Gene therapy with AR isoform 2 rescues spinal and bulbar muscular atrophy phenotype by modulating AR transcriptional activity.

Spinal and bulbar muscular atrophy (SBMA) is an X-linked, adult-onset neuromuscular condition caused by an abnormal polyglutamine (polyQ) tract expansion in androgen receptor (AR) protein. SBMA is a disease with high unmet clinical need. Recent studies have shown that mutant AR-altered transcriptional activity is key to disease pathogenesis. Restoring the transcriptional dysregulation without affecting other AR critical functions holds great promise for the treatment of SBMA and other AR-related conditions; however, how this targeted approach can be achieved and translated into a clinical application remains to be understood. Here, we characterized the role of AR isoform 2, a naturally occurring variant encoding a truncated AR lacking the polyQ-harboring domain, as a regulatory switch of AR genomic functions in androgen-responsive tissues. Delivery of this isoform using a recombinant adeno-associated virus vector type 9 resulted in amelioration of the disease phenotype in SBMA mice by restoring polyQ AR-dysregulated transcriptional activity.

Molecular Mechanisms and Therapeutics for SBMA/Kennedy's Disease.

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by a polyglutamine (polyQ) expansion in the androgen receptor (AR). Despite the fact that the monogenic cause of SBMA has been known for nearly 3 decades, there is no effective treatment for this disease, underscoring the complexity of the pathogenic mechanisms that lead to a loss of motor neurons and muscle in SBMA patients. In the current review, we provide an overview of the system-wide clinical features of SBMA, summarize the structure and function of the AR, discuss both gain-of-function and loss-of-function mechanisms of toxicity caused by polyQ-expanded AR, and describe the cell and animal models utilized in the study of SBMA. Additionally, we summarize previously conducted clinical trials which, despite being based on positive results from preclinical studies, proved to be largely ineffective in the treatment of SBMA; nonetheless, these studies provide important insights as researchers develop the next generation of therapies.

Src inhibition attenuates polyglutamine-mediated neuromuscular degeneration in spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) is a neuromuscular disease caused by an expanded CAG repeat in the androgen receptor (AR) gene. Here, we perform a comprehensive analysis of signaling pathways in a mouse model of SBMA (AR-97Q mice) utilizing a phosphoprotein assay. We measure the levels of 17 phosphorylated proteins in spinal cord and skeletal muscle of AR-97Q mice at three stages. The level of phosphorylated Src (p-Src) is markedly increased in the spinal cords and skeletal muscles of AR-97Q mice prior to the onset. Intraperitoneal administration of a Src kinase inhibitor improves the behavioral and histopathological phenotypes of the transgenic mice. We identify p130Cas as an effector molecule of Src and show that the phosphorylated p130Cas is elevated in murine and cellular models of SBMA. These results suggest that Src kinase inhibition is a potential therapy for SBMA.

From gene to therapy in spinal and bulbar muscular atrophy: Are we there yet?

Abnormal polyglutamine expansions in the androgen receptor (AR) cause a muscular condition, known as Kennedy's disease or spinal and bulbar muscular atrophy (SBMA). The disease is transmitted in an X-linked fashion and is clinically characterized by weakness, atrophy and fasciculations of the limb and bulbar muscles as a result of a toxic gain-of-function of the mutant protein. Notably, affected males also show signs of androgen insensitivity, such as gynaecomastia and reduced fertility. The characterization of the natural history of the disease, the increasing understanding of the mechanism of pathogenesis and the elucidation of the functions of normal and mutant AR have offered a momentum for developing a rational therapeutic strategy for this disease. In this special issue on androgens and AR functions, we will review the molecular, biochemical, and cellular mechanisms underlying the pathogenesis of SBMA. We will discuss recent advances on therapeutic approaches and opportunities for this yet incurable disease, ranging from androgen deprivation, to gene silencing, to an expanding repertoire of peripheral targets, including muscle. With the advancement of these strategies into the clinic, it can be reasonably anticipated that the landscape of treatment options for SBMA and other neuromuscular conditions will change rapidly in the near future.

Kennedy disease (X-linked recessive bulbospinal neuronopathy): A comprehensive review from pathophysiology to therapy.

Kennedy's disease, also known as spinal and bulbar muscular atrophy (SBMA), is a rare, adult-onset, X-linked recessive neuromuscular disease caused by expansion of a CAG repeat sequence in exon 1 of the androgen receptor gene (AR) encoding a polyglutamine (polyQ) tract. The polyQ-expanded AR accumulates in nuclei, and initiates degeneration and loss of motor neurons and dorsal root ganglia. While the disease has long been considered a pure lower motor neuron disease, recently, the presence of major hyper-creatine-kinase (CK)-emia and myopathic alterations on muscle biopsy has suggested the presence of a primary myopathy underlying a wide range of clinical manifestations. The disease, which affects male adults, is characterized by muscle weakness and atrophy localized proximally in the limbs, and bulbar involvement. Sensory disturbances are associated with the motor phenotype, but may be subclinical. The most frequent systemic symptom is gynecomastia related to androgen insensitivity, but other abnormalities, such as heart rhythm and urinary disturbances, have also been reported. The course of the disease is slowly progressive with normal life expectancy. The diagnosis of SBMA is based on genetic testing, with 38 CAG repeats taken as pathogenic. Despite several therapeutic attempts made in mouse models, no effective disease-modifying therapy is yet available, although symptomatic therapy is beneficial for the management of the weakness, fatigue and bulbar symptoms.

New routes to therapy for spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy's disease, is a genetically inherited neuromuscular disorder characterized by loss of lower motor neurons in the brainstem and spinal cord and skeletal muscle fasciculation, weakness, and atrophy. SBMA is caused by expansion of a polyglutamine (polyQ) tract in the gene coding for the androgen receptor (AR). PolyQ expansions cause at least eight other neurological disorders, which are collectively known as polyQ diseases. SBMA is unique in the family of polyQ diseases in that the disease manifests fully in male individuals only. The sex specificity of SBMA is the result of the interaction between mutant AR and its natural ligand, testosterone. Here, we will discuss emerging therapeutic perspectives for SBMA in light of recent findings regarding disease pathogenesis.

Role of androgen receptor polyQ chain elongation in Kennedy's disease and use of natural osmolytes as potential therapeutic targets.

Instability of CAG triplet repeat encoding polyglutamine (polyQ) stretches in the gene for target protein has been implicated as a putative mechanism in several inherited neurodegenerative diseases. Expansion of polyQ chain length in the androgen receptor (AR) causes spinal and bulbar muscular atrophy (SBMA) or Kennedy's disease. Although the mechanisms underlying gain-of-neurotoxic function are not completely understood, suggested pathological mechanisms of SBMA involve the formation of AR nuclear and cytoplasmic aggregates, a characteristic feature of patients with SBMA. The fact that certain AR coactivators are sequestered into the nuclear inclusions in SBMA possibly through protein-protein interactions supports the notion that AR transcriptional dysregulation may be a potential pathological mechanism leading to SBMA. AR conformational states associated with aberrant polyQ tract also modulate the interaction of AR with several coactivators. In many cases, such diseases can be treated through protein replacement therapy; however, because recombinant proteins do not cross the blood-brain barrier, the effectiveness of such therapies is limited in case of neurodegenerative diseases that warrant alternative therapeutic approaches. Among different approaches, inhibiting protein aggregation with small molecules that can stimulate protein folding and reverse aggregation are the most promising ones. Thus, naturally occurring osmolytes or "chemical chaperones" that can easily cross the blood-brain barrier and stabilize the functional form of a mutated protein by shifting the folding equilibrium away from degradation and/or aggregation is a useful therapeutic approach. In this review, we discuss the role of polyQ chain length extension in the pathophysiology of SBMA and the use of osmolytes as potential therapeutic tool.

Molecular pathophysiology and disease-modifying therapies for spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA), or Kennedy disease, is an adult-onset lower motor neuron disease characterized by slowly progressive muscle weakness and atrophy. The disease is caused by the expansion of a trinucleotide CAG repeat encoding a polyglutamine tract within the first exon of the androgen receptor (AR) gene. During the 2 decades since the discovery of the AR gene mutation in SBMA, basic and clinical research have deepened our understanding of the disease phenotype and pathophysiology. Spinal and bulbar muscular atrophy exclusively affects men, whereas women homozygous for the AR mutation do not fully develop the disease. The ligand-dependent nuclear accumulation of pathogenic AR protein is central to the pathogenesis, although additional steps, eg, DNA binding and interdomain interactions of AR, are required for toxicity. Downstream molecular events, eg, transcriptional dysregulation, axonal transport disruption, and mitochondrial dysfunction, are implicated in the neurodegeneration in SBMA. Pathogenic AR-induced myopathy also contributes to the degeneration of motor neurons. Several potential therapies, including hormonal manipulation, have emerged from animal studies, some of which have been tested in clinical trials.

Perspectives of Kennedy's disease.

Kennedy's disease, also known as bulbospinal muscular atrophy (BSMA), is a rare, adult-onset, X-linked, recessive trinucleotide, polyglutamine (poly-G) disorder, caused by expansion of an unstable CAG-tandem-repeat in exon 1 of the androgen-receptor (AR) gene on chromosome Xq11-12. Poly-Q-expanded AR accumulates in nuclei, undergoes fragmentation and initiates degeneration and loss of motor neurons and dorsal root ganglia. Phenotypically, patients present with weakness and wasting of the facial, bulbar and extremity muscles, sensory disturbances, and endocrinological disturbances, such as gynecomastia and reduced fertility. In the limb muscles weakness and wasting may be symmetric or asymmetric, proximal or distal, or may predominate at the lower or upper limb muscles. There may be mild to severe hyper-CK-emia, elevated testosterone or other sexual hormones, abnormal motor and sensory nerve conduction studies, and neuropathic or rarely myopathic alterations on muscle biopsy. BSMA is diagnosed if the number of CAG-repeats exceeds 40. No causal therapy is available but symptomatic therapy may be beneficial for weakness, tremor, endocrinological abnormalities, muscle cramps, respiratory failure, or dysphagia. The course is slowly progressive and the ability to walk lost only late in life. Only few patients require ventilatory support and life expectancy is only slightly compromised.

[Molecular-targeted therapies for spinal and bulbar muscular atrophy].

Spinal and bulbar muscular atrophy (SBMA) is a polyglutamine-mediated lower motor neuron disease characterized by slowly progressive muscle weakness and atrophy. The cause of this disease is the expansion of a trinucleotide CAG repeat, which encodes the polyglutamine tract, within the first exon of the androgen receptor (AR) gene. SBMA exclusively occurs in adult males, whereas both heterozygous and homozygous females are usually asymptomatic. Testosterone-dependent nuclear accumulation of the pathogenic AR protein has been considered to be a fundamental step of neurodegenerative process, which is followed by several molecular events such as transcriptional dysregulation, axonal transport disruption, and mitochondria dysfunction. Androgen deprivation suppresses the toxicity of the mutant AR in animal models of SBMA, and these insights have been translated to clinic. Animal studies have also suggested that activation of protein quality control systems are potential therapies for SBMA. To optimize "proof of concept", the process for testing candidate therapies in humans, it is of importance to identify responders to each therapy, to initiate interventions in early stages of the disease, and to establish biomarkers which can be used for evaluating the efficacy of treatment.