DeCure for Obesity due to congenital leptin deficiency
DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for obesity due to congenital leptin deficiency — screening already-approved drugs against its 2-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleObesity due to congenital leptin deficiency maps to a 2-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 obesity due to congenital leptin deficiency 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
leptin (LEP) — LEP 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 1AX8 · 2.4 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
In a cohort of 300 subjects with hyperphagia and severe early-onset obesity, including 90 probands from consanguineous families, 8 individuals (3%) carried nonsense or missense mutations in the leptin-receptor gene (LEPR). Seven were homozygotes, one was a compound heterozygote, and all missense mutations impaired receptor signalling. Affected subjects showed hyperphagia, severe obesity, altered immune function, and delayed puberty due to hypogonadotropic hypogonadism. Their clinical features were less severe than those seen in congenital leptin deficiency. Serum leptin levels were within the range predicted by elevated fat mass, so leptin concentration cannot serve as a marker for receptor deficiency. The authors concluded that congenital leptin-receptor deficiency should be considered in any child with hyperphagia and severe obesity without developmental delay or dysmorphism.
For congenital leptin deficiency itself—mutations in the LEP gene rather than LEPR—exogenous leptin administration has been reported to partially reverse some phenotypes, including disrupted energy homeostasis, hormonal disorders, and abnormal immune responses. A review of cases noted that some of these features can be partially reversed by leptin replacement therapy. The same review also mentioned possible treatment strategies such as leptin sensitizers and anti-inflammatory drugs, but provided no trial data or response rates for these approaches.
No randomised controlled trial data were presented in these abstracts for leptin replacement therapy in leptin-receptor deficiency. The 2007 study of LEPR mutations did not test any treatment. The 2021 review focused on congenital leptin deficiency, not receptor deficiency, and did not report survival or response rates. The 2020 mini-review repeated that obesity due to a single-gene mutation is not the most common cause of obesity, and stressed the importance of diagnosis for quality of life and life expectancy, but gave no new clinical results.
What is still missing: adequately powered trials of leptin replacement therapy specifically in leptin-receptor-deficient patients, validated biomarkers to identify receptor versus ligand deficiency without genetic sequencing, and any long-term outcome data on weight, metabolic complications, or survival for either condition beyond small case series. Patient stratification by mutation type and functional impact on receptor signalling has not been systematically linked to treatment response.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
New England Journal of Medicine · 2007 · 733 citations · open access
Clinical and Molecular Genetic Spectrum of Congenital Deficiency of the Leptin Receptor
AbstractBACKGROUND: A single family has been described in which obesity results from a mutation in the leptin-receptor gene (LEPR), but the prevalence of such mutations in severe, early-onset obesity has not been systematically examined. METHODS: We sequenced LEPR in 300 subjects with hyperphagia and severe early-onset obesity, including 90 probands from consanguineous families, and investigated the extent to which mutations cosegregated with obesity and affected receptor function. We evaluated metabolic, endocrine, and immune function in probands and affected relatives. RESULTS: Of the 300 subjects, 8 (3%) had nonsense or missense LEPR mutations--7 were homozygotes, and 1 was a compound heterozygote. All missense mutations resulted in impaired receptor signaling. Affected subjects were characterized by hyperphagia, severe obesity, alterations in immune function, and delayed puberty due to hypogonadotropic hypogonadism. Serum leptin levels were within the range predicted by the elevated fat mass in these subjects. Their clinical features were less severe than those of subjects with congenital leptin deficiency. CONCLUSIONS: The prevalence of pathogenic LEPR mutations in a cohort of subjects with severe, early-onset obesity was 3%. Circulating levels of leptin were not disproportionately elevated, suggesting that serum leptin cannot be used as a marker for leptin-receptor deficiency. Congenital leptin-receptor deficiency should be considered in the differential diagnosis in any child with hyperphagia and severe obesity in the absence of developmental delay or dysmorphism.
Hormone Research in Paediatrics · 2007 · 37 citations
Insights from the Genetics of Severe Childhood Obesity
AbstractBACKGROUND: The identification and characterization of monogenic obesity syndromes have improved our understanding of the inherited component of severe obesity and have had undoubted medical benefits. This knowledge has also helped to dispel the notion that obesity represents an individual defect in behaviour with no biological basis. CONCLUSIONS: For individuals at highest risk for complications of severe obesity, such findings provide a starting point for providing more rational mechanism-based therapies, as has successfully been achieved for congenital leptin deficiency.
Frontiers in Endocrinology · 2021 · 35 citations · open access
When Leptin Is Not There: A Review of What Nonsyndromic Monogenic Obesity Cases Tell Us and the Benefits of Exogenous Leptin
AbstractObesity is a pandemic condition of complex etiology, resulting from the increasing exposition to obesogenic environmental factors combined with genetic susceptibility. In the past two decades, advances in genetic research identified variants of the leptin-melanocortin pathway coding for genes, which are related to the potentiation of satiety and hunger, immune system, and fertility. Here, we review cases of congenital leptin deficiency and the possible beneficial effects of leptin replacement therapy. In summary, the cases presented here show clinical phenotypes of disrupted bodily energy homeostasis, biochemical and hormonal disorders, and abnormal immune response. Some phenotypes can be partially reversed by exogenous administration of leptin. With this review, we aim to contribute to the understanding of leptin gene mutations as targets for obesity diagnostics and treatment strategies.
Greater South Information System · 2020 · 0 citations · open access
Leptin Gene and Receptor Mutations and its Association with Obesity and Overweight: A Mini Review
AbstractOverweight and obesity are considered a global epidemic in the twenty first century, it is a multifactorial disease due, in part, to a genetic component. The most common genetic alteration is one that affects the neuroregulatory pathway of Leptin, a fundamental hormone for appetite regulation. Mutations that affect the LEP gene are present in the different exons of this gene and have been described for many years. Although obesity due to a genetic mutation is not the most common cause, its diagnosis is of paramount importance since it can affect the quality of life and life expectancy of the patients suffering from this condition. The purpose of this mini review is to present up-to-date evidence regarding Leptin gene mutations, possible treatment strategies such as Leptin Replacement Therapy (LRT), leptin sensitizers and anti-inflammatory drugs, and discuss the importance of stablishing health policies worldwide to achieve a timely and successful approach to this disease.
Greater South Information System · 2020 · 0 citations · open access
Leptin Gene and Receptor Mutations and its Association with Obesity and Overweight: A Mini Review
AbstractOverweight and obesity are considered a global epidemic in the twenty first century, it is a multifactorial disease due, in part, to a genetic component. The most common genetic alteration is one that affects the neuroregulatory pathway of Leptin, a fundamental hormone for appetite regulation. Mutations that affect the LEP gene are present in the different exons of this gene and have been described for many years. Although obesity due to a genetic mutation is not the most common cause, its diagnosis is of paramount importance since it can affect the quality of life and life expectancy of the patients suffering from this condition. The purpose of this mini review is to present up-to-date evidence regarding Leptin gene mutations, possible treatment strategies such as Leptin Replacement Therapy (LRT), leptin sensitizers and anti-inflammatory drugs, and discuss the importance of stablishing health policies worldwide to achieve a timely and successful approach to this disease.
Journal of Endocrinological Science · 2020 · 0 citations · open access
Leptin Gene and Receptor Mutations and its Association with Obesity and Overweight: A Mini Review
AbstractOverweight and obesity are considered a global epidemic in the twenty first century, it is a multifactorial disease due, in part, to a genetic component. The most common genetic alteration is one that affects the neuroregulatory pathway of Leptin, a fundamental hormone for appetite regulation. Mutations that affect the LEP gene are present in the different exons of this gene and have been described for many years. Although obesity due to a genetic mutation is not the most common cause, its diagnosis is of paramount importance since it can affect the quality of life and life expectancy of the patients suffering from this condition. The purpose of this mini review is to present up-to-date evidence regarding Leptin gene mutations, possible treatment strategies such as Leptin Replacement Therapy (LRT), leptin sensitizers and anti-inflammatory drugs, and discuss the importance of stablishing health policies worldwide to achieve a timely and successful approach to this disease.
Oxford University Press eBooks · 2009 · 0 citations
Human Leptin and Leptin Receptor Deficiency
AbstractSeveral monogenic forms of human obesity have now been identified by searching for mutations homologous to those causing obesity in mice. Although such monogenic obesity syndromes are rare, the characterization of these disorders has provided insights into the role of leptin in human physiology. Importantly, administration of recombinant human leptin in leptin deficiency represents the first rational, mechanistically based therapy for obesity and has the potential to provide immense clinical benefits for the patients concerned.
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.
