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Research Updates

2023 Research Updates

2023 Research

Unexpected frequency of the pathogenic AR CAG repeat expansion in the general population

CAG repeat expansions in exon 1 of the AR gene on the X chromosome cause spinal and bulbar muscular atrophy, a male-specific progressive neuromuscular disorder associated with a variety of extra-neurological symptoms. The disease has a reported male prevalence of 1:30,303 or less, but the AR repeat expansion frequency is unknown. We established a pipeline, which combines the use of the ExpansionHunter tool and visual validation, to detect AR CAG expansion on whole-genome sequencing data, benchmarked it to fragment PCR sizing, and applied it to 74,277 unrelated individuals from four large cohorts. Our pipeline showed sensitivity of 100% (95% C.I. 90.8-100%), specificity of 99% (95% C.I. 94.2-99.7%), and positive predictive value of 97.4% (95% C.I. 84.4-99.6%). We found the mutation frequency to be 1:3,182 (95% C.I. 1:2,309-1:4,386, n=117,734) X chromosomes - ten times more frequent than the reported disease prevalence. Modelling using the novel mutation frequency led to estimate disease prevalence of 1:6,887 males, more than four times more frequent than the reported disease prevalence. This discrepancy is possibly due to underdiagnosis of this neuromuscular condition, reduced prevalence, and/or pleomorphic clinical manifestations. To access the abstract and the full text source, click here.

Spinal and bulbar muscular atrophy: From molecular pathogenesis to pharmacological intervention targeting skeletal muscle

"The clinical characteristics of SBMA, also known as Kennedy's disease (OMIM 313200), were initially documented by Dr. H Kawahara in the 18th century and a hundred years later by Dr. W. Kennedy. SBMA is a neuromuscular disease caused by expansions of a CAG microsatellite tandem repeat in exon 1 of the androgen receptor (AR) gene located on the X chromosome. These expansions result in the production of AR with an aberrantly expanded polyglutamine (polyQ) tract. In this review, we explore recent advancements in the significance of gene expression changes in skeletal muscle and discuss how pharmacological interventions targeting this aspect of disease pathogenesis can potentially be translated into therapies for SBMA patients."  KDA Comment - The research for this article was funded in part by a KDA grant to two of the authors. To read the complete paper, click here.

European Neuromuscular Consortium (ENMC)  SBMA Workshop  

On October 20-22, 2023, in the Netherlands, 26 scientists from academia, healthcare, and industry representing 11 countries (Denmark, France, Germany, Israel, Italy, Portugal, Spain, Switzerland, United Kingdom, USA, and Japan) gathered with four patient representatives from AIMAK, KDUK, and KDA. This workshop, led by Maria Pennuto, Gianni Sorarù, Linda Greensmith, and Pierre-Francois Pradat, focused on advancements in research and clinical practices related to Kennedy's Disease (KD), also known as Spinal and Bulbar Muscular Atrophy (SBMA).

The workshop aimed to consolidate knowledge and collaborations among experts and patient representatives, align on trial designs and outcome measures, and promote participative medicine, thereby enhancing the chances of developing effective treatments for SBMA.

Please follow this link for a preliminary report of this workshop.

Increased SIRT3 combined with PARP inhibition rescues motor function of SBMA mice

A combination approach of increasing the SIRT3 protein and inhibiting PARPs (poly-ADP ribose polymerase) helps rescue motor endurance of mice modeling the neuromuscular disease spinal bulbar and muscular atrophy (SBMA), also known as Kennedy's disease, according to a new study by Philadelphia College of Osteopathic Medicine (PCOM) researchers.

The study, published in iScience, was led by Heather L. Montie, PhD, an associate professor of Neuroscience, Physiology and Pharmacology at PCOM, and the primary author is David Garcia Castro, DO, PhD '23, now an anesthesiology resident at Yale. The study first examined how activating or increasing SIRT3—a protein in the sirtuin family that regulates mitochondrial and metabolic function—could reduce oxidative stress and death of cells modeling SBMA. This approach looked promising in cell models, but it wasn’t nearly as effective in mice, though overexpressing the SIRT3 protein resulted in a trend in motor recovery, as well as a correction of a metabolic pathway involved in energy production known as the TCA cycle.

From there, the research team sought to boost blunted SIRT3 activity by giving it more of its diminished molecular fuel, NAD+ (an acronym to describe a molecule that's critical to proper cell function). The team found that mice modeling SBMA have very low levels of SIRT3 protein, and its molecular fuel, NAD+, is also severely diminished. That means that, even in cells that were given more SIRT3, “it was not able to work as well as it should,” Montie said, due to the low fuel source.

Since NAD+ is diminished in SBMA but critical to SIRT3 activity and overall metabolism, the team focused on restoring NAD+ in mice modeling SBMA. That's where PARPs, proteins that aid in repairing damaged DNA, came into the study. When PARPs are active they use up a lot of NAD+, and they could have potentially contributed to the low NAD+ in the SBMA mice. Although the researchers found that inhibition of PARPs did not rescue reduced NAD+ in the skeletal muscle of mice modeling SBMA, increasing SIRT3 and inhibiting PARPs fully restored hexokinase, the initial enzyme of glycolysis, which is a cellular pathway critical for energy production. This combination treatment rescued exercise endurance of the mice modeling SBMA.

This combination approach that targets the metabolic anomalies in SBMA restored motor function “downstream” of the disease-causing protein, polyglutamine-expanded (mutant) androgen receptor. That means the toxic, disease-initiating proteins still exist, but the mess they make—disruption of “multiple cellular processes, including mitochondrial function, metabolism, and energy production,” according to the authors—could be fixed up enough to reduce the burden of disease. “As researchers develop strategies to reduce the toxic protein, perhaps we could layer on treatments like this to further boost the restoration of muscle function,” Montie said. “It's exciting that we can make an effective change without targeting that toxic protein.”

In the study, the mice treated with increased SIRT3 and PARP inhibition doubled the time they spent running on a treadmill, illustrating that muscle endurance—more than other measures, such as grip strength—significantly improved. That effect points back to the importance of metabolism, which is severely disrupted in SBMA, and its critical role in maintenance of muscle function. To read the complete paper, click here.

Nido Biosciences announces the development of NIDO-361

Nido Biosciences, a Boston-based company specializing in precision treatments for neurological diseases, has announced the development of NIDO-361, a clinical stage therapeutic targeting the gene mutation that causes Kennedy’s disease (Spinal and Bulbar Muscular Atrophy, or SBMA). NIDO-361 is based on original research by Dr. J. Paul Taylor of St. Jude Children’s Research Hospital and a former member of KDA’s Scientific Review Board. “NIDO-361 is a novel small molecule that binds to a distinct site on the androgen receptor and corrects transcriptional dysregulation to restore healthy cell function,” according to Nido Bio. The company initiated clinical studies of NIDO-361 in people late last year. Nido Bio and KDA are close partners and the company will keep us informed as their plans for clinical trials further develop. For more information on Nido Bio and NIDO-361, visit their website by clicking here.

The KDA Supported the Gordon Conference on CAG Repeat Diseases

Support for research and education on Kennedy’s Disease (SBMA) are the main functions of the KDA, with almost 95% of all donated funds going to research on and education about this devastating disease.  This year, in addition to funding our annual grants and fellowships programs, the KDA provided $5,000 for scholarships to allow researchers to attend the 2023 Gordon Conference on “CAG Triplet Repeat Disorders” held in June in Vermont. This conference was part of the Gordon Research Conferences, an internationally recognized program for scientists to present and discuss new research in many fields.  The Vermont conference will focus on SBMA in addition to related, CAG repeat diseases such as Huntington’s disease, the spinocerebellar ataxias 1, 2, 3, 6, 7, 12 and 17, and dentatorubral-pallidoluysian atrophy. Conference attendees will hear presentations from senior SBMA researchers and have a chance to participate in discussions about potential treatments. 

The French Protocol for KD Diagnostics & Management Report

The French national protocol for Kennedy’s disease (SBMA): consensus diagnostic and management recommendations report provides a reference care pathway for patients with KD both for general practitioners and general neurologist who may be less familiar with the condition. The protocol is based on currently available scientific evidence and provides a consensus statement for the care of KD patients. The multi-centre working group included French specialists and therapists with experience in the diagnosis and management of KD, international experts, and representatives of the French Association for Research in ALS (ARSLA). Contributors for each section were selected based on their clinical expertise in specific aspects of KD. Guideline development was coordinated by the first author and supported by a group of the multidisciplinary working group. The co-authors contributed to specific manuscript sections based on their sub-specialty and clinical expertise. To view and download the report with a summary page, click here.

Kennedy's Disease/SBMA Voice of the Patient Report

This report is based on the “Patient-Focused Drug Development (PFDD)” meeting held at the KDA 2022 conference and related patient input.  Voice of the Patient reports are used by the U.S. Food and Drug Administration as an important source of information used to evaluate clinical trial results. 

The Kennedy’s Disease Association is very grateful to the patients, caregivers, and carriers who participated in the PFDD at KDA 2022. We also want to thank those who responded to the pre-meeting survey or contributed after the meeting in comments on social media. It is our hope that the KD/SBMA Voice of the Patient report will be read by scientists and generate additional research into the mechanisms of Kennedy’s Disease and, more importantly, into an eventual cure for this devastating disease. To read the report, click here.

Mexiletine in spinal and bulbar muscular atrophy: a randomized controlled trial

Abstract Objective: Patients with spinal and bulbar muscular atrophy (SBMA) often experience muscular weakness under cold exposure. Methods: In our previously conducted observational study, we assessed nerve conduction and grip strength to examine the effect of cold exposure on motor function, based on which we conducted a randomized controlled trial to evaluate the efficacy and safety of mexiletine hydrochloride in SBMA (MEXPRESS). Results: In the observational study, 51 consecutive patients with SBMA and 18 healthy controls (HCs) were enrolled. Of the patients with SBMA, 88.0% experienced cold paresis. Patients with SBMA exhibited greater prolongation of ulnar nerve distal latency under cold (SBMA, 5.6 1.1 msec; HC, 4.3 0.6 msec; p <0.001); the change in the distal latencies between room temperature and cold exposure conditions correlated with the change in grip power. In the MEXPRESS trial, 20 participants took mexiletine or lactose, three times a day for 4 weeks with a crossover design. There was no difference in distal latencies at room temperature and under cold exposure between mexiletine and placebo groups as the primary endpoint. However, tongue pressure and 10-sec grip and release test under cold exposure were improved in the mexiletine group. There were no serious adverse events throughout the study period. Interpretation: Cold paresis is common and associated with prolongation of distal latency in SBMA. The results of the phase II clinical trial revealed that mexiletine showed short-term safety, but it did not restore cold exposure-induced prolongation of distal latency. To download the PDF research article, click here.

Characteristics of spinal and bulbar muscular atrophy in South Korea: a cross-sectional study of 157 patients

Spinal and bulbar muscular atrophy, namely Kennedy disease, is a rare progressive neurodegenerative disorder caused by the expansion of a CAG repeat in the first exon of the androgen receptor gene on the X chromosome.

We assessed the clinical history, laboratory findings, functional scales and electrophysiological data, as well as the levels of luteinizing hormone, follicle-stimulating hormone and testosterone, in 157 Korean patients with genetically confirmed spinal and bulbar muscular atrophy (mean age at data collection = 56.9 years; range = 33–83 years).

Hand tremor was the first symptom noticed by patients at a median age of 35 years, followed by gynaecomastia, orofacial fasciculation, cramps and fatigability in ascending order. Clinical symptoms such as paraesthesia and dysphagia appeared during the later stages of the disease. Cane use during ambulation began at a median age of 62 years. There were statistically significant differences between patients and controls in the results of sensory nerve studies, motor conduction velocity, and distal latencies. Furthermore, among the hormone markers analysed, the level of luteinizing hormone exhibited a negative correlation with the spinal and bulbar muscular atrophy functional rating scale, Korean version. However, among the patients with a disease duration of ≤5 years, the levels of luteinizing hormone showed a significant correlation with assessments using the amyotrophic lateral sclerosis functional rating scale-revised, spinal and bulbar muscular atrophy functional rating scale, Korean version and the 6-minute walk test. In conclusion, our findings provide clinical information from a substantial number of patients with spinal and bulbar muscular atrophy in Korea that accorded with that of patients with this disease worldwide but with updated clinical features. For ways to view the complete journal article, click here.

The French national protocol for Kennedy’s Disease (SBMA): consensus diagnostic and management recommendations

The French national Kennedy’s disease protocol provides management recommendations for patients with KD. In a low-incidence condition, sharing and integrating regional expertise, multidisciplinary experience and defining consensus best-practice recommendations is particularly important. Well-coordinated collaborative efforts will ultimately pave the way to the development of evidence-based international guidelines. To read the PDF, click here

Bicalutimide and Trehalose Ameliorate Spinal and Bulbar Muscular Atrophy Pathology in Mice

Spinal and bulbar muscular atrophy (SBMA) is characterized by motor neuron (MN) degeneration that leads to slowly progressive muscle weakness. It is considered a neuromuscular disease since muscle has a primary role in disease onset and progression. SBMA is caused by a CAG triplet repeat expansion in the androgen receptor (AR) gene. The translated poly-glutamine (polyQ) tract confers a toxic gain of function to the mutant AR altering its folding, causing its aggregation into intracellular inclusions, and impairing the autophagic flux. In an in vitro SBMA neuronalmodel, we previously showed that the antiandrogen bicalutamide and trehalose, a natural disaccharide stimulating autophagy, block ARpolyQ activation, reduce its nuclear translocation and toxicity and facilitate the autophagic degradation of cytoplasmic AR aggregates. Here, in a knock-in SBMA mouse model (KI AR113Q), we show that bicalutamide and trehalose ameliorated SBMA pathology. Bicalutamide reversed the formation of the AR insoluble forms in KI AR113Q muscle,preventing autophagic flux blockage. We demonstrated that apoptosis is activated in KI AR113Q muscle, and that both compounds prevented its activation. We detected a decrease of mtDNA and an increaseof OXPHOS enzymes,already at early symptomatic stages;these alterations were revertedby trehalose. Overall,bicalutamide and/or trehaloseled to a partial recoveryof muscle morphology and func- tion, and improved SBMA mouse motor behavior, inducingan extension of their survival.Thus, bicalutamide and trehalose, by counteracting ARpolyQ toxicity in skeletal muscle, are valuable candidates for future clinical trials in SBMA patients.

Link: Bicalutamide and Trehalose Ameliorate Spinal and Bulbar Muscular Atrophy Pathology in Mice - PubMed (