DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for GNE myopathy — 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 moduleGNE myopathy 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 gne myopathy 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
glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase (GNE) — GNE 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 udpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 4ZHT · 2.69 Å · ligand URIDINE-5'-DIPHOSPHATE (UDP). Experimental structure, not a prediction.
What the evidence adds up to
In an open-label phase 2 study at the NIH, 12 patients with GNE myopathy received oral N-acetylmannosamine (ManNAc). Plasma N-acetylneuraminic acid (Neu5Ac) increased by 2,159 nmol/L (p < 0.0001) and sarcolemmal sialylation improved (p = 0.0090) at day 90. Most drug-related adverse events were gastrointestinal; no serious adverse events occurred. Compared to natural history, slower decline was observed for upper extremity strength (p = 0.0139), lower extremity strength (p = 0.0006), and the Adult Myopathy Assessment Tool (p = 0.0453). A disease progression model estimated decreased progression at 12 months (γ = 0.61, 95% CI: 0.09 to 1.27) and 18 months (γ = 0.55, 95% CI: 0.12 to 1.02). A separate case report described a Chinese patient with a compound heterozygous GNE mutation (c.620A>T and a novel exon 1 deletion) who was given sialic acid 6 g daily for one year; her symptoms did not progress further during that period.
The Japanese nationwide registry Remudy-GNE myopathy enrolled 121 genetically confirmed patients from 73 hospitals. Mean age at onset was 27.7 years. Mean time from onset to using a cane or braces was 12.4 years, to wheelchair use 15.2 years, and to loss of ambulation 21.1 years. Only 19.8% of patients could walk without assistance. A Korean study of 44 patients reported that wrist and neck were the last joints to lose antigravity function, regardless of whether weakness began at the ankle or hip. Patients with biallelic kinase domain mutations tended to progress faster than those with epimerase and kinase domain mutations. Two-thirds of Korean patients could walk independently or with an aid.
A 2015 review noted that GNE myopathy is an autosomal recessive disorder caused by mutations in the GNE gene, which encodes a bifunctional enzyme in sialic acid synthesis. The condition was described as rare but prevalent in Persian Jewish communities and in East Asia. Diagnosis relies on clinical clues, muscle imaging, and genetic confirmation; treatment remained purely supportive at that time. A 2015 genetic analysis identified 154 GNE myopathy-associated variants and estimated worldwide prevalence at 6 per 1,000,000, corresponding to roughly 40,000 patients globally and 3,000 in the USA, far higher than earlier estimates. The same analysis reported a diagnostic delay of about 10 years after initial symptoms.
What is still missing is a randomised controlled trial with a placebo arm and adequate sample size to confirm the preliminary efficacy signals from the open-label ManNAc study. The natural history data from registries remain retrospective and heterogeneous, and no validated biomarker or patient stratification method has been agreed upon to predict who might benefit from sialic acid precursors. Funding for a definitive phase 3 trial and for prospective natural history studies that include standardised outcome measures is needed.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Genetics in Medicine · 2021 · 57 citations · open access
Safety and efficacy of N-acetylmannosamine (ManNAc) in patients with GNE myopathy: an open-label phase 2 study
AbstractPURPOSE: To evaluate the safety and efficacy of N-acetylmannosamine (ManNAc) in GNE myopathy, a genetic muscle disease caused by deficiency of the rate-limiting enzyme in N-acetylneuraminic acid (Neu5Ac) biosynthesis. METHODS: We conducted an open-label, phase 2, single-center (NIH, USA) study to evaluate oral ManNAc in 12 patients with GNE myopathy (ClinicalTrials.gov NCT02346461). Primary endpoints were safety and biochemical efficacy as determined by change in plasma Neu5Ac and sarcolemmal sialylation. Clinical efficacy was evaluated using secondary outcome measures as part of study extensions, and a disease progression model (GNE-DPM) was tested as an efficacy analysis method. RESULTS: Most drug-related adverse events were gastrointestinal, and there were no serious adverse events. Increased plasma Neu5Ac (+2,159 nmol/L, p < 0.0001) and sarcolemmal sialylation (p = 0.0090) were observed at day 90 compared to baseline. A slower rate of decline was observed for upper extremity strength (p = 0.0139), lower extremity strength (p = 0.0006), and the Adult Myopathy Assessment Tool (p = 0.0453), compared to natural history. Decreased disease progression was estimated at 12 (γ = 0.61 [95% CI: 0.09, 1.27]) and 18 months (γ = 0.55 [95% CI: 0.12, 1.02]) using the GNE-DPM. CONCLUSION: ManNAc showed long-term safety, biochemical efficacy consistent with the intended mechanism of action, and preliminary evidence clinical efficacy in patients with GNE myopathy.
Orphanet Journal of Rare Diseases · 2014 · 55 citations · open access
Nationwide patient registry for GNE myopathy in Japan
AbstractBACKGROUND: GNE myopathy is a slowly progressive autosomal recessive myopathy caused by mutations in the GNE (glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase) gene. This study aimed to (1) develop a nationwide patient registry for GNE myopathy in order to facilitate the planning of clinical trials and recruitment of candidates, and (2) gain further insight into the disease for the purpose of improving therapy and care. METHODS: Medical records of genetically-confirmed patients with GNE myopathy at the National Center Hospital of the National Center of Neurology and Psychiatry (NCNP) were retrospectively reviewed in order to obtain data reflecting the severity and progression of the disease. We also referred to items in the datasheet of the nationwide registry of dystrophinopathy patients in the Registry of Muscular Dystrophies (Remudy). Items selected for the registration sheet included age, sex, age at onset, past history and complications, family history, body weight and height, pathological findings of muscle biopsy, grip power, walking ability, respiratory function, cardiac function, willingness to join upcoming clinical trials, and participation in patient associations. A copy of the original genetic analysis report was required of each patient. RESULTS: We successfully established the Remudy-GNE myopathy. Currently, 121 patients are registered nationwide, and 93 physicians from 73 hospitals collaborated to establish the registry. The mean age at onset was 27.7 ± 9.6 years, and 19.8% (24/121) of patients could walk without assistance. Mean presumed durations from onset to use of assistive devices (cane and/or braces) and a wheelchair, and loss of ambulation were 12.4, 15.2, and 21.1 years, respectively. Three patients had a past history and/or complication of idiopathic thrombocytopenia. To share the progress of this study with the community, newsletters were published on a regular basis, and included information regarding new phase I clinical trials for GNE myopathy. The newsletters also served as a medium to bring attention to the importance of respiratory evaluation and care for respiratory insufficiency. CONCLUSION: The Japanese Remudy-GNE myopathy is useful for clarifying the natural history of the disease and recruiting patients with genetically-confirmed GNE myopathy for clinical trials.
Journal of Clinical Neurology · 2019 · 20 citations · open access
Progression of GNE Myopathy Based on the Patient-Reported Outcome
AbstractBACKGROUND AND PURPOSE: gene, and frequently accompanied by rimmed vacuoles in muscle pathology. The initial symptom of foot drop or hip-girdle weakness eventually spreads to all limbs over a period of decades. Recent advances in pathophysiologic research have facilitated therapeutic trials aimed at resolving the core biochemical defect. However, there remains unsettled heterogeneity in its natural course, which confounds the analysis of therapeutic outcomes. We performed the first large-scale study of Korean patients with GNE myopathy. METHODS: We gathered the genetic and clinical profiles of 44 Korean patients with genetically confirmed GNE myopathy. The clinical progression was estimated retrospectively based on a patient-reported questionnaire on the status of the functional joint sets and daily activities. RESULTS: The wrist and neck were the last joints to lose antigravity functionality irrespective of whether the weakness started from the ankle or hip. Two-thirds of the patients could walk either independently or with an aid. The order of losing daily activities could be sorted from standing to eating. Patients with limb-girdle phenotype showed an earlier age at onset than those with foot-drop onset. Patients with biallelic kinase domain mutations tended to progress more rapidly than those with epimerase and kinase domain mutations. CONCLUSIONS: The reported data can guide the clinical management of GNE myopathy, as well as provide perspective to help the development of clinical trials.
A case report: identification of a novel exon 1 deletion mutation in the GNE gene in a Chinese patient with GNE myopathy
AbstractRATIONALE: GNE myopathy is caused by mutations in the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase(GNE) gene and is clinically characterized by progressive weakness and atrophy of the lower-limb muscles with quadriceps sparing. Nearly all GNE mutations that have been reported thus far in various ethnic populations around the world have been missense or nonsense mutations. PATIENT CONCERNS: We describe the case of a 32-year-old woman with GNE myopathy. The patient presented with progressive weakness of the lower-limb muscles that had spread to her legs. Her serum creatine kinase level was higher than the normal range. Mild myogenic changes were detected in the tibialis anterior muscles on electromyography, and moderate fatty infiltration was observed in various lower-limb muscles on magnetic resonance imaging. Histopathological examination of a skeletal muscle biopsy specimen revealed variation in muscle fiber size, rimmed vacuoles, and disorganized intermyofibrillar networks. DNA sequencing testing revealed a compound heterozygous mutation consisting of a known mutation (c.620A > T in exon 3) and a novel (exon 1 deletion) mutation. DIAGNOSES: Taken together, the clinical features, laboratory testing and DNA findings eventually made the diagnosis of GNE myopathy. INTERVENTIONS AND OUTCOMES: Based on the diagnosis of the GNE myopathy, the patient was administered sialic acid 6 g a day for 1 year, and up to now, her symptoms did not progress further. LESSONS: We have reported the case of a GNE myopathy patient with compound heterozygous GNE gene mutations. This case expands the genotypic spectrum of GNE myopathy.
médecine/sciences · 2015 · 3 citations · open access
Myopathie GNE
AbstractGNE myopathy is a rare neuromuscular disease whose description is fairly recent. It predominantly affects the adult population and is an inherited autosomal recessive disorder. Although universal and ubiquitous, GNE myopathy prevails in the Jewish community of Persian origin, living in Iran, Israel or in the United States. This condition has also been reported in great number in populations of far-East Asia (Japan and neighboring countries) and, closer to France, in Bulgaria. GNE myopathy causes muscle weakness in the extremities (distal myopathy), affecting initially and predominantly foot flexor muscles. The generic term of GNE myopathy is now fully accepted and encompasses two previously described entities: the quadriceps sparing myopathy, (also referred to as the autosomal recessive form of inclusion body myopathy (hIBM) and the Nonaka type distal myopathy (or distal myopathy with rimmed vacuoles DMRV). This myopathy is due to mutations in the GNE gene encoding a bifunctional enzyme, the UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase. This enzyme plays a role at two levels in the metabolic pathway leading to the synthesis of sialic acid. Sialic acid, also known as N-acetylneuraminic acid (Neu5Ac or NANA), is a monosaccharide essential to other protein or lipid molecules requiring sugar residues on their surface in order to function efficiently. GNE myopathy is characterized by histological lesions (rimmed vacuoles) within muscle fibers. They are fairly typical in a suggestive context, but non-specific and inconsistent from one muscle to another. The diagnosis of GNE myopathy is essentially based on clinical clues, including muscle imaging, and is confirmed by genetic studies. If promising therapeutic trials are being developed to compensate for this recently unveiled metabolic defect, the treatment of this myopathy remains purely supportive to date.
Genetic Analysis Reveals that GNE Myopathy is an Underdiagnosed Neuromuscular Disorder (P2.044)
AbstractOBJECTIVE: To support our GNE myopathy natural history study and subject recruitment for clinical trials, we analyzed all reported GNE variants associated with GNE myopathy and estimated world-wide prevalence of the disease. BACKGROUND: GNE myopathy (also called HIBM, DMRV, IBM-2, Nonaka myopathy, QSM) is an adult-onset progressive myopathy, caused by bi-allelic GNE gene variants. GNE encodes the key enzyme in sialic acid synthesis. The pathomechanism of GNE myopathy likely involves aberrant muscle sialylation. Clinical trials with sialylation-increasing compounds are ongoing. DESIGN/METHODS: We gathered all known GNE myopathy-associated GNE variants and used next-generation databases to estimate the prevalence of the disease. RESULTS: We identified 154 GNE myopathy-associated GNE variants and assessed their predicted effects on protein function. Exome sequence database analysis revealed three frequently occurring, unreported GNE missense variants/polymorphisms, important for sequence interpretations. Based on allele frequencies, the estimate world-wide prevalence of GNE myopathy was estimated to be at least 6/1,000,000. CONCLUSIONS: The unrecognized high prevalence of GNE myopathy (~ 40,000 patients worldwide; ~3000 patients in USA, instead of previously estimated ~ 400) confirms suspicions that many patients escape diagnosis. Indeed, our ongoing natural history study revealed significant diagnostic delay (~10 years) after initial symptoms in most patients, due to the rare nature of the disease and the lack of conclusive, inexpensive diagnostic tests. Genetic testing for pathogenic, bi-allelic GNE variants ultimately confirms the diagnosis. GNE myopathy should be considered in any young adult with distal, lower extremity muscle weakness. Delayed diagnosis causes emotional hardship for the patient, delays proper disease-management, and influences eligibility to enroll in clinical trials. Awareness among physicians and geneticists for GNE myopathy is essential for the identification of new patients, preferably in early stages of disease. This will support understanding of the disorder’s pathomechanism and success of ongoing treatment trials. Support: NHGRI and NCATS Intramural Programs, NIH, Bethesda, USA
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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