use as effective outcome measures in clinical trials will require robust multicenter study designs.

Wednesday, October 10, 2018

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.

Monday, October 8, 2018

Planning for Long-Term Care: The Costs and Potential Issues


A special "thank you" to Hazel Bridges who has written another informative article on long-term care. 

Long-Term Care


Planning for long-term care can be tricky, to say the least; you never know what might happen in the next five or 10 years, and it can be difficult to think about financial planning when you’re unsure of what the future may bring. For seniors, however, it’s imperative to start thinking about how you might pay for your care should you need to stay in a hospital or nursing facility for an extended amount of time. Health insurance and Medicare are wonderful resources, but they only cover so much of the cost associated with long-term care.

For now, think about how to boost your savings and ensure that you are doing everything in your power to prevent issues down the road. This means making your health and mobility a priority and making changes to your home to make it more accessible. This will ensure that you are able to live in it longer, even if your health should fall into decline, and that you will stay safe.

Keep reading for some great tips on how to plan for long-term care.

Turn Your Home Into a Safe Haven


Prevention is one of the best ways to ensure that your health and safety are a priority. Making changes to your home is a great way to start, as it will help you remain there longer without the need for an assisted living facility. For example, you might add grab bars in the shower, place sturdy railings on both sides of the stairs, widen doorways to allow for medical equipment, add lighting to prevent falls, or remove loose rugs or carpeting that can be trip hazards. Think about what each room in your home needs in regard to safety and comfort, and do a little research to figure out what the cost will be to make the changes. Check out this guide for some great tips on which changes you should make and how to get started.

Know Your Policies


You may have a health insurance policy that will help pay for care down the road, but how much will it cover in the long term? Take a good look at your policy, and carefully read over your Medicare or Medicaid paperwork to see exactly what you will be responsible for should you need long-term or daily care due to an injury or major health issue.

Consider Selling Your Life Insurance Policy


If you need a large sum of money to cover care costs, or if you just want to pad your savings account, consider selling your life insurance policy or see if your policy offers a cash value option that would allow you to take money from the total benefit amount now. This will reduce the amount that your loved ones would receive in the event of your death, but it could be a viable option if you need cash to pay medical bills or to put aside for your future needs.

Make Lifestyle Changes


Along with the changes to your home, you can make changes to your lifestyle that will allow you to stay healthy, which, in turn, can possibly reduce the risk that you will need long-term care down the road. This includes eating right, getting daily exercise, and eliminating bad habits, such as smoking or using substances such as alcohol to excess.

Planning for long-term care does not have to be stressful. By starting now, you are on the right track toward ensuring that your healthcare needs won’t be overwhelming in the future. Make the necessary changes to help your body and mind stay healthy, and remember to ask for help when you need it.
Photo via Pixabay by Sabinevanerp

Monday, October 1, 2018

Symptoms of Kennedy's Disease (SBMA)

Any time I list the potential symptoms of Kennedy’s Disease, aka Spinal Bulbar Muscular Atrophy (SBMA), there is a tendency for someone to comment, “I have that. Do you think it’s Kennedy’s Disease?”

My answer is always the same. “I don’t know. You need to see your primary care doctor and discuss your symptoms with her/him.”

When my symptoms started, there was no DNA test for Kennedy’s Disease (SBMA). Most doctors and many neurologists did not know about SBMA. Neurologists put you through a series of tests, some not very pleasant, to help determine the cause of the symptoms. Most often, it was an educated guess based upon available evidence. In my case, I was diagnosed with ALS.

Several years later, another doctor diagnosed it as SBMA and sent me to see Dr. Fischbeck for a second opinion. I still remember walking into Dr. Fischbeck’s office that morning. He saw my gate, nodded his head, and said, “You have the walk.” He performed a DNA test and confirmed Kennedy’s Disease.

Today, because of the DNA test, a doctor can draw a little blood and send it off to a lab. Within a few weeks you will have an answer as to if you have Kennedy’s Disease. If not, you will still have to go through more testing, but at least SBMA is ruled out.

In regards to the list of symptoms below, those of us living with Kennedy’s Disease normally do not have all of them. We will have several and some might not appear until later in the progression. The most common early symptoms are severe cramping, hand tremors, unexplained fasciculations, and gynecomastia.

Please note there is a wealth of information available on the Kennedy’s Disease Association website (http://www.kennedysdisease.org/index.php/about-kennedys-disease/what-is-kennedys-disease).



SYMPTOMS

(I apologize for the formatting problem below)
Neurological:

Bulbar Signs
The Bulbar muscles are those supplied by the motor nerves coming off the brain stem. They control breathing, swallowing, talking and other functions of the throat. Bulbar signs are problems with these functions.
Dysphagia
Trouble swallowing. (One of the Bulbar signs.)
Intention Tremor
Hand tremors when trying to do something.
Normal Babinski
Normal plantar response, ie., when the bottom of the foot is scraped, the toes bend down. An abnormal response would be an upward bending of the toes indicating a problem in the brain itself.
Lower Motor Neuropathy
The lower motor nerves are those that run from the spinal cord to the muscles that they stimulate to move. Loss of that nerve leads to weakness and wasting of the muscle.
Primary Sensory  Neuropathy
Numbness over certain areas. Loss of sensation.
Decreased or Absent Deep Tendon Reflexes
When a doctor taps the knee with his hammer there is no response.
 Muscular:

Fasciculations
Twitching of small muscles without purposeful movement. These can be seen through the skin.
Cramps
Large muscle spasms.
Postural Tremor
Shaky muscles with certain positions.
Muscular Atrophy
Wasting and shrinkage of muscles that occurs when the lower motor nerve does not stimulate the muscle adequately.
Hypertrophied Calves
Calf muscles that become thicker because of cramps.
 Thoracic:

Gynecomastia
Enlarged breasts.
 Endrocrine

Androgen Deficiency
Loss of masculinizing effect (qualities that are perceived as masculine).
Estrogen Excess
More of an apparent estrogen effect because of the lost of masulinizing effect.
 Genito-Urinary:

Impotence
Erectile dysfunction.
Reduced Fertility
Low sperm count.
Testicular Atrophy
Testicles become smaller and less functional.
 Miscellaneous Characteristics:

Late Apparent Onset
Symptoms could become apparent in 20's or 30's, but might not appear until the 60's or 70's.
Slow Progression
Near-normal lifespan.
Asymmetry of Clinical Signs
Muscles of one side may be more affected than the same muscles on the other side.
 Laboratory:

Elevated Serum Creatine Kinase
Elevation of CPK enzyme in the blood test.  Can be confused with the enzyme released during a heart attack.

Thursday, September 20, 2018

MDA Grant for Research on SBMA

The following article appears in NewsWise. Click on the link below to read the entire article.

Dr. Carlo Rinaldi Receives Co-Funded AANEM Foundation/MDA Grant for Research on Spinal and Bulbar Muscular Atrophy

 Carlo Rinaldi, MD, PhD, has been selected as the recipient of a development grant co-funded by the AANEM Foundation and the Muscular Dystrophy Association (MDA). Dr. Rinaldi, who works as an Associate Professor in the Department of Physiology, Anatomy and Genetics in the Division of Medical Sciences at the University of Oxford in the United Kingdom, will be using this funding to increase understanding of the pathophysiology of spinal and bulbar muscular atrophy (SBMA). SBMA is a neuromuscular disorder characterized by the degeneration of lower motor neurons and primary muscle atrophy. Dr. Rinaldi’s ultimate goal is to develop effective therapeutic treatments for this yet incurable condition.

Dr. Rinaldi’s research objective is to characterize the role of the androgen receptor (AR) isoform 2 on AR biology and its impact on SBMA toxicity. His central hypothesis is that AR45 is a key regulator of AR activity and represents a promising therapeutic target for SBMA.

“There is currently no treatment available for SBMA,” explained Dr. Rinaldi. “This research work has the potential to shed new light on the role of the AR isoforms in both health and disease, advance understanding of the mechanisms of pathogenesis in SBMA, and provide a new therapeutic target in close relationship with the disease-causing mutation.” 

“Dr. Rinaldi has the strong support of the Neuroscience community in Oxford to pursue his research into the mechanisms of motor neuron degeneration in SBMA,” noted Kevin Talbot, MB, PhD, FRCP, Head of the Division of Clinical Neurology and Professor of Motor Neuron Biology and Consultant Neurologist at John Radcliffe Hospital in Oxford. “This is a neglected area and he is in an excellent position to be a leader in this field, both within Europe and worldwide.” …

Monday, September 17, 2018

Research Proves My Wife Wrong


For several years, my wife has told me, “You’re getting dumber every day.” She follows it up with something like, “I don’t know if it is the Kennedy’s Disease or what, but…”

Well, researchers have proven her wrong ‘once again’, and I love it. 😊

Nature.Com published in September the results of a study of patients with Spinal Bulbar Muscular Atrophy. Click on the link below to read the entire study.

UnimpairedNeuropsychological Performance and Enhanced Memory Recall in Patients with SBMA:A Large Sample Comparative Study

Abstract:

“Peculiar cognitive profile of patients with SBMA has been described by fragmented literature. Our retrospective study reports the neuropsychological evaluations of a large cohort of patients in order to contribute towards the understanding of this field. We consider 64 neuropsychological evaluations assessing mnesic, linguistic and executive functions collected from 2013 to 2015 in patients attending at Motor Neuron Disease Centre of University of Padova (Italy)…”

“…the aim of the present study is to report the neuropsychological evaluation of a large sample of SMBA patients in order to contribute towards the definition of these patients’ cognitive profile.”

“…administered brief neuropsychological battery aimed to a fast evaluation of short- and long-term memory, linguistic abilities and executive functioning (for details please see methodological section). The tasks’ choice had a clinical finality and was aimed to assess the integrity of the cognitive functions in order to eventually consider hinderances to an adequate communication with the doctor, or that could undermine patients’ compliance in the home management of care…”

Results:

Neuropsychological findings - “ANCOVA results showed no statistically significant difference between groups in all the examined test performance, except for the Babcock Story Recall Test score, in which patients performed better than control participants, with no relevant influence of age and education. Education level was instead a statistically significant covariate for all the other measures, while participants’ age was found statistically significant for the TMT B-A and the DSf scores only…”

Discussion – “No frank cognitive impairment was found in our retrospective study on 64 patients with SBMA, as deduced from the scores of patients on neuropsychological tests, compared with those of healthy male subjects. Surprisingly, patients showed better performance on the Prose Memory test score…”

“…This interpretation nicely fits with the phenomenon of the so called somatic mosaicism, characterizing this pathology. It implies that the number of CAG-repeats is not constant in every cell of an individual, but it may vary across tissues, including the cerebral ones; such an instability is typical of other neuromuscular diseases…”

Full Disclosure:  My ‘wonderful’ wife never said those things. She has questioned my intelligence, however, when I do something dumb and end up falling.

A Special Thank you:  Istvan Reinhardt sent me the link to the above study.

Monday, September 10, 2018

Long-Term Care Options

Below is a guest post from Hazel Bridges. I consider it an excellent primer for an important subject facing most everyone at sometime in their life, not just those of us living with Kennedy's Disease. Thanks, Hazel, for sharing this information.


Living with a Chronic Disease
Long-Term Care Options


When you wake up in pain every morning, can’t handle daily living tasks, or have difficulty with cognitive functions, you need help. Often, that help comes in the form of loving friends and family who want to lend a hand. However, the reality is that you must also plan for long-term care needs that can’t be handled by your loved ones.

Planning for Long-Term Care

Barriers to Self-Care

Chronic illnesses present specific barriers to long-term self-care. The Lippincott Nursing Center categorizes these as psychological, physical, cognitive, economic, and social and cultural. Regardless of the reason care is required, the decision to choose at-home or residential/nursing care is deeply personal and requires planning and preparation.

Care at Home

Home is the most comfortable place for the vast majority of people with chronic illnesses. And with a little help, it can be a safe haven for recovery or just to enjoy life on your own terms. HomeAdvisor explains there are numerous forms of at-home services. These include:

     Home health aides. A home health aide is an individual who helps with daily tasks such as hygiene and bathing. They may also assist with cooking, laundry, and grocery shopping. Home health aides are not licensed for offer medical services.

     Adult day care. These facilities are designed to cater to older adults or those with physical and cognitive disabilities. They offer supervision and assist with dispensing medications and hygiene as needed.

     Skilled nursing. For individuals with health needs beyond the capabilities of themselves, friends, and family, a licensed nurse can provide more in-depth and involved medical services. This may include administering injected medications and assisting with physical therapy activities.

Residential/Nursing Facilities

If home health care is no longer feasible, an assisted living or skilled nursing care facility is an option. While typically associated with seniors, these housing programs may also be available to adults, teens, and children with severe disabilities.

     Assisted living. An assisted living campus is one where individuals and couples (typically seniors) live in their own apartment, home, or condominium. They have access to a central campus area that provides recreational activities. Assisted living often includes housekeeping, meals, and help taking medication.

     Skilled nursing. A skilled nursing care facility is different from assisted living in that people who live here are not able to care for themselves without direct medical intervention. Those who reside in a skilled nursing care facility may have the option of living in a private room or sharing accommodations with another patient in order to receive a discounted fee and enjoying constant companionship.

Paying for Long-Term Care

Covering Costs

One of the main concerns of receiving paid care is the question of financing it. Elmcroft Senior Living estimates that long-term nursing care averages between $225 and $253 per day. À la carte home services may be less expensive with an at-home caregiver charging an average of between $10 and $35 per hour. Medicare does not cover the cost of assisted living or skilled nursing care for the long-term. Paying for these accommodations and services often falls to private health insurance, Medicaid, individual savings, or SSI disability.

Lifestyle Factors That Affect the Need for Care

Those living with a chronic disease may have no choice other than to receive care the vast majority of their lives. Others, however, may find that small lifestyle changes reduce reliance on others. People who smoke are more likely to need intense medical supervision later in life than those that don’t. Exercise can also help preserve independence by keeping muscles strong and improving balance, which will lower the possibility of sustaining a falling injury. Excessive drinking, drug use, and engaging in risk-taking behaviors can also increase the chances that you or a loved one will need medical care. Minor home modifications, such as added lighting and a wheelchair ramp, may also extend your ability to remain independent.

For more information on making the decision to enter or put a loved one into nursing care, visit the AARP online.

Image via Pixabay

Friday, September 7, 2018

Don’t Give Up The Ship

"Don't give up the ship" was the dying command of James Lawrence in 1813 aboard the USS Chesapeake. Those words should be the battle cry for all of us living with Kennedy’s Disease, aka Spinal Bulbar Muscular Atrophy.

At times, it is easy to feel defeated. This is especially true after a ‘slide’. When we experience them, the first thought is will I bounce back. The next thought is usually laced with fear. What happens if I do not bounce back?

In my 40+ years of living with Kennedy’s Disease, I have experienced my share of slides. When I was a little younger and more resilient, my slides were steep and my bounces just as dramatic. These last few years, my bounces are not as dramatic and sometimes there is no bounce at all.

A few months back my choking became a daily issue. Almost everything I tried to eat would not go down without a fight. It took me thirty to sixty minutes to eat a meal. Many times, I could not finish a meal because of the choking. I lost more weight and began to research other options for receiving the required nutrition.

These choking episodes went on for a couple of months. It got to a point where I did not want it to be mealtime. Yet, something inside kept telling me to practice my swallowing exercises. Then, during the first week of August, I noticed an improvement. Food was going down easier. I found myself eating more and enjoying my meals again. The last few weeks I discovered I am putting on weight again.

During the ‘bounce back’, I continued to practice what I learned during the choking period. I drink water to help wash food down. I use more gravy and other juices to make it easier to swallow. I limit ‘sticky’ foods like bread that have crumbs and are more difficult to swallow. And, most importantly, I now practice my swallowing exercises at least three times a day.

Once again I learned no to give up the ship without a fight!
 

P.S. Want to learn more about the Captain Lawrence and the battle? [Click on this link]

"...During the War of 1812, Captain James Lawrence, commanding the 49-gun frigate U.S.S. Chesapeake, was attacked off Boston Harbor by the British ship H.M.S. Shannon.

In less than 15 minutes, Lawrence's crew was overwhelmed. Mortally wounded, Lawrence shouted, "Tell the men to fire faster and not to give up the ship; fight her till she sinks!" ..."

Friday, August 31, 2018

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.

Wednesday, August 29, 2018

Study: Systemic Delivery of MicroRNA



István Reinhardt emailed me a link to a recent Kennedy’s Disease (SBMA) study. The video is also interesting. Clink on the link below to go to the site or download a PDF copy of the study with this link:  https://www.jove.com/pdf/55724

Systemic Delivery of MicroRNA Using Recombinant Adeno-associated Virus Serotype 9 toTreat Neuromuscular Diseases in Rodents

ABSTRACT

RNA interference via the endogenous miRNA pathway regulates gene expression by controlling protein synthesis through post-transcriptional gene silencing. In recent years, miRNA-mediated gene regulation has shown potential for treatment of neurological disorders caused by a toxic gain of function mechanism. However, efficient delivery to target tissues has limited its application. Here we used a transgenic mouse model for spinal and bulbar muscular atrophy (SBMA), a neuromuscular disease caused by polyglutamine expansion in the androgen receptor (AR), to test gene silencing by a newly identified AR-targeting miRNA, miR-298. We overexpressed miR-298 using a recombinant adeno-associated virus (rAAV) serotype 9 vector to facilitate transduction of non-dividing cells. A single tail-vein injection in SBMA mice induced sustained and widespread overexpression of miR-298 in skeletal muscle and motor neurons and resulted in amelioration of the neuromuscular phenotype in the mice.

In a 2011 post, Ed Meyerthoen explained the defective AR gene. You can read his post by following this link:  https://kennedysdisease.blogspot.com/2011/05/what-is-ar-and-why-is-it-important.html

Friday, August 24, 2018

New Funding for SBMA Research

The MDA announced the funding of $9.9 million dollars in research grants. The grant below is for the study of Kennedy's Disease.


Carlo Rinaldi, Ph.D., associate professor and clinician scientist at the University of Oxford in England, was awarded an MDA Development Grant to study how variants in the gene of the androgen receptor (AR) protein cause spinal-bulbar muscular atrophy (SBMA) and investigate whether a novel antisense oligonucleotide therapy approach can target these toxic variants. The results of the study will provide a better understanding of SBMA disease mechanisms, as well as develop a new therapy potentially capable of treating the disease.
This work has potential implications for other diseases of the motor unit as well, including spinal muscular atrophy (SMA) and ALS. This grant is co-funded by the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM).

Additional information was provided on another page:

“Better understanding of the underlying disease mechanisms, coupled with improvement of gene vector design, therapeutic gene selection, and methods of delivery, have made gene therapy a realistic option for neuromuscular conditions — and neurological diseases in general — for which no treatment option was available until few years ago. Many challenges still lie ahead, but we have good reasons to be very optimistic for the future.”

Carlo Rinaldi, associate professor and clinician scientist at the University of Oxford in England, was awarded an MDA Development Grant totaling $120,000 over 3 years to study the role of androgen receptor isoforms in SBMA pathogenesis and the potential as therapeutic targets. This grant is co-funded by the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM).

Mutations in the gene encoding the androgen receptor (AR) protein cause spinal and bulbar muscular atrophy (SBMA). SBMA is an adult-onset neuromuscular condition affecting males with unmet clinical need. It is not undestood how mutations in AR lead to primary degeneration of motor neurons and muscle in patients. The activity of AR and other hormone receptors can be modulated in human cells by isoforms and/or splice variants, which may block or enhance their functions.

Dr. Rinaldi and colleagues plan to investigate the role of AR alternative isoforms in mediating SBMA toxicity. By revealing how these isoforms regulate AR activity in health and disease, researchers expect to better understand the mechanisms of disease in SBMA and provide a novel rational therapeutic target. If successful, the work could pinpoint tissue-specific targets for therapy development, with implications not only for SBMA but for other diseases of the motor unit as well, including spinal muscular atrophy and amyotrophoic lateral sclerosis.

Tuesday, August 21, 2018

Creatine Monohydrate Trial


I found this report on a trial conducted in 2014 and 15. I searched for the final analysis and can’t locate it. Perhaps you will have better luck than me. If so, let me know.

Treatment with Creatine Monohydrate in Spinal and Bulbar Muscular Atrophy: Protocol for a Randomized, Double-Blind, Placebo-Controlled Trial


Yasuhiro Hijikata, MD, PhD, Masahisa Katsuno, MD, PhD, Keisuke Suzuki, MD, PhD, Atsushi Hashizume, MD, PhD, Amane Araki, MD, PhD, Shinichiro Yamada, MD, PhD, Tomonori Inagaki, MD, Daisuke Ito, MD, Akihiro Hirakawa, PhD, Fumie Kinoshita, MSc, Masahiko Gosho, PhD, and Gen Sobue, MD, PhD


Background
Although spinal and bulbar muscular atrophy (SBMA) has been classified as a motor neuron disease, several reports have indicated the primary involvement of skeletal muscle in the pathogenesis of this devastating disease. Recent studies reported decreased intramuscular creatine levels in skeletal muscles in both patients with SBMA and transgenic mouse models of SBMA, which appears to contribute to muscle weakness.

Objective
The present study aimed to examine the efficacy and safety of oral creatine supplementation to improve motor function in patients with SBMA.

Results
Participant enrollment in the trial started from June 2014 and follow-up was completed in July 2015. The study is currently being analyzed.

Monday, August 20, 2018

What and Why

Someone asked why I haven't posted many articles this month. That;s a good question and it deserves an answer.

I have focused much of my time the last couple of months on "Shattered Lives," the latest historical fiction novel I am writing.  It is about Treblinka, the Nazi death camp. I am into the second edit and had to do a few rewrites. The amount of research required to write the book was amazing, but nothing compared to the rewrite and editing process.

I hope to have most the the rewrite work finished soon. Then I can devote more time to the Living with KD blog. In the meantime, if  I read/find something important about Kennedy's Disease, you can be assured it will be posted.

Thanks for your understanding. 'Bruce of many hats'



Wednesday, August 8, 2018

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.