DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for amyotrophic lateral sclerosis type 4 — 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 moduleAmyotrophic lateral sclerosis type 4 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 amyotrophic lateral sclerosis type 4 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
The 2015 review notes that initial enthusiasm for transgenic mouse models of ALS has not been followed by rapid advances in therapy or prevention, and that monogenic models may have masked the true complexity of the human disease. A 2005 review states that riluzole remains the only available therapy, with only marginal effects on survival. A 2017 review of clinical trials reports that no treatment exists for ALS, though edaravone had been recently approved in Japan and was pending in the USA. The same review notes that drug repositioning has achieved approval of some orphan drug applications in late phases of clinical development.
A 2018 study of 8 ALS cases and 17 controls found that loss of TARDBP splicing function in spinal cord, brainstem, motor cortex, and occipital cortex differentiated ALS from controls with an area under the curve of 0.85. The study demonstrated that TARDBP is required for maintaining expression of ATG4B, and that ATG4B overexpression alone prevented the increase of SQSTM1 induced by TARDBP downregulation in human neural tissue cells. This indicates abnormal alternative splicing of ATG4B transcripts in ALS neural tissue, leading to impaired autophagy.
A 2017 chapter states that gene discoveries have implicated diverse biological pathways essential for motor neuron health and have begun to inform understanding of ALS pathogenesis as a heterogeneous and multistep process. A 2020 review describes current approaches to repurposing old drugs for ALS, noting that many molecular and cellular processes compromised in ALS are also compromised in other diseases, and that a repertoire of drugs able to partially restore their functionality has been developed.
What is still missing is a successful transfer of therapeutic compounds from preclinical studies to the clinic, as noted in the 2005 review. The 2015 review stresses the continuing relevance of clinical observations amid increasing molecular complexity. No abstract provides data on survival or response rates for any specific repurposed drug in ALS type 4 or any other subtype. The 2017 review of clinical trials does not report results from those trials.
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 Neurology Neurosurgery & Psychiatry · 2015 · 129 citations · open access
The expanding syndrome of amyotrophic lateral sclerosis: a clinical and molecular odyssey
AbstractRecent advances in understanding amyotrophic lateral sclerosis (ALS) have delivered new questions. Disappointingly, the initial enthusiasm for transgenic mouse models of the disease has not been followed by rapid advances in therapy or prevention. Monogenic models may have inadvertently masked the true complexity of the human disease. ALS has evolved into a multisystem disorder, involving a final common pathway accessible via multiple upstream aetiological tributaries. Nonetheless, there is a common clinical core to ALS, as clear today as it was to Charcot and others. We stress the continuing relevance of clinical observations amid the increasing molecular complexity of ALS.
Cryptic exon splicing function of TARDBP interacts with autophagy in nervous tissue
AbstractTARDBP (TAR DNA binding protein) is one of the components of neuronal aggregates in sporadic amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration. We have developed a simple quantitative method to evaluate TARDBP splicing function that was applied to spinal cord, brainstem, motor cortex, and occipital cortex in ALS (n = 8) cases compared to age- and gender-matched control (n = 17). Then, we quantified the abundance of a TARDBP-spliced cryptic exon present in ATG4B (autophagy related 4B cysteine peptidase) mRNA. Results of these analyses demonstrated that the loss of this TARDBP function in spinal cord, brainstem, motor cortex, and occipital cortex differentiated ALS from controls (area under the curve of receiver operating characteristic: 0.85). Significant correlations were also observed between cryptic exon levels, age, disease duration, and aberrant mRNA levels. To test if TARDBP function in splicing is relevant in ATG4B major function (autophagy) we downregulated TARDBP expression in human neural tissue and in HeLa cells, demonstrating that TARDBP is required for maintaining the expression of ATG4B. Further, ATG4B overexpression alone is sufficient to completely prevent the increase of SQSTM1 induced by TARDBP downregulation in human neural tissue cells and in cell lines. In conclusion, the present findings demonstrate abnormal alternative splicing of ATG4B transcripts in ALS neural tissue in agreement with TARDBP loss of function, leading to impaired autophagy. ABBREVIATIONS: ALS: amyotrophic lateral sclerosis; ATG4B: autophagy related 4B cysteine peptidase; AUC: area under the curve; FTLD: frontotemporal lobar degeneration; iPSC: induced pluripotent stem cells; ROC: receiver operating characteristic; TARDBP: TAR DNA binding protein; RT-qPCR: quantitative RT-PCR.
Current Opinion in Neurology · 2005 · 62 citations
Amyotrophic lateral sclerosis: recent advances and future therapies
AbstractPURPOSE OF REVIEW: Amyotrophic lateral sclerosis is a rare but fatal motoneuron disorder. Despite intensive research riluzole remains the only available therapy, with only marginal effects on survival. Here we review some of the recent advances in the search for a disease-modifying therapy for amyotrophic lateral sclerosis. RECENT FINDINGS: A number of established agents have recently been re-investigated for their potential as neuroprotective agents, including beta-lactam antibiotics and minocycline. Progress has also been made in exploiting growth factors for the treatment of amyotrophic lateral sclerosis, partly due to advances in developing effective delivery systems to the central nervous system. A number of new therapies have also been identified, including a novel class of compounds, heat-shock protein co-inducers, which upregulate cell stress responses thereby mediating neuroprotection. Non-drug-based therapies are also under development, with progress in gene-silencing and stem cell therapies. SUMMARY: In the past few years, significant advances have been made in both our understanding of amyotrophic lateral sclerosis pathogenesis and the development of new therapeutic approaches. However, caution must be exercised in view of the long-standing failure to successfully transfer therapeutic compounds to the clinic. A deeper awareness in the research community of the need for clinically relevant preclinical studies, coupled with a better understanding of the issues surrounding clinical trial design for amyotrophic lateral sclerosis, offers hope that the growing list of validated preclinical therapeutics can finally yield an effective disease-modifying treatment.
Expert Opinion on Investigational Drugs · 2017 · 33 citations
Drugs in clinical development for the treatment of amyotrophic lateral sclerosis
AbstractINTRODUCTION: Amyotrophic Lateral Sclerosis (ALS) is a fatal motor neuron progressive disorder for which no treatment exists to date. However, there are other investigational drugs and therapies currently under clinical development may offer hope in the near future. Areas covered: We have reviewed all the ALS ongoing clinical trials (until November 2016) and collected in Clinicaltrials.gov or EudraCT. We have described them in a comprehensive way and have grouped them in the following sections: biomarkers, biological therapies, cell therapy, drug repurposing and new drugs. Expert opinion: Despite multiple obstacles that explain the absence of effective drugs for the treatment of ALS, joint efforts among patient's associations, public and private sectors have fueled innovative research in this field, resulting in several compounds that are in the late stages of clinical trials. Drug repositioning is also playing an important role, having achieved the approval of some orphan drug applications, in late phases of clinical development. Endaravone has been recently approved in Japan and is pending in USA.
Oxford University Press eBooks · 2017 · 29 citations
Amyotrophic Lateral Sclerosis
AbstractRecent advances in sequencing technologies have dramatically expanded the number of genes associated with amyotrophic lateral sclerosis, including rare but highly penetrant causative mutations as well as common risk alleles. This chapter discusses these gene discoveries and how they have implicated a diverse array of biological pathways essential for motor neuron health and have begun to inform our understanding of ALS pathogenesis as a heterogeneous and multistep process. Insights from these discoveries are leading to a new generation of targeted therapies directed at specific genes and are poised to inform how patients with amyotrophic lateral sclerosis are evaluated and treated in the clinic.
In a search for efficient treatment for amyotrophic lateral sclerosis: Old drugs for new approaches
AbstractRecent progress in understanding the pathological changes in the nervous system and in certain other body systems (e.g., immune system) that lead to the development and progression of amyotrophic lateral sclerosis (ALS) revealed a number of molecular and cellular processes that can potentially be used as therapeutic targets. Many of these processes are compromised not only in ALS but also in other diseases and a repertoire of drugs able to restore, at least partially, their functionality has been developed. In this review, we briefly describe current approaches to the repurposing of such "old" drugs for treatment of patients with ALS.
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.
