Wednesday, March 20, 2019

SBMA Patients are More Likely to be Affected by Metabolic Disorders, Heart and Liver Disease

The following was reported in SMA News Today. The information is not new and from my perspective reflects mainly on the sedentary lifestyle after the progression has reached a point where the person can no longer perform aerobic physical exercise.

I believe it also reflects the need to continue to exercise (safely), change your diet, and be mindful of the possibility of these conditions in discussions with your doctor.

Heredity also plays an important factor in many of these conditions. 

SBMA Patients are More Likely to be Affected by Metabolic Disorders, Heart and Liver Disease

Patients with spinal-bulbar muscular atrophy (SBMA) are more likely to be affected by metabolic disorders, including insulin resistance and fatty liver disease, which can lead to heart disease and serious liver damage, a study says.

The study, “Prevalence of metabolic syndrome and non-alcoholic fatty liver disease in a cohort of Italian patients with spinal-bulbar muscular atrophy,” was published in Acta Myologica.

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).

The disorder is caused by mutations in the androgen receptor (AR) gene — located on the X chromosome — that lead to an abnormal expansion of a CAG nucleotide (the building blocks of DNA) repeat in the AR gene sequence and to the production of a much larger dysfunctional protein.

Besides neurologic symptoms, SBMA patients also tend to be affected by medical conditions associated with metabolic syndrome (a series of conditions that increase patients’ risk of developing heart disease, stroke or type 2 diabetes), such as insulin resistance, obesity, and glucose intolerance.

In the study, researchers at the University of Padua, in Italy, assessed the incidence of metabolic syndrome, insulin resistance, and non-alcoholic fatty liver disease (NAFLD) in a group of SBMA patients.

The study involved a total of 47 Italian patients with a confirmed diagnosis of SBMA who underwent a battery of biochemical tests to assess metabolic functions. A subset of 24 patients were examined by abdominal sonography (an imaging technique that allows physicians to visualize structures in the patients’ abdominal cavity).Results showed that 49% of the patients had abnormally high levels of fasting glucose (commonly used to diagnose diabetes), and 66% showed signs of insulin resistance.

In addition, 51% of the patients had high levels of total cholesterol, 38% had high LDL-cholesterol (“bad” cholesterol), and 38% had high triglycerides. Conversely, 77% had low levels of HDL-cholesterol(“good” cholesterol). More than half of the patients (55%) had three or more medical conditions associated with metabolic syndrome.

Researchers also found a positive relationship between insulin resistance and the length of CAG repeats in the AR gene sequence.

Biochemical tests showed high levels of two liver enzymes that, when elevated, may indicate liver inflammation or damage: aspartate transaminase (AST) levels were abnormally high in 62% of patients, and alanine transaminase (ALT) levels were high in 38% of patients.

Abdominal sonography revealed that 92% of the patients had liver steatosis (fatty liver disease) at different levels of severity, and one patient had liver cirrhosis (scarring of the liver).

“These alterations can be explained mainly by the reduction of testosterone activity because of (CAG repeats’) expansion in AR gene and must be considered as a main characteristic of Kennedy’s disease,” the researchers wrote.

“Metabolic alterations in SBMA are a suggestive model of androgen deprivation in male and require a multidisciplinary approach to disease. However, considering the conflicting data on the role of androgen stimulation in the metabolic involvement, further studies are needed to understand the pathogenesis of NAFLD and (insulin resistance) in SBMA patients and the possible detrimental consequences of anti-androgen approaches to disease,” they concluded.

Sunday, March 17, 2019

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

Saturday, March 16, 2019

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.”

Monday, March 4, 2019

New Gene Therapy Approach Able to Repair Mutations

Below is a small portion of the article in SMA News. Since the focus is on repairing triplet disorders, Kennedy's Disease (SBMA) could also benefit.

New Gene Therapy Approach Able to Repair Mutations Causing SMA, Other Inherited Diseases, Mouse Study Suggests

A new gene therapy approach using RNA molecules called transfer RNAs (tRNAs) was able to repair a subset of mutations causing spinal muscular atrophy (SMA) and other inherited diseases in living muscle tissue of mice, a study shows.

These genetic alterations, called nonsense mutations, alter the DNA sequence and introduce so-called stop codons — triplets of nucleotides, which are the building blocks for DNA — that prematurely stop gene expression and impair protein production. Besides SMA, these mutations also underlie diseases such as Duchenne muscular dystrophy, cystic fibrosis, and polycystic kidney disease.

The study, “Engineered transfer RNAs for suppression of premature termination codons,” was published in the journal Nature Communications.

Several lines of research have attempted to find compounds that are able to repair nonsense mutations. However, previous research has shown that certain small molecules can generate a different type of mutation that is able to disrupt protein function, but they can be toxic to the ears and kidneys. In addition, using the CRISPR/Cas9 gene editing technique — a potential treatment for diseases caused by nonsense mutations — has presented other challenges, such as off-target effects.

Aiming to find a suitable approach with the ability to repair nonsense mutations precisely, a team from the University of Iowa Carver College of Medicine, The Wistar Institute, the Cystic Fibrosis Foundation Therapeutics Lab and Integrated DNA Technologies investigated the potential of using tRNAs.

All genetic information contained within genes (DNA) is ultimately translated into proteins. However, the process is complex, with several steps: DNA is transformed into messenger RNA (mRNA), then a process called translation begins, which results in the production of proteins.

tRNA is a type of RNA molecule that helps decode a messenger mRNA sequence into a protein. Through specific sequences called anticodons, tRNA molecules match up with the corresponding mRNA and deliver the correct amino acid to build a protein in a cellular structure called ribosome.

Researchers engineered tRNAs to recognize and suppress three different stop codons — triplets of nucleotides that prematurely stop gene expression and impair protein production. (Gene expression is the process by which information in a gene is synthesized to create a working product, such as a protein). ...

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