Studies of inherited neuromuscular diseases

National Institute Of Neurological Disorders And Stroke

Investigators

Linked publications & trials

Abstract

We have made progress in establishing the infrastructure of the inherited neuromuscular and achieving the following Specific Aims below: Aim 1). Measure disease progression in patients with slowly progressive motor neuron disease. Aim 2). To characterize the mechanism by which mutations in senataxin (SETX) result in motor neuron degeneration in ALS4. Aim 3). Identify markers of clinical benefit and therapeutic engagement in SBMA. Aim 4). Characterize the cellular pathways that result in motor neuron vulnerability in disease. Aim 1). Improvements in the ability to detect disease progression would allow for more rapid and efficient testing of candidate therapeutics. Patients with ALS4 (NCT04394871) and SBMA (NCT04944940) are being followed at regular intervals to measure clinical and molecular features of disease, including measures of physical function and muscle MRI. We are evaluating new modalities of fluid biomarkers, muscle imaging, including MRI spectroscopy and ultrasound, and developing clinical tools to track disease progression and quantify severity. Opal accelerometers are used to instrument measures of muscle function and improve the sensitivity of muscle function testing. Aim 2). We are developing an allele-specific approach to selectively reduce the expression of the mutant allele containing the 1166 T>C, L389S mutation in ALS4. siRNA to selectively target the mutant allele has been generated, and effort to develop an oligonucleotide therapy that is allele specific is currently underway. We are characterizing the mechanisms of motor neuron degeneration from Senataxin gene mutation and the resulting changes in the disease-treated motor neurons that will inform pharmacodynamic assessments in future therapeutic studies. Aim 3). An important debate in the field of SBMA is the importance of muscle versus nerve toxicity to the underlying disease process. We are analyzing clinical and molecular markers of androgen receptor toxicity in the spinal fluid and muscle tissue samples collected under our natural history study (NCT04944940), which will serve as important tissue-specific biomarkers in clinical studies. We have identified candidate fluid biomarkers in blood and CSF from patients with SBMA that could be used to evaluate efficacy in future SBMA clinical trials. An SBMA Health Index (SBMA-HI) has been developed and can be employed in future therapeutic studies as a patient reported outcome measure. We have evaluated the safety and efficacy of a curcumin analog (AJ201) as part of a clinical trial (NCT05517603) in patients with SBMA and the results of this study are supportive of additional investigation of AJ201 in SBMA patients. Aim 4). We used a CRISPR interference (CRISPRi) strategy to conduct a genetic screen in iPSC derived motor neuron and cortical neuron cells. Cellular pathways that result in motor neuron degeneration have been characterized.