DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for giant axonal neuropathy 2 — 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 moduleGiant axonal neuropathy 2 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 giant axonal neuropathy 2 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
DDB1 and CUL4 associated factor 8 (DCAF8) — DCAF8 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 apo structuredrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 9U7T · 3.1 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Giant axonal neuropathy is a rare, severe neurodegenerative disease. One case report describes a boy with kinky hair who presented at age 4 with unsteady gait, nystagmus, cerebellar ataxia, distal sensory loss, and weakness. A sural nerve biopsy at age 8 confirmed giant axonal neuropathy. He became increasingly demented and incapacitated, and died at 18. Postmortem examination showed Rosenthal fibres, a distal axonopathy affecting corticospinal tracts, middle cerebellar peduncles, and posterior columns, and olivocerebellar degeneration. Evoked potential studies in three boys aged 14 to 16 with giant axonal neuropathy found absent waveforms and prolonged latencies in auditory, visual, and somatosensory modalities, with increased brainstem conduction time on auditory brainstem evoked responses, confirming central nervous system involvement.
A separate report describes a large Tunisian kindred with six patients who had a slowly progressive autosomal recessive form of giant axonal neuropathy. The propositus had infantile onset of distal amyotrophy in all four limbs, brisk reflexes, diffuse fasciculations, bulbar signs, and deep sensory loss in the lower limbs. EMG and nerve biopsy showed hypertrophic neuritis. Four patients had giant axons filled with neurofilaments with normal conduction velocity. The youngest boy had a less severe deficit, and his biopsy showed only a few unmyelinated axons filled with neurofilaments. The authors suggest this kindred represents a different genetic defect from other reported cases.
Severe early-onset axonal neuropathy can be caused by homozygous or compound heterozygous mutations in the MFN2 gene. In three individuals with such mutations, all parents were asymptomatic or mildly symptomatic, some with hearing problems and signs of peripheral neuropathy. The authors conclude this is a semi-dominant mechanism rather than true recessive inheritance. Thalidomide, used for multiple myeloma, can cause a sensory neuropathy. In six patients with thalidomide-induced polyneuropathy, all had sensory abnormalities in all four limbs; spinal cord MRI showed high signal in the posterior columns in only one patient. The neuropathy is usually an axonal length-dependent neuropathy, less frequently a ganglionopathy.
More than ten genes causing axonal Charcot-Marie-Tooth disease have been identified. Animal and cellular models exist, and therapeutic strategies are being explored, but no specific treatment for giant axonal neuropathy is described in these abstracts. What is missing is a clear genetic diagnosis for many patients, a reliable animal model that recapitulates the full human disease, and any clinical trial data for a drug that might slow or reverse the neuropathy.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Neurology · 2008 · 112 citations
Severe early-onset axonal neuropathy with homozygous and compound heterozygous <i>MFN2</i> mutations
AbstractOBJECTIVE: Severe early-onset axonal neuropathy (SEOAN) is a heterogeneous phenotype first delineated by Ouvrier et al., characterized by progressive axonal degeneration with gait problems often progressing to wheelchair requirement and later respiratory involvement. Most cases are sporadic single cases. Some have heterozygous mitofusin 2 (MFN2) mutations, many of which are de novo dominant mutations. The aim of this study was to investigate the mode of inheritance in three individuals with severe early-onset axonal neuropathy and homozygous or compound heterozygous MFN2 mutations. METHODS: The clinical and molecular findings in the parents of three individuals with SEOAN with homozygous or compound heterozygous MFN2 mutations were examined. RESULTS: All parents were asymptomatic or mildly symptomatic with some signs of peripheral neuropathy indicating a minimal phenotype. Two had hearing problems. All parents carried the relevant single base (heterozygous) MFN2 variations. CONCLUSION: Severe early-onset axonal neuropathy due to MFN2 mutations can present as an apparently recessively inherited neuropathy but the minimal phenotype in the parents suggests a semi-dominant mechanism.
Current Opinion in Neurology · 2004 · 75 citations
IgM paraproteinaemic neuropathies
AbstractPURPOSE OF REVIEW: To conduct a critical review of recent studies on the pathogenesis and treatment of IgM paraproteinaemic neuropathies and analyse their implication for patient management. RECENT FINDINGS: A better definition and classification of IgM monoclonal gammopathies has led to recommendations on therapeutic strategies for these patients, particularly for those with the asymptomatic form of Waldenström macroglobulinemia. Studies on the pathogenetic role of IgM paraprotein in neuropathy have led to the identification of a novel antibody reactivity against trisulfated heparin disaccharide, which was associated with painful, predominantly sensory, axonal distal neuropathy. Pathological studies on patients with axonal polyneuropathy and no antibody reactivity of the IgM paraprotein have shown that vasculitis may play an important role in this form of neuropathy, as possibly confirmed by its positive response to steroids. A number of open pilot trials have addressed the effect in IgM paraproteinaemic neuropathies of the humanized monoclonal antibody (rituximab) directed against the CD20 antigen. Even if the results of these studies are less promising than initially hoped, they provide evidence that rituximab may be effective in some patients with this neuropathy. SUMMARY: New insights into the pathogenesis of axonal forms of IgM paraproteinaemic neuropathy have derived from the identification of novel antibody reactivity and of vasculitis. The latter finding may justify the use of steroids, otherwise ineffective in IgM paraproteinaemic neuropathy. Rituximab has opened the way to more selective and apparently safer immune therapies for this neuropathy, but its efficacy needs to be confirmed by randomized controlled trials.
Thalidomide neuropathy: clinical, electrophysiological and neuroradiological features
AbstractOBJECTIVE: Thalidomide is a promising therapy for multiple myeloma. Sensory neuropathy is a side effect of thalidomide and resulted to be partially reversible in 50% of cases, suggesting a sensory ganglionopathy. Spinal cord magnetic resonance imaging (MRI) was found to be useful in the diagnosis of sensory ganglionopathies and we use it to determine if thalidomide neuropathy has features of a ganglionopathy. MATERIAL AND METHODS: Six patients with multiple myeloma developed thalidomide-induced polyneuropathy. Nerve conduction studies, somatosensory-evoked potentials (SEPs) and cervical and dorsal spinal cord MRI were obtained in all. RESULTS: All patients had a sensory neuropathy, with clinical or electrophysiological abnormalities involving all four limbs. Spinal cord MRI showed high signal intensity in the posterior columns in only one patient, with abnormal central conduction time at SEPs. CONCLUSION: Our results suggest that thalidomide can induce either an axonal length-dependent neuropathy or, less frequently, a ganglionopathy.
Giant axonal neuropathy: Correlation of clinical findings with postmortem neuropathology
AbstractWe report the clinical and postmortem neuropathological findings in a case of long-standing giant axonal neuropathy. The patient, a caucasian male with kinky hair, was first seen at 4 years of age because of increasing unsteadiness of gait. Clinical examination showed nystagmus, cerebellar ataxia, distal sensory loss, and weakness. A sural nerve biopsy at 8 years of age revealed giant axonal neuropathy. The patient became increasingly demented and was incapacitated by weakness and ataxia; he died at 18 years of age. Histological examination of the brain and spinal cord showed numerous Rosenthal fibers, a distal axonopathy that most severely affected the corticospinal tracts, middle cerebellar peduncles, and posterior columns, and olivocerebellar degeneration.
Giant axonal neuropathy with inherited multisystem degeneration in a Tunisian kindred
AbstractWe describe a large kindred of 6 patients with a slowly progressive autosomal recessive form of giant axonal neuropathy (GAN). The propositus presented with progressive infantile onset of distal amyotrophy of 4 limbs, brisk reflexes, diffuse fasciculations, bulbar signs, and deep sensory loss in both lower limbs. The EMG and nerve biopsy showed typical hypertrophic neuritis. In 4 patients, there were giant axons filled with neurofilaments, with normal conduction velocity. In the youngest boy, the neurologic deficit was less severe, and the nerve biopsy revealed only a few unmyelinated axons filled with neurofilaments. These cases appear to represent a different genetic defect from other reported cases of GAN.
Current Opinion in Neurology · 2011 · 41 citations
Axonal Charcot–Marie–Tooth disease
AbstractPURPOSE OF REVIEW: The aim is to specify the genetic causes of dominantly and recessively inherited axonal forms of Charcot-Marie-Tooth disease (CMT) and review the biological basis for these disorders. RECENT FINDINGS: More than 10 genes that cause axonal CMT have been identified over the past decade. Many of these genes express proteins that are ubiquitously expressed. Clinical phenotypes of many of these disorders are being studied and animal and cellular models of these neuropathies have been created. SUMMARY: Identification of these new genetic causes of axonal neuropathy has not only been important for patients and their families but it has also provided exciting new information about disease mechanisms involved in neuronal degeneration. These mechanisms extend beyond the field of axonal CMT and have relevance to sensory neuropathies and motor neuron disorders. Therapeutic strategies for some of these are also provided. We hope that this review will be of interest to clinicians and scientists interested in axonal forms of CMT.
Giant axonal neuropathy: Central abnormalities demonstrated by evoked potentials
AbstractPrevious studies of giant axonal neuropathy have reported clinical and pathological findings that indicate involvement of the central nervous system. We studied 3 boys with giant axonal neuropathy, who were 14 to 16 years of age, using auditory, visual, and somatosensory evoked potentials. Absence of waveforms and prolongation of peak and interwave latencies were found. Abnormalities were noted in all modalities. The auditory brainstem evoked response in particular indicated a significant increase in brainstem conduction time. These studies add clinical neurophysiological confirmation of the central nervous system involvement in this disorder and may also provide a means of quantitative evaluation of its progression.
Journal of Neurology Research · 2013 · 0 citations · open access
Severe Neuropathy and Tetraparesis Induced by Adalimumab
AbstractWe report a case of severe axonal and demyelinating peripheral polyneuropathy with consecutive tetraparesis following the second application of adalimumab in a 55-year-old man with rheumatoid arthritis. The treatment provided 40 mg of adalimumab s.c. every 2 weeks. Modest muscle pain and weakness followed the first dose, but the second dose resulted in progressive tetraparesis and complete immobility. Electroneurography revealed almost complete denervation of all muscles of the upper extremities, and no motor response at the lower extremities. The finding was suggestive of severe subchronic axonal and demyelinating peripheral polyneuropathy induced by adalimumab. A comprehensive medical work out excluded the possibility of other etiology. At discharge, methylprednisolone was continued for the next 3 months. Nine months of physical rehabilitation and supportive treatment resulted in a modest recovery. Anti-TNF- α agents may induce vasculitis neuropathy at any time during treatment which must be distinguished from the neuropathy of the underlying disease. Appropriate therapy should be initiated immediately and continued long enough. J Neurol Res. 2013;3(2):81-83 doi: https://doi.org/10.4021/jnr189e
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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