RARE DISEASE
Kennedy disease
Kennedy disease
Kennedy disease
Synonyms: SBMA, SMAX1, X-linked BSMA, X-linked bulbospinal amyotrophy, X-linked bulbospinal muscular atrophy, X-linked spinal and bulbar muscular atrophy
Synonyms: SBMA, SMAX1, X-linked BSMA, X-linked bulbospinal amyotrophy, X-linked bulbospinal muscular atrophy, X-linked spinal and bulbar muscular atrophy
Synonyms: SBMA, SMAX1, X-linked BSMA, X-linked bulbospinal amyotrophy, X-linked bulbospinal muscular atrophy, X-linked spinal and bulbar muscular atrophy
Drug discovery
5
drugs
With orphan designations
Overview
Kennedy disease (KD), also known as spinal and bulbar muscular atrophy (SBMA), is a rare X-linked recessive neuromuscular disorder caused by a CAG trinucleotide repeat expansion in the androgen receptor gene. It manifests in adulthood (30–60 years) with progressive limb and bulbar muscle weakness, atrophy, tremors, dysphagia, and endocrine features (gynecomastia, hypogonadism). Slow progression preserves ambulatory capacity for decades, with near-normal lifespan but increased mortality from respiratory complications [1][2][5][6].
Therapies
Symptomatic management: Medications (e.g., leuprorelin for androgen suppression [7][11]), speech/swallowing therapy, physiotherapy, and assistive devices [1][5][13].
Experimental approaches: Small-molecule RNA modulators targeting mutant mRNA splicing (e.g., ReviR Therapeutics’ VoyageR platform [3]).
Categories: rare genetic diseases, rare infertility disorders, rare neurological diseases
Research Papers
344 drug discovery papers about Kennedy disease, with 3 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
344 drug discovery papers about Kennedy disease, with 3 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-05-07 | PGC-1α pathway dysregulation disrupts myofiber specification in a mouse model of SBMA.
Skeletal muscle pathology is a critical but poorly understood contributor to neuromuscular degeneration in spinal and bulbar muscular atrophy (SBMA), a CAG/polyglutamine (polyQ) expansion disorder caused by mutation in the androgen receptor (AR). Using a gene-targeted SBMA mouse model, we applied single-nucleus RNA sequencing to identify a disease-specific population of skeletal muscle myonuclei that replaced normal myonuclear subtypes. This transition was associated with dysregulation of the pathway governed by PGC-1α, a central regulator of myofiber specification and metabolic identity. PGC-1α dysfunction in SBMA muscle was age-, hormone-, and polyQ length-dependent and was partially rescued by subcutaneous delivery of AR-targeted antisense oligonucleotides. Integrated ChIP-seq and RNA-seq analyses revealed that aberrant PGC-1α activity promoted the expression of a distinct set of myofiber specification genes while downregulating those that define healthy Type IIb and Type IIx myonuclei. We propose a model in which this dysfunction arose downstream of polyQ-mediated sequestration of PGC-1α cofactors MEF2, CREB, and CBP, leading to transcriptional reprogramming and cellular dysfunction. These findings implicated PGC-1α dysregulation as a key event linking AR polyQ expansion to skeletal muscle degeneration and suggested a shared mechanism for polyQ-mediated muscle pathology across related neurodegenerative diseases.
2026-03-28 | Restoring early postnatal synaptic dysregulation rescues motor neuron degeneration in a mouse model of Spinal and Bulbar Muscular Atrophy.
Spinal and bulbar muscular atrophy (SBMA) is an adult-onset neurodegenerative disorder caused by expansion of a polyglutamine tract in the androgen receptor (AR). Here, we show that polyglutamine-expanded AR accumulates in the nucleus of motor neurons and induces aberrant upregulation of glutamatergic synaptic genes through dysfunction of the master transcriptional repressor REST during early postnatal development in a mouse model of SBMA (AR-97Q mice). Reducing mutant AR or restoring REST function using antisense oligonucleotides during the neonatal period attenuated the upregulation of glutamatergic synaptic genes and ameliorated the disease phenotype and histopathology in AR-97Q mice. Furthermore, we observed increased calcium activity in induced pluripotent stem cell-derived motor neurons from SBMA patients compared to those from healthy controls, reflecting neuronal hyperexcitability. Late-onset neurodegeneration in SBMA is attributable to early synaptic defects and the resulting hyperexcitability of motor neurons, which may represent therapeutic targets.
2026-03-12 | A case of type 2 diabetes with spinal and bulbar muscular atrophy treated with oral semaglutide while sparing muscle reduction for two years: a case report with literature review.
Semaglutide has demonstrated beneficial effects in patients with type 2 diabetes; however, its long-term impact on skeletal muscle remains uncertain, particularly in individuals with multiple risk factors for muscle decline. We report a case of a 65-year-old man with type 2 diabetes who developed progressive proximal muscle weakness and was subsequently diagnosed with spinal and bulbar muscular atrophy (SBMA), for which leuprorelin therapy was initiated. Following treatment initiation, he exhibited worsened glycemic control, increased body weight and fat mass, along with reductions in both skeletal muscle mass and strength. At the age of 72, oral semaglutide was introduced. Over the following two years, improvements in glycemic parameters and reductions in fat mass were observed. Importantly, skeletal muscle mass and strength were relatively preserved, with only a minor annual decrease in muscle mass (- 0.1 kg/year), consistent with changes reported in previous studies of semaglutide-treated patients without neuromuscular conditions. To our knowledge, this is the first reported case describing the use of semaglutide in a patient with diabetes and SBMA under leuprorelin treatment, suggesting the potential utility of GLP-1 receptor agonists in managing metabolic parameters in individuals at high risk for muscle decline.
2026-03-10 | In silico Modeling for Small Molecule PRMT6 Inhibitors for the Treatment of Spinal Bulbar Muscular Atrophy (SBMA)
Spinal Bulbar Muscular Atrophy (SBMA), or Kennedy’s disease, is a rare, inherited neuromuscular disorder that leads to progressive muscle degeneration, weakness, and twitching. While it affects approximately 1 in 100,000 individuals worldwide, currently, there are no approved treatments for SBMA, leaving a substantial unmet medical need. Our program focuses on developing a novel therapeutic approach targeting PRMT6, a co-activator of the Androgen Receptor (AR) implicated in SBMA progression. The aim is to design a highly selective, brain-penetrant PRMT6 inhibitor targeting an allosteric site on the enzyme. Preliminary studies have shown that inhibiting PRMT6 reduces mutant AR activity and improves motor function in disease models. Here, we employ AI-guided in silico modeling to optimize the PRMT6 probe scaffold SGC6870 as a potential therapeutic for the treatment of SBMA. This workflow integrates computational drug design, medicinal chemistry, and molecular biology, with subsequent in vitro and in vivo ADME optimization of prioritized compounds. Table of key terms and definitions: Key term Definition PRMT6 Protein arginine methyltransferase 6, a transcriptional co-regulator Androgen receptor (AR) Type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone, in the cytoplasm and then translocating into the nucleus SBMA X-linked, slowly progressive neuromuscular disorder that affects adult males, typically presenting with muscle weakness, bulbar dysfunction, and endocrine abnormalities SGC6870 A potent, selective and cell active allosteric inhibitor of PRMT6 S-adenosyl-L-methionine (SAM) Methyltransferase cofactor SAR Structure activity relationship ADME Absorption, Distribution, Metabolism and Excretion DMPK Drug metabolism and pharmacokinetics
2026-01-19 | An acyclic nucleic acid-modified siRNA targeting CAG expansions for polyglutamine disease treatment.
Polyglutamine (polyQ) diseases are inherited neurological disorders caused by an expansion of the cytosine-adenine-guanine (CAG) repeat in the causative genes. These include Huntington's disease, spinal and bulbar muscular atrophy (SBMA), and spinocerebellar ataxias (SCAs). Clinical trials have been conducted using nucleic acid therapeutics to silence the causative gene for these diseases, but none have been approved for use. Furthermore, while oligonucleotides targeting the CAG repeats are an attractive therapeutic option, concomitant silencing of the wild-type allele with normal CAG repeats can result in neuronal dysfunction. In this study, we developed an acyclic serinol nucleic acid (SNA)-modified small interfering RNA (siRNA) targeting CAG repeats. We also evaluated the safety and efficacy of the siRNA in different mouse models of polyQ diseases. Intracerebroventricularly administered siRNA was widely distributed throughout the central nervous system, where it selectively silenced the alleles encoding polyQ proteins without affecting their wild-type counterparts. Consequently, the intranuclear aggregation of polyQ proteins was reduced in mouse models of SBMA and SCA type 3. The siRNA attenuated neuromuscular degeneration and improved the lifespan and motor function of the SBMA mice. These findings suggest that SNA-modified siRNAs targeting CAG repeats represent a promising approach for treating polyQ diseases.
2026-05-07 | PGC-1α pathway dysregulation disrupts myofiber specification in a mouse model of SBMA.
Skeletal muscle pathology is a critical but poorly understood contributor to neuromuscular degeneration in spinal and bulbar muscular atrophy (SBMA), a CAG/polyglutamine (polyQ) expansion disorder caused by mutation in the androgen receptor (AR). Using a gene-targeted SBMA mouse model, we applied single-nucleus RNA sequencing to identify a disease-specific population of skeletal muscle myonuclei that replaced normal myonuclear subtypes. This transition was associated with dysregulation of the pathway governed by PGC-1α, a central regulator of myofiber specification and metabolic identity. PGC-1α dysfunction in SBMA muscle was age-, hormone-, and polyQ length-dependent and was partially rescued by subcutaneous delivery of AR-targeted antisense oligonucleotides. Integrated ChIP-seq and RNA-seq analyses revealed that aberrant PGC-1α activity promoted the expression of a distinct set of myofiber specification genes while downregulating those that define healthy Type IIb and Type IIx myonuclei. We propose a model in which this dysfunction arose downstream of polyQ-mediated sequestration of PGC-1α cofactors MEF2, CREB, and CBP, leading to transcriptional reprogramming and cellular dysfunction. These findings implicated PGC-1α dysregulation as a key event linking AR polyQ expansion to skeletal muscle degeneration and suggested a shared mechanism for polyQ-mediated muscle pathology across related neurodegenerative diseases.
2026-03-28 | Restoring early postnatal synaptic dysregulation rescues motor neuron degeneration in a mouse model of Spinal and Bulbar Muscular Atrophy.
Spinal and bulbar muscular atrophy (SBMA) is an adult-onset neurodegenerative disorder caused by expansion of a polyglutamine tract in the androgen receptor (AR). Here, we show that polyglutamine-expanded AR accumulates in the nucleus of motor neurons and induces aberrant upregulation of glutamatergic synaptic genes through dysfunction of the master transcriptional repressor REST during early postnatal development in a mouse model of SBMA (AR-97Q mice). Reducing mutant AR or restoring REST function using antisense oligonucleotides during the neonatal period attenuated the upregulation of glutamatergic synaptic genes and ameliorated the disease phenotype and histopathology in AR-97Q mice. Furthermore, we observed increased calcium activity in induced pluripotent stem cell-derived motor neurons from SBMA patients compared to those from healthy controls, reflecting neuronal hyperexcitability. Late-onset neurodegeneration in SBMA is attributable to early synaptic defects and the resulting hyperexcitability of motor neurons, which may represent therapeutic targets.
2026-03-12 | A case of type 2 diabetes with spinal and bulbar muscular atrophy treated with oral semaglutide while sparing muscle reduction for two years: a case report with literature review.
Semaglutide has demonstrated beneficial effects in patients with type 2 diabetes; however, its long-term impact on skeletal muscle remains uncertain, particularly in individuals with multiple risk factors for muscle decline. We report a case of a 65-year-old man with type 2 diabetes who developed progressive proximal muscle weakness and was subsequently diagnosed with spinal and bulbar muscular atrophy (SBMA), for which leuprorelin therapy was initiated. Following treatment initiation, he exhibited worsened glycemic control, increased body weight and fat mass, along with reductions in both skeletal muscle mass and strength. At the age of 72, oral semaglutide was introduced. Over the following two years, improvements in glycemic parameters and reductions in fat mass were observed. Importantly, skeletal muscle mass and strength were relatively preserved, with only a minor annual decrease in muscle mass (- 0.1 kg/year), consistent with changes reported in previous studies of semaglutide-treated patients without neuromuscular conditions. To our knowledge, this is the first reported case describing the use of semaglutide in a patient with diabetes and SBMA under leuprorelin treatment, suggesting the potential utility of GLP-1 receptor agonists in managing metabolic parameters in individuals at high risk for muscle decline.
2026-03-10 | In silico Modeling for Small Molecule PRMT6 Inhibitors for the Treatment of Spinal Bulbar Muscular Atrophy (SBMA)
Spinal Bulbar Muscular Atrophy (SBMA), or Kennedy’s disease, is a rare, inherited neuromuscular disorder that leads to progressive muscle degeneration, weakness, and twitching. While it affects approximately 1 in 100,000 individuals worldwide, currently, there are no approved treatments for SBMA, leaving a substantial unmet medical need. Our program focuses on developing a novel therapeutic approach targeting PRMT6, a co-activator of the Androgen Receptor (AR) implicated in SBMA progression. The aim is to design a highly selective, brain-penetrant PRMT6 inhibitor targeting an allosteric site on the enzyme. Preliminary studies have shown that inhibiting PRMT6 reduces mutant AR activity and improves motor function in disease models. Here, we employ AI-guided in silico modeling to optimize the PRMT6 probe scaffold SGC6870 as a potential therapeutic for the treatment of SBMA. This workflow integrates computational drug design, medicinal chemistry, and molecular biology, with subsequent in vitro and in vivo ADME optimization of prioritized compounds. Table of key terms and definitions: Key term Definition PRMT6 Protein arginine methyltransferase 6, a transcriptional co-regulator Androgen receptor (AR) Type of nuclear receptor that is activated by binding any of the androgenic hormones, including testosterone and dihydrotestosterone, in the cytoplasm and then translocating into the nucleus SBMA X-linked, slowly progressive neuromuscular disorder that affects adult males, typically presenting with muscle weakness, bulbar dysfunction, and endocrine abnormalities SGC6870 A potent, selective and cell active allosteric inhibitor of PRMT6 S-adenosyl-L-methionine (SAM) Methyltransferase cofactor SAR Structure activity relationship ADME Absorption, Distribution, Metabolism and Excretion DMPK Drug metabolism and pharmacokinetics
2026-01-19 | An acyclic nucleic acid-modified siRNA targeting CAG expansions for polyglutamine disease treatment.
Polyglutamine (polyQ) diseases are inherited neurological disorders caused by an expansion of the cytosine-adenine-guanine (CAG) repeat in the causative genes. These include Huntington's disease, spinal and bulbar muscular atrophy (SBMA), and spinocerebellar ataxias (SCAs). Clinical trials have been conducted using nucleic acid therapeutics to silence the causative gene for these diseases, but none have been approved for use. Furthermore, while oligonucleotides targeting the CAG repeats are an attractive therapeutic option, concomitant silencing of the wild-type allele with normal CAG repeats can result in neuronal dysfunction. In this study, we developed an acyclic serinol nucleic acid (SNA)-modified small interfering RNA (siRNA) targeting CAG repeats. We also evaluated the safety and efficacy of the siRNA in different mouse models of polyQ diseases. Intracerebroventricularly administered siRNA was widely distributed throughout the central nervous system, where it selectively silenced the alleles encoding polyQ proteins without affecting their wild-type counterparts. Consequently, the intranuclear aggregation of polyQ proteins was reduced in mouse models of SBMA and SCA type 3. The siRNA attenuated neuromuscular degeneration and improved the lifespan and motor function of the SBMA mice. These findings suggest that SNA-modified siRNAs targeting CAG repeats represent a promising approach for treating polyQ diseases.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
5 orphan drug designations for Kennedy disease.
5 orphan drug designations for Kennedy disease.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
3-(5-(2-Hydroxy-2-methylpropoxy)-6-methylpyrazin-2-yl)-1H-indole-7-carbonitrile | small molecules | EMA | 2024-10-11 | — | FGK Representative Service GmbH |
Insulin-like Growth Factor-1 | proteins | FDA | 2023-06-21 | — | Sarcomed AB |
geranylgeranylacetone | small molecules | FDA | 2020-06-26 | — | RNR BioMedical Inc. |
(1E,6E)-1,7-bis(3,4-dimethoxyphenyl)-4-cyclobutylmethyl-1,6-heptadiene-3,5-dione | small molecules | EMA | 2016-04-28 | — | ICON Clinical Research Limited |
1E,6E)-1,7-Bis(3,4-dimethoxyphenyl)-4-cyclobutylmethyl-1,6-heptadiene-3,5-dione or [(1E, 4Z,6E)-4-(cyclobutylmethyl)-1,7-bis(3,4-dimethoxyphenyl)-5-hydroxyhepta-1,4,6-trien-3-one] | small molecules | FDA | 2016-02-17 | — | AnnJi Pharmaceutical Co. Ltd. |
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