DeCure for Autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6)
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for autosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6) — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleAutosomal dominant limb-girdle muscular dystrophy type 1D (DNAJB6) maps to a 1-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for autosomal dominant limb-girdle muscular dystrophy type 1d (dnajb6) is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
What the evidence adds up to
Autosomal dominant limb-girdle muscular dystrophy type 1D (LGMDD1) is caused by mutations in the DNAJB6 gene. In 2011, exome sequencing in a family with dominant LGMD and vacuolar pathology identified a Phe93Leu mutation in the G/F domain of DNAJB6, and a second G/F domain mutation (Pro96Arg) was found in another pedigree. Affected muscle showed mild dystrophic changes, vacuoles, and abnormal aggregation of proteins including TDP-43 and DNAJB6 itself. DNAJB6 is a co-chaperone of HSP70, and the mutations are thought to compromise its function in preventing protein aggregation.
No treatments are currently available for LGMDD1. Two isoforms of DNAJB6 exist, DNAJB6a and DNAJB6b, with evidence suggesting DNAJB6b is primarily responsible for disease pathogenesis. A 2023 study developed an isoform-specific knockdown approach using morpholinos, achieving selective reduction of each isoform in vitro in primary mouse myotubes and human LGMDD1 myoblasts, and in vivo in mouse skeletal muscle. In myotube cultures from a knockin LGMDD1 mouse model, selective reduction of DNAJB6b levels corrected much of the proteomic disease signature toward wild type levels. The authors note that additional in vivo functional data is required to determine if this is a viable therapeutic target.
Another 2023 proposal describes an allele-specific knockdown (ASKD) strategy using silencing RNA (siRNA) to selectively target mutant DNAJB6, based on evidence that mutations exert a dominant toxic gain-of-function. Global DNAJB6 knockdown is precluded because knockout mice are embryonic lethal, though heterozygous knockout mice are viable with no apparent skeletal muscle phenotype, and frameshift or nonsense mutations are seen in healthy control individuals. Preliminary results indicate ASKD is feasible and can correct a proteomic signature of LGMDD1 disease in vitro. The proposal aims to validate ASKD in an LGMDD1 mouse model and in human in vitro models, and to optimise ASKD targeting a common single nucleotide polymorphism to expand applicability to multiple mutations.
What is still missing: in vivo functional data for the isoform-specific knockdown approach, completion of preclinical validation in mouse models and human cells for the allele-specific knockdown strategy, and funding to carry out those experiments. No trial has yet tested any of these approaches in patients, and the optimal patient stratification (by specific DNAJB6 mutation or isoform expression) remains to be determined.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Annals of Neurology · 2011 · 177 citations · open access
Exome sequencing reveals <i>DNAJB6</i> mutations in dominantly‐inherited myopathy
AbstractOBJECTIVE: To identify the causative gene in an autosomal dominant limb-girdle muscular dystrophy (LGMD) with skeletal muscle vacuoles. METHODS: Exome sequencing was used to identify candidate mutations in the studied pedigree. Genome-wide linkage was then used to narrow the list of candidates to a single disease-associated mutation. Additional pedigrees with dominant or sporadic myopathy were screened for mutations in the same gene (DNAJB6) using exome sequencing. Skeletal muscle from affected patients was evaluated with histochemistry and immunohistochemical stains for dystrophy-related proteins, SMI-31, TDP43, and DNAJB6. RESULTS: Exome analysis in 3 affected individuals from a family with dominant LGMD and vacuolar pathology identified novel candidate mutations in 22 genes. Linkage analysis excluded all variants except a Phe93Leu mutation in the G/F domain of the DNAJB6 gene, which resides within the LGMD locus at 7q36. Analysis of exome sequencing data from other pedigrees with dominant myopathy identified a second G/F domain mutation (Pro96Arg) in DNAJB6. Affected muscle showed mild dystrophic changes, vacuoles, and abnormal aggregation of proteins, including TDP-43 and DNAJB6 itself. INTERPRETATION: Mutations within the G/F domain of DNAJB6 are a novel cause of dominantly-inherited myopathy. DNAJB6 is a member of the HSP40/DNAJ family of molecular co-chaperones tasked with protecting client proteins from irreversible aggregation during protein synthesis or during times of cellular stress. The abnormal accumulation of several proteins in patient muscle, including DNAJB6 itself, suggest that DNAJB6 function is compromised by the identified G/F domain mutations.
DNAJB6 isoform specific knockdown: Therapeutic potential for limb girdle muscular dystrophy D1
AbstractDominant missense mutations in DNAJB6, a co-chaperone of HSP70, cause limb girdle muscular dystrophy (LGMD) D1. No treatments are currently available. Two isoforms exist, DNAJB6a and DNAJB6b, each with distinct localizations in muscle. Mutations reside in both isoforms, yet evidence suggests that DNAJB6b is primarily responsible for disease pathogenesis. Knockdown treatment strategies involving both isoforms carry risk, as DNAJB6 knockout is embryonic lethal. We therefore developed an isoform-specific knockdown approach using morpholinos. Selective reduction of each isoform was achieved in vitro in primary mouse myotubes and human LGMDD1 myoblasts, as well as in vivo in mouse skeletal muscle. To assess isoform specific knockdown in LGMDD1, we created primary myotube cultures from a knockin LGMDD1 mouse model. Using mass spectrometry, we identified an LGMDD1 protein signature related to protein homeostasis and myofibril structure. Selective reduction of DNAJB6b levels in LGMDD1 myotubes corrected much of the proteomic disease signature toward wild type levels. Additional in vivo functional data is required to determine if selective reduction of DNAJB6b is a viable therapeutic target for LGMDD1.
California Digital Library · 2023 · 0 citations · open access
Allele Specific Knockdown for LGMDD1
AbstractWhile the promise of gene-based therapies for disabling neuromuscular diseases is finally becoming a reality, research efforts thus far have primarily focused on gene replacement strategies for recessive, loss-of-function disorders. Such strategies are not translatable to most dominant muscular dystrophies, hindering the development of new treatment strategies. Our group recently identified mutations in DNAJB6 that cause limb girdle muscular dystrophy D1 (LGMDD1), a dominantly inherited disabling myopathy with no current treatment options. The overarching goal of this proposal is to develop novel therapies for this devastating disease. Addressing this unmet need will advance the field’s understanding of how to treat LGMDD1 and establish the optimal approach to therapeutic development for other dominantly inherited disorders with complex, heterogeneous disease mechanisms. Several lines of preliminary data indicate that mutations in DNAJB6 exert a dominant effect via a toxic gain-of-function. The potential for deleterious effects preclude a global DNAJB6 knockdown strategy, as DNAJB6 knockout (KO) mice are embryonic lethal due to aggregation of client proteins. Haploinsufficiency appears to be tolerated, as heterozygous KO mice are viable, with no apparent skeletal muscle phenotype, and DNAJB6 frameshift and nonsense mutations are seen in healthy “control” patients in genetic databases. We propose to selectively knockdown mutant DNAJB6 using silencing RNA (siRNA). Our preliminary results indicate that allele specific knockdown (ASKD) is feasible and capable of correcting a proteomic signature of LGMDD1 disease in vitro. Thus, our central hypothesis is that ASKD of mutant DNAJB6 is a viable therapeutic approach to address the toxic gain-of-function mechanism of LGMDD1, while avoiding complete knockdown. In this project we will validate that ASKD of mutant DNAJB6 improves disease phenotypes in an LGMDD1 mouse model (Aim 1) and in vitro human LGMDD1 models (Aim 2). Finally, we will optimize ASKD targeting a common DNAJB6 single nucleotide polymorphism (SNP) to expand the applicability of this therapy to multiple DNAJB6 mutations (Aim 3). Successful completion of the proposed aims will produce essential preclinical data supporting the therapeutic translation of ASKD for LGMDD1.
Sri Lanka Journal of Neurology · 2023 · 0 citations · open access
Limb-girdle muscular dystrophies: An update
AbstractLimb-girdle muscular dystrophies (LGMDs) are a heterogenous group of genetically driven muscle disorders, which share the two common features of progressive, predominantly proximal girdle skeletal muscle involvement and dystrophic changes on pathology. This is a rapidly expanding landscape in neurology both in relation to diagnosis as well as evolving targeted treatment options. Thirty-one LGMD subtypes are described to date; five of autosomal dominant inheritance and 26 of autosomal recessive transmission. This article describes their pathogenesis, clinical presentation, diagnosis and recent therapeutic advances.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
