DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for Charcot-Marie-Tooth disease type 1 — screening already-approved drugs against its 14-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleCharcot-Marie-Tooth disease type 1 maps to a 14-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 charcot-marie-tooth disease type 1 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.
Molecular view
MORC family CW-type zinc finger 2 (MORC2) — MORC2 is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet anpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 9CDH · 1.95 Å · ligand PHOSPHOAMINOPHOSPHONIC ACID-ADENYLATE ESTER (ANP). Experimental structure, not a prediction.
What the evidence adds up to
In a retrospective diagnostic study of 64 patients with suspected Charcot-Marie-Tooth disease, 25 (39%) were diagnosed by multiplex ligation probe amplification. Among 50 patients who then underwent next-generation sequencing for targeted gene panels, 18 (36%) had pathogenic or likely pathogenic variants. Whole-exome sequencing on five patients with normal next-generation sequencing results gave a diagnostic yield of 80%, higher in the childhood group. The authors note that patients without a molecular diagnosis remain in all the literature, suggesting undiscovered genes or mechanisms.
A second family with a dominantly inherited CMT harbouring the MFN2 mutation c.2222T>G (p.Leu741Trp) has been reported, confirming the pathogenicity of this mutation. Disease onset in this second family was much later than in the previously reported cases.
A phase 3 randomised double-blind placebo-controlled trial of PXT3003 (baclofen/naltrexone/D-sorbitol) enrolled 323 subjects with mild-to-moderate CMT1A. The high-dose group (6/0.70/210 mg) was discontinued early because of unexpected crystal formation in the formulation, leading to a high discontinuation rate. The statistical analysis plan was adapted for missing data, and a modified full analysis set was used. High-dose PXT3003 showed a statistically significant improvement in the Overall Neuropathy Limitations Scale total score versus placebo (mean difference −0.37 points; 97.5% CI −0.68 to −0.06; p = 0.008). Both doses were reported as safe and well-tolerated. The same trial is described in two separate publications from 2021 and 2024.
What is still missing is a treatment that reliably slows or reverses disease progression in CMT1A. The PXT3003 trial’s positive result was obtained after a protocol change and with a high dropout rate in the active arm, and the effect size was small. No trial data exist for repurposed drugs in other CMT subtypes. Diagnostic algorithms still leave many patients without a genetic diagnosis, limiting the ability to stratify patients for targeted trials. Funding for larger, more robust trials with better formulations and for discovery of new causative genes remains insufficient.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
BMJ Case Reports · 2009 · 7 citations · open access
AbstractCharcot-Marie tooth disease (CMT) is a heterogenous group of peripheral neuropathies caused by various genetic defects. Three cases of mitochondrial myopathy, neuropathy and gastrointestinal encephalopathy (MNGIE) which initially presented with a peripheral neuropathy resembling CMT are described here. The diagnosis in all three cases was made after they developed eye signs and abdominal complaints. Young patients with mutation negative CMT should be followed up to monitor for signs of MNGIE.
Revista da Associação Médica Brasileira · 2023 · 6 citations · open access
High diagnostic yield with algorithmic molecular approach on hereditary neuropathies
AbstractOBJECTIVE: Charcot-Marie-Tooth disease covers a group of inherited peripheral neuropathies. The aim of this study was to investigate the effect of targeted next-generation sequencing panels on the molecular diagnosis of Charcot-Marie-Tooth disease and its subtypes in routine clinical practice, and also to show the limitations and importance of next-generation sequencing in the diagnosis of Charcot-Marie-Tooth diseases. METHODS: This is a retrospective study. Three different molecular methods (multiplex ligation probe amplification, next-generation sequencing, and whole-exome sequencing) were used to detect the mutations related to Charcot-Marie-Tooth disease. RESULTS: In total, 64 patients (33 males and 31 females) with suspected Charcot-Marie-Tooth disease were analyzed for molecular etiology. In all, 25 (39%) patients were diagnosed by multiplex ligation probe amplification. With an extra 11 patients with normal PMP22 multiplex ligation probe amplification results that were consulted to our laboratory for further genetic analysis, a total of 50 patients underwent next-generation sequencing for targeted gene panels associated with Charcot-Marie-Tooth disease. Notably, 18 (36%) patients had pathogenic/likely pathogenic variants. Whole-exome sequencing was performed on five patients with normal next-generation sequencing results; the diagnostic yield by whole-exome sequencing was 80% and it was higher in the childhood group. CONCLUSION: The molecular etiology in Charcot-Marie-Tooth disease patients can be determined according to pre-test evaluation, deciding the inheritance type with pedigree analysis, the clinical phenotype, and an algorithm for the genetic analysis. The presence of patients without a molecular diagnosis in all the literature suggests that there are new genes or mechanisms waiting to be discovered in the etiology of Charcot-Marie-Tooth disease.
Journal of Neuromuscular Diseases · 2019 · 2 citations
Late onset CMT2A in a Family with an MFN2 Variant: c.2222T>G (p.Leu741Trp)
AbstractMutations in MFN2 cause a range of Charcot-Marie-Tooth disease (CMT) phenotypes with different inheritance patterns and underlying pathogenic mechanisms. Recently, a family with a dominantly inherited CMT harboring c.2222T>G (p.Leu741Trp) mutation in MFN2 has been reported for the first time. Here, we report a second family also with a dominantly inherited CMT harboring the same mutation, thereby confirming the pathogenicity of this mutation. Interestingly, the disease onset of this second family is much later than the previously reported cases.
A double-blind, placebo-controlled, randomized trial of PXT3003 for the treatment of Charcot–Marie–Tooth type 1A
AbstractAbstract Background Charcot–Marie–Tooth disease type 1A (CMT1A) is a rare, orphan, hereditary neuromuscular disorder with no cure and for which only symptomatic treatment is currently available. A previous phase 2 trial has shown preliminary evidence of efficacy for PXT3003 in treating CMT1A. This phase 3, international, randomized, double-blind, placebo-controlled study further investigated the efficacy and safety of high- or low-dose PXT3003 (baclofen/naltrexone/D-sorbitol [mg]: 6/0.70/210 or 3/0.35/105) in treating subjects with mild to moderate CMT1A. Methods In this study, 323 subjects with mild-to-moderate CMT1A were randomly assigned in a 1:1:1 ratio to receive 5 mL of high- or low-dose PXT3003, or placebo, orally twice daily for up to 15 months. Efficacy was assessed using the change in Overall Neuropathy Limitations Scale total score from baseline to months 12 and 15 (primary endpoint). Secondary endpoints included the 10-m walk test and other assessments. The high-dose group was discontinued early due to unexpected crystal formation in the high-dose formulation, which resulted in an unanticipated high discontinuation rate, overall and especially in the high-dose group. The statistical analysis plan was adapted to account for the large amount of missing data before database lock, and a modified full analysis set was used in the main analyses. Two sensitivity analyses were performed to check the interpretation based on the use of the modified full analysis set. Results High-dose PXT3003 demonstrated significant improvement in the Overall Neuropathy Limitations Scale total score vs placebo (mean difference: − 0.37 points; 97.5% CI [− 0.68 to − 0.06]; p = 0.008), and consistent treatment effects were shown in the sensitivity analyses. Both PXT3003 doses were safe and well-tolerated. Conclusion The high-dose group demonstrated a statistically significant improvement in the primary endpoint and a good safety profile. Overall, high-dose PXT3003 is a promising treatment option for patients with Charcot–Marie–Tooth disease type 1A.
A double-blind, placebo-controlled, randomized trial of PXT3003 for the treatment of Charcot–Marie–Tooth type 1A
AbstractAbstract Background Charcot–Marie–Tooth disease type 1A (CMT1A) is a rare, orphan, hereditary neuromuscular disorder with no cure and for which only symptomatic treatment is currently available. A previous phase 2 trial has shown preliminary evidence of efficacy for PXT3003 in treating CMT1A. This phase 3, international, randomized, double-blind, placebo-controlled study further investigated the efficacy and safety of high- or low-dose PXT3003 (baclofen/naltrexone/D-sorbitol [mg]: 6/0.70/210 or 3/0.35/105) in treating subjects with mild to moderate CMT1A. Methods In this study, 323 subjects with mild-to-moderate CMT1A were randomly assigned in a 1:1:1 ratio to receive 5 mL of high- or low-dose PXT3003, or placebo, orally twice daily for up to 15 months. Efficacy was assessed using the change in Overall Neuropathy Limitations Scale total score from baseline to months 12 and 15 (primary endpoint). Secondary endpoints included the 10-m walk test and other assessments. The high-dose group was discontinued early due to unexpected crystal formation in the high-dose formulation, which resulted in an unanticipated high discontinuation rate, overall and especially in the high-dose group. The statistical analysis plan was adapted to account for the large amount of missing data before database lock, and a modified full analysis set was used in the main analyses. Two sensitivity analyses were performed to check the interpretation based on the use of the modified full analysis set. Results High-dose PXT3003 demonstrated significant improvement in the Overall Neuropathy Limitations Scale total score vs placebo (mean difference: − 0.37 points; 97.5% CI [− 0.68 to − 0.06]; p = 0.008), and consistent treatment effects were shown in the sensitivity analyses. Both PXT3003 doses were safe and well-tolerated. Conclusion The high-dose group demonstrated a statistically significant improvement in the primary endpoint and a good safety profile. Overall, high-dose PXT3003 is a promising treatment option for patients with Charcot–Marie–Tooth disease type 1A.
INDIGO (University of Illinois at Chicago) · 2022 · 0 citations · open access
sj-pdf-2-imr-10.1177_03000605221139718 - Supplemental material for Novel mutation in the <i>MPZ</i> gene causes early-onset but slow-progressive Charcot–Marie–Tooth disease in a Russian family: a case report
AbstractSupplemental material, sj-pdf-2-imr-10.1177_03000605221139718 for Novel mutation in the <i>MPZ</i> gene causes early-onset but slow-progressive Charcot–Marie–Tooth disease in a Russian family: a case report by Anastasiya Aleksandrovna Kozina, Natalia Vladimirovna Baryshnikova, Anna Yurievna Ilinskaya, Anna Alexandrovna Kim, Nikolay Alekseevich Plotnikov, Nadezhda Andreevna Pogodina, Ekaterina Ivanovna Surkova, Peter Alekseevich Shatalov and Valery Vladimirovich Ilinsky in Journal of International Medical Research
Sage Journals Data · 2022 · 0 citations · open access
sj-pdf-2-imr-10.1177_03000605221139718 - Supplemental material for Novel mutation in the <i>MPZ</i> gene causes early-onset but slow-progressive Charcot–Marie–Tooth disease in a Russian family: a case report
AbstractSupplemental material, sj-pdf-2-imr-10.1177_03000605221139718 for Novel mutation in the <i>MPZ</i> gene causes early-onset but slow-progressive Charcot–Marie–Tooth disease in a Russian family: a case report by Anastasiya Aleksandrovna Kozina, Natalia Vladimirovna Baryshnikova, Anna Yurievna Ilinskaya, Anna Alexandrovna Kim, Nikolay Alekseevich Plotnikov, Nadezhda Andreevna Pogodina, Ekaterina Ivanovna Surkova, Peter Alekseevich Shatalov and Valery Vladimirovich Ilinsky in Journal of International Medical Research
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.
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