Disease mechanism, biomarker and therapeutics for spinal and bulbar muscular atrophy (SBMA)

Abstract

Spinal and bulbar muscular atrophy (SBMA) is a hereditary neuromuscular disorder caused by CAG trinucleotide expansion in the gene encoding the androgen receptor (AR). In the central nervous system, lower motor neurons are selectively affected, whereas pathology of patients and animal models also indicates involvement of skeletal muscle including loss of fast-twitch type 2 fibres and increased slow-twitch type 1 fibres, together with a glycolytic-to-oxidative metabolic switch. Evaluation of muscle and fat using MRI, in addition to biochemical indices such as serum creatinine level, are promising biomarkers to track the disease progression. The serum level of creatinine starts to decrease before the onset of muscle weakness, followed by the emergence of hand tremor, a prodromal sign of the disease. Androgen-dependent nuclear accumulation of the polyglutamine-expanded AR is an essential step in the pathogenesis, providing therapeutic opportunities via hormonal manipulation and gene silencing with antisense oligonucleotides. Animal studies also suggest that hyperactivation of Src, alteration of autophagy and a mitochondrial deficit underlie the neuromuscular degeneration in SBMA and provide alternative therapeutic targets.

Nucleic Acid-Based Therapeutic Approach for Spinal and Bulbar Muscular Atrophy and Related Neurological Disorders

“…The optimal dose and frequency of intrathecal or systemic administration of the AR-ASOs remain to be determined for clinical application. Furthermore, although SBMA pathology may be mainly due to gain-of-function toxicity of polyQ-expanded AR [ 3 ], we cannot exclude the possibility that the loss of native AR function under the ASO treatment may cause motor and sexual dysfunction. As with AR-ASOs, LNP-delivered siRNAs and AAV vector-based approaches showed therapeutic potential in the mouse models of SBMA.…”

“…Patients with SBMA develop progressive neurological symptoms, including muscle weakness and atrophy, tremor, fasciculation, muscle cramping and dysphasia. A neuropathological hallmark of SBMA is the degeneration of motor neurons in the brain stem and spinal cord [ 3 , 4 ]. However, recent evidence strongly suggests that the disturbance of skeletal muscle also contributes to disease pathogenesis [ 5 , 6 , 7 ].…”

Nerve ultrasound detects abnormally small nerves in patients with spinal and bulbar muscular atrophy

“…Spinal and bulbar muscular atrophy (SBMA), or Kennedy's disease, is an X‐linked adult‐onset neuromuscular disorder caused by expansion of a CAG repeat (>39) in the androgen receptor gene 1‐4 …”

Skeletal Muscle Pathogenesis in Polyglutamine Diseases

“…This is especially important in patients suffering from neurodegenerative diseases that undergo progressive deterioration. Skeletal muscle is also important for two other reasons: first, several biomarkers are found in muscle [21,22], an aspect that is particularly relevant in disease conditions that can be misdiagnosed as others [22]. Second, intervention in the muscle is predicted to have beneficial effects not only in this tissue but also in the innervated motor neurons and the entire body homeostasis, as observed in animal models [23].…”