DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for arthrogryposis, distal, type 2B3 — 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 moduleArthrogryposis, distal, type 2B3 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 arthrogryposis, distal, type 2b3 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
No drug treatment is described in any of the three abstracts. The 2019 upper-extremity review states that initial management consists of stretching and splinting, and that surgical procedures aim to improve function and daily living activities, but that not all contractures need surgical correction. It reports that quality of life scores in this patient population are comparable to age-adjusted general population scores, despite lower overall functioning scores. The 2019 symposium summary reports that clinical and research advances were shared at the 3rd International Symposium on Arthrogryposis in 2018, but gives no specific results or numbers.
The 2021 case report of a Japanese family with autosomal dominant proximal arthrogryposis identified a heterozygous nonsense variant in TNNI1 (c.523A>T, p.K175*) in a 14-year-old boy who had proximal joint contractures, elevated serum creatine kinase, and muscle biopsy showing a moth-eaten appearance in some type 1 fibres with Z disk streaming on electron microscopy. The authors note that compared with patients who have TNNI2 variants, this patient had a milder phenotype and proximal rather than distal arthrogryposis. The 2018 study of two Chinese families found a heterozygous missense mutation in TPM2 (c.308A>G, p.Q103R) in a family with distal arthrogryposis type 2B, and a novel variant in PIEZO2 (c.8153G>A, p.R2718Q) in a family with mild distal arthrogryposis. That study reports that there was no relation between the types or locations of TPM2 mutations and clinical characteristics, and that different inheritance modes and mutation types in PIEZO2 cause distinct clinical manifestations.
What is still missing for any drug-repurposing effort in distal arthrogryposis type 2B3 is any identified drug target, any preclinical or clinical trial testing a pharmacological agent, and any evidence that a drug can modify the contractures or the underlying genetic pathway. No patient stratification strategy, no funding for a drug screen, and no trial design exist in these abstracts.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Journal of Bone and Joint Surgery · 1968 · 289 citations
Arthrogryposis Multiplex Congenita
AbstractForty-five patients with arthrogryposis multiplex congenita treated at the Los Angeles Unit of the Shriners' Hospitals for Crippled Children between 1952 and 1964 were reviewed. The prenatal course, birth history, and family history of most of the patients were also investigated. The results of various surgical procedures used to treat these patients were analyzed. The patients were classified according to pretreatment involvement of both the upper extremities and lower extremities, and also according to total involvement. The interim or end results were rated in a similar manner. Thirty-three of the patients who were followed two years or more were evaluated. The average length of follow-up in this group was 7.4 years. Two conclusions were made on the basis of this detailed study of forty-five patients with arthrogryposis multiplex congenita: 1. There is a very high incidence of recurrence of deformity, especially at the ankle and foot, following correction by casts, braces, surgery, or combinations of the three. Many times the surgery must be repeated. Treatment must be constant, prolonged, and radical. After the deformities are corrected, the position must be maintained with braces, casts, or bivalved casts until the end of the growth period in order to minimize recurrence. 2. With prolonged treatment using casts, splints, braces, and multiple radical soft-tissue and bone operations, deformities can be corrected, and fair to good results can be achieved in many cases.
American Journal of Medical Genetics Part C Seminars in Medical Genetics · 2019 · 36 citations · open access
Treatment and outcomes of arthrogryposis in the upper extremity
AbstractUpper extremity involvement in patients with arthrogryposis multiplex congentia is quite frequent. Treatment initially consists of stretching and splinting as significant gains can be seen in the first years of life. The goal of any surgical procedure is to improve upper extremity function and performance of daily living activities, yet it is important to treat each patient individually and understand that areas do not always need to be addressed surgically. Despite overall lower functioning scores in this patient population, quality of life scores are comparable to the general aged adjusted population. This article will discuss the clinical presentation, treatment procedures and outcomes when addressing the upper extremities of patients presenting with arthrogryposis.
American Journal of Medical Genetics Part C Seminars in Medical Genetics · 2019 · 13 citations
Summary of the 3rd international symposium on arthrogryposis
AbstractThe 1st international symposium on arthrogryposis (ISA) was held in 2007 in Birmingham, UK, to bring together a multinational group of experts in the field of arthrogryposis, patients and their families to discuss various aspects of care for individuals with Arthrogryposis Multiplex Congenita (AMC). These "lessons learnt" set the tone for the 2nd ISA held in Saint Petersburg, Russia in 2014. Clinical and research advances have recently been made in the field of arthrogryposis and were shared at the 3rd ISA, in Philadelphia, in 2018. Highlights of the 3ISA and future directions are presented.
Neurology Genetics · 2021 · 5 citations · open access
<i>TNNI1</i> Mutated in Autosomal Dominant Proximal Arthrogryposis
Abstract<h3>Objectives</h3> The main objective of this case report is to identify a gene associated with a Japanese family with autosomal dominant arthrogryposis. <h3>Methods</h3> We performed clinicopathologic diagnosis and genomic analysis using trio-based exome sequencing. <h3>Results</h3> A 14-year-old boy had contractures in the proximal joints, and the serum creatine kinase level was elevated. Muscle biopsy demonstrated a moth-eaten appearance in some type 1 fibers, and electron microscopic analysis revealed that type 1 fibers had Z disk streaming. We identified a heterozygous nonsense variant, c.523A>T (p.K175*), in <i>TNNI1</i> in the family. <h3>Discussion</h3> The altered amino acid residue is within the tropomyosin-binding site near the C-terminus, in a region homologous to the variational hotspot of Troponin I2 (TNNI2), which is associated with distal arthrogryposis type 1 and 2b. Compared with patients with <i>TNNI2</i> variants, our patient had a milder phenotype and proximal arthrogryposis. We report here a case of proximal arthrogryposis associated with a <i>TNNI1</i> nonsense variant, which expands the genetic and clinical spectrum of this disease. Further functional and genetic studies are required to clarify the role of <i>TNNI1</i> in the disease.
Novel mutations in TPM2 and PIEZO2 are responsible for distal arthrogryposis (DA) 2B and mild DA in two Chinese families
AbstractAbstract Background Distal arthrogryposis (DA) is a group of clinically and genetically heterogeneous disorders that involve multiple congenital limb contractures and comprise at least 10 clinical subtypes. Here, we describe our findings in two Chinese families: Family 1 with DA2B (MIM 601680) and Family 2 with mild DA. Methods To map the disease locus, two-point linkage analysis was performed with microsatellite markers closed to TPM2, TNNI2/TNNT3 and TNNC2. In Family 1, a positive LOD (logarithm of odds) score was only obtained at the microsatellite marker close to TPM2 and mutation screening was performed using direct sequencing of TPM2 in the proband. In Family 2, for the LOD score that did not favor linkage to any markers, whole-exome sequencing (WES) was performed on the proband. PCR–restriction fragment length polymorphism (RFLP) and bioinformatics analysis were then applied to identify the pathogenic mutations in two families. In order to correlate genotype with phenotype in DA, retrospective analyses of phenotypic features according to the TPM2 and PIEZO2 mutation spectrums were carried out. Results A heterozygous missense mutation c.308A > G (p.Q103R) in TPM2 in Family 1, and a novel variation c.8153G > A (p.R2718Q) in PIEZO2 in Family 2 were identified. Each of the two novel variants was co-segregated with the DA manifestations in the corresponding family. Bioinformatics analysis from several tools supported the pathogenicity of the mutations. Furthermore, our study suggests that there is no relation between the types or locations of TPM2 mutations and the clinical characteristics, and that different inheritance modes and mutation types concerning PIEZO2 cause distinct clinical manifestations. Conclusions We report two novel mutations within TPM2 and PIEZO2 responsible for DA2B and mild DA in two Chinese families, respectively. Our study expands the spectrum of causal mutations in the TPM2 and PIEZO2 genes.
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.
