DeCure for Inclusion body myopathy with Paget disease of bone and frontotemporal dementia
DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for inclusion body myopathy with Paget disease of bone and frontotemporal dementia — screening already-approved drugs against its 3-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleInclusion body myopathy with Paget disease of bone and frontotemporal dementia maps to a 3-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 inclusion body myopathy with paget disease of bone and frontotemporal dementia 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
valosin containing protein (VCP) — VCP 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 adpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 10QQ · 2.13 Å · ligand ADENOSINE-5'-DIPHOSPHATE (ADP). Experimental structure, not a prediction.
What the evidence adds up to
In 182 patients from 29 families described in the literature, inclusion body myopathy is a conspicuously penetrant symptom, while Paget disease of bone has lower penetrance when associated with mutations in the AAAD1 domain and frontotemporal dementia has lower penetrance when associated with mutations in the Junction (L1-D1) domain. The R93C mutation is likely associated with the penetrance of all three clinical symptoms. A German family carrying a novel G157R mutation in the N-terminal region of the VCP gene presented with mild to moderate proximal muscle weakness, Paget disease of bone, and early cognitive decline beginning in the fourth decade; two members also showed sensorineural hearing impairment, a symptom not previously described in IBMPFD. A Brazilian family with the R93C mutation showed progressive limb-girdle myopathy, Paget disease confirmed by bone pathology, and frontotemporal dementia diagnosed by clinical, neuropsychological and language evaluations, with brain MRI revealing severe atrophy of the anterior temporal lobes including the hippocampi.
A French patient carrying the R155H mutation, the most frequent of the 18 known VCP mutations, developed progressive limb weakness in his fifties until he was confined to a wheelchair, then acute behavioural changes including irritability, severe anxiety and major depression leading to psychiatric hospitalisation, along with aphasia and executive function impairment. The mean onset of inclusion body myopathy is 42 years, of Paget disease around 40 years, and of frontotemporal dementia around 55 years, appearing nearly a decade later than muscle or bone disease. Frontotemporal dementia is seen in about one third of patients and is mostly the behavioural form. In addition to cognitive dysfunction, motor neuron involvement and cerebellar signs have also been observed. Muscle pathology shows cytoplasmic and nuclear inclusions, rimmed vacuoles, and disorganised myofibrils together with neurogenic changes.
Paget disease of bone is reported in about half of patients around age 40 but is less common in Japanese patients. Affected muscles are variable, and patients are sometimes misdiagnosed with limb girdle muscular dystrophy or GNE myopathy. The disorder is not as rare as previously thought, but its complex clinical findings make diagnosis difficult. No treatment data appear in these abstracts. What is still missing are prospective natural history studies that systematically track the full triad over time, validated biomarkers to distinguish IBMPFD from other myopathies and dementias, and any clinical trial testing a mechanism-based intervention — no drug has been studied in a controlled fashion for this VCP-related disease.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Muscle & Nerve · 2009 · 63 citations
A novel mutation in the VCP gene (G157R) in a german family with inclusion‐body myopathy with paget disease of bone and frontotemporal dementia
AbstractMutations in the valosin-containing protein (VCP) are known to cause autosomal-dominant inclusion-body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD). We report a novel missense mutation (G157R) in the N-terminal region of the VCP gene in a German family. Family members presented with mild to moderate proximal muscle weakness, Paget disease of bone, and signs of early cognitive decline, with onset in the fourth decade. Two family members also showed signs of early hearing impairment, which was confirmed to be sensorineural in one person, a symptom not yet described in the context of IBMPFD.
An Italian family with inclusion‐body myopathy and frontotemporal dementia due to mutation in the <i>VCP</i> gene
AbstractMutations of the valosin-containing protein gene (VCP) are responsible for autosomal-dominant hereditary inclusion-body myopathy associated with frontotemporal dementia and Paget's disease of bone. We identified the p.R155C missense mutation in the VCP gene segregating in an Italian family with three affected siblings, two of whom had a progressive myopathy associated with dementia, whereas one exhibited a progressive myopathy and preclinical signs of Paget's disease of bone. Our study demonstrates that VCP mutations are found in patients of Italian background and may lead to a variable clinical phenotype even within the same kinship.
Brazilian Journal of Medical and Biological Research · 2011 · 26 citations · open access
A Brazilian family with hereditary inclusion body myopathy associated with Paget disease of bone and frontotemporal dementia
AbstractInclusion body myopathy associated with Paget disease and frontotemporal dementia (IBMPFD) is a progressive and usually misdiagnosed autosomal dominant disorder. It is clinically characterized by a triad of features: proximal and distal myopathy, early onset Paget disease of bone (PDB), and frontotemporal dementia (FTD). It is caused by missense mutations in the valosin-containing protein (VCP) gene. We describe here the clinical and molecular findings of the first Brazilian family identified with IBMPFD. Progressive myopathy affecting the limb girdles was detected by clinical examination followed by muscle biopsy and creatine kinase measurement. PDB was suggested after anatomopathological bone examination and FTD was diagnosed by clinical, neuropsychological and language evaluations. Brain magnetic resonance revealed severe atrophy of the anterior temporal lobes, including the hippocampi. A R93C mutation in VCP was detected by direct sequencing screening in subject W (age 62) and in his mother. Four more individuals diagnosed with "dementia" were reported in this family. We also present a comprehensive genotype-phenotype correlation analysis of mutations in VCP in 182 patients from 29 families described in the literature and show that while IBM is a conspicuously penetrant symptom, PDB has a lower penetrance when associated with mutations in the AAAD1 domain and FTD has a lower penetrance when associated with mutations in the Junction (L1-D1) domain. Furthermore, the R93C mutation is likely to be associated with the penetrance of all the clinical symptoms of the triad.
Frontotemporal dementia associated with a <i>Valosin‐Containing Protein</i> mutation: report of three families
AbstractObjective: The phenotype of inclusion body myopathy with Paget disease of the bone and frontotemporal dementia (FTD) (IBMPFD), associated with Valosin‐Containing Protein ( VCP ) mutations is described in 3 families. Methods: Probands were identified on the basis of a pathological diagnosis of frontotemporal lobar degeneration with neuronal intranuclear ubiquitin/TDP‐43‐positive inclusions (FTLD‐U type IV). VCP sequencing was carried out. Clinical data on affected family members were reviewed. Results: Family A: 4 subjects had a myopathy (M): 2 showed also Parkinsonism (P) and FTD. Proband's brain had FTLD‐U type IV and brainstem‐type Lewy body pathology. Muscle displayed neurogenic changes and VCP(+)‐rimmed vacuoles. A VCP R191Q mutation was found in one allele. Family B: 8 subjects developed IBMPFD: FTD was seen in 4, M in 3, P in 2 and primary progressive aphasia (PPA) in one. Proband's brain showed FTLD‐U type IV, hippocampal sclerosis (HS) as well as Lewy neurites in the substantia nigra. A novel VCP T262A mutation was found in one allele. Family C: 2 subjects developed IBMPFD. The proband had FTD while a brother presented M and dementia. Proband's brain had FTLD‐U type IV and HS. A VCP R159C mutation was found in one allele. Conclusions: We identified three new families with IBMPFD associated with VCP mutations. A novel T262A mutation was found. One individual had PPA: a novel finding in IBMPFD. Supported by AG10133
Case Reports in Neurology · 2013 · 14 citations · open access
Psychiatric Presentation of Frontotemporal Dementia Associated with Inclusion Body Myopathy due to the VCP Mutation (R155H) in a French Family
AbstractINTRODUCTION: Inclusion body myopathy with Paget's disease of the bone and frontotemporal dementia (IBMPFD) is a rare late-onset autosomal dominant disorder due to a mutation of the valosin-containing protein (VCP) gene. CASE REPORT: We report the case of a patient who developed progressive weakness of the limbs in his fifties, until he was confined to a wheelchair. At that time, he developed acute behavioural changes including irritability, severe anxiety and major depression, which led to him being hospitalised in a psychiatric hospital. He also suffered from aphasia and executive function impairment, which helped us to diagnose a behavioural form of frontotemporal dementia (FTD). The diagnosis of IBMPFD due to a mutation in the VCP gene was confirmed by a genetic study of the VCP gene (R155H mutation). DISCUSSION: THE CLINICAL DIAGNOSIS OF IBMPFD IS SUGGESTED BY THE PRESENCE OF AT LEAST ONE OF THREE MAJOR MANIFESTATIONS AS FOLLOWS: inclusion body myopathy (mean onset at 42 years of age), Paget's disease of the bone and FTD (mean onset at 55 years of age). It is mostly the behavioural form of FTD (behavioural changes, executive dysfunction and aphasia). One interesting finding in our report is the predominance of the psychiatric symptoms at the beginning of the behavioural changes, which led to the diagnosis of FTD. The diagnosis of IBMPFD was confirmed by the genetic study: the R155H mutation found on exon 5 domain CDC48 is the most frequent of the 18 known mutations in the VCP gene.
Rinsho Shinkeigaku · 2013 · 2 citations · open access
Inclusion body myopathy with Paget’s disease of bone and frontotemporal dementia
AbstractInclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD) is an autosomal dominant disease caused by mutations in the VCP gene. VCP encodes a well-conserved multifunctional protein, valosin containing protein (VCP), which has important roles in protein quality control via proteasome and autophagy, protein aggregation, quality control of mitochondria, cell proliferation, and so on. Clinically, muscle weakness is the most common symptom of which disease onset is around 40 years. Affected muscles are variable, and the patients are sometimes diagnosed as limb girdle muscular dystrophy or GNE myopathy. Muscle pathology shows characteristic features including cytoplasmic/nuclear inclusions, rimmed vacuoles, and disorganized myofibrills, together with neurogenic changes. Paget's disease of bone is reported to be observed in a half of the patients around the age of 40 years, but less common in Japanese patients. Frontotemporal dementia is seen around one third of the patients which appears nearly 10 years later than muscle or bone disease. In addition to cognitive dysfunctions, motor neuron involvement and cerebellar signs were also seen in our series. IBMPFD is not so rare disease as previously thought, but complicate clinical findings may make its diagnosis difficult.
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.
