DeCure's autonomous Metabolic AI scientist is researching a drug-repurposing hypothesis for thyroid dyshormonogenesis 1 — 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 moduleThyroid dyshormonogenesis 1 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 thyroid dyshormonogenesis 1 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
In a cohort of 62 patients with Down’s syndrome and hypothyroidism, median TSH at first visit was 10.40 µIU/mL and median free T4 was 1.18 ng/dL. Only nine of 54 patients had a normal-sized thyroid gland; median total thyroid volume was 0.89 mL, and volume was negatively correlated with L-thyroxine dose at last visit. The authors concluded that thyroid dysgenesis is prevalent in this population, an association they said had not been reported before.
A Brazilian study screened 63 children with confirmed thyroid dysgenesis for mutations in PAX-8, NKX2-5, TSH-R, and HES-1 and found no mutations in any of these candidate genes. The most common subtype was an in situ thyroid gland (71.1%), followed by ectopia (78% — likely a typo in the abstract), hypoplasia (9.6%), hemiagenesis (6.0%), and agenesis (5.5%). The highest neonatal screening TSH levels were in the agenesis group. The authors concluded that thyroid dysgenesis is probably a polygenic disorder and that epigenetic factors may be involved.
Thyroglobulin gene mutations cause a rare form of dyshormonogenesis with an estimated incidence of 1 in 100,000 newborns. One hundred seventeen deleterious mutations have been identified, including 57 missense, 23 nonsense, and 19 splice site mutations. The mutations p.R277*, p.R1511*, p.A2215D, p.R2223H, and p.R2317* are most frequent in Caucasians, while c.274+2T>G, p.C1058R, p.C1245R, and p.C1977S are most common in Asians. Inheritance is autosomal recessive. The abstract notes that new sequencing technology will allow faster identification of mutations and detection of multiple mutations in the same or different thyroid genes.
A review of murine knockout models states that most knowledge of thyroid morphogenesis comes from gene-targeting experiments in mice, and that several genes involved in thyroid organogenesis have been identified. A single case report describes a patient with Graves’ disease whose free T3 paradoxically rose during propylthiouracil treatment despite low free T4; thyroid tissue from that patient contained very high levels of type 1 and type 2 deiodinase, attributed to high levels of thyroid stimulating antibodies. What remains missing for thyroid dyshormonogenesis 1 specifically is a clear genetic or molecular target for drug repurposing: the candidate gene screens have been negative, the known mutations are rare and recessive, and the animal models have not yet pointed to a druggable pathway in the common sporadic form. Funding for large-scale sequencing in well-phenotyped cohorts, and trial designs that stratify patients by genetic subtype rather than by clinical diagnosis alone, are still lacking.
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 Clinical Research in Pediatric Endocrinology · 2013 · 62 citations · open access
Profile of Hypothyroidism in Down’s Syndrome
AbstractOBJECTIVE: Although the association between Down's syndrome (DS) and thyroid dysfunction is well recognized, the cause of this condition is not known. METHODS: Hospital records of patients with DS and hypothyroidism referred to our clinic were retrospectively reviewed. Initial thyroid hormone and thyrotropin (TSH) levels, age at admission, initial anthropometric measurements, age at the beginning of therapy, initial L-thyroxine (L-T4) doses, time to normalization of the thyroid function tests, and L-T4 dose at last visit were recorded. Thyroid ultrasound imaging was used to measure the size of the gland. Descriptive data were expressed as mean±SD values. Skewed data were shown as median and interquartile ranges (IQR). RESULTS: There were 62 patients with DS (32 male and 30 female). Median TSH level at the first visit was 10.40 (19.4) µIU/mL and median free T4 level was 1.18 (0.43) ng/dL. There was no statistical difference in terms of age, hormone and antibody levels, thyroid volume and L-T4 doses between boys and girls. Thyroid volumes of 54 patients were measured. Only nine of these patients had a normal-sized thyroid gland. Median total thyroid volume was 0.89 (2.07) mL. Thyroid volume was negatively correlated to L-T4 dose at last visit (p=0.006, r=-0.387). CONCLUSIONS: We found a high prevalence of thyroid dysgenesis in patients with DS and hypothyroidism. This association has not been reported before. Further studies investigating the thyroid gland size in these patients need to be performed to confirm the results.
Murine Models for the Study of Thyroid Gland Development
AbstractGene targeting technology has allowed the generation of mouse mutants which lack specific genes. These mice represent a valuable tool for identifying the in vivo functions of proteins and for dissecting the pathways that control the development and differentiation of the numerous structures of the body. What we know about thyroid morphogenesis is largely due to studies on murine models generated in gene-targeting experiments. Although several points remain to be elucidated, a number of genes involved in thyroid organogenesis have been identified in recent years. In addition, this information has greatly improved our knowledge of the pathogenetic mechanisms of thyroid dysgenesis in humans. This review summarizes the complex processes leading to thyroid development mostly by describing the phenotype of currently available knockout animals.
European Journal of Endocrinology · 2003 · 17 citations
Thyroid over-expression of type 1 and type 2 deiodinase may account for the syndrome of low thyroxine and increasing triiodothyronine during propylthiouracil treatment
AbstractAlthough propylthiouracil inhibits type 1 deiodinase, leading to a more rapid fall in triiodothyronine (T(3)) than thyroxine (T(4)) levels in patients treated for hyperthyroidism, we report a patient with Graves' disease whose free T(3) paradoxically rose during such treatment, despite low free T(4) levels and increasing doses of propylthiouracil. A similar response has previously been associated with high levels of thyroid stimulating antibodies, but it has been unclear why there should be a dichotomy in the circulating thyroid hormone profile. Thyroid tIssue from our patient contained very high levels of type 1 and, especially, type 2 deiodinase, in contrast to other patients treated with Graves' disease, which were most likely secondary to high levels of thyroid stimulating antibodies. This unusual response to propylthiouracil is important to recognise therapeutically, and represents a further situation in which abnormal expression of deiodinase enzymes has clinical significance.
Archives of Endocrinology and Metabolism · 2018 · 15 citations · open access
Mutation screening in the genes PAX-8, NKX2-5, TSH-R, HES-1 in cohort of 63 Brazilian children with thyroid dysgenesis
AbstractOBJECTIVE: To evaluate the candidate genes PAX-8, NKX2-5, TSH-R and HES-1 in 63 confirmed cases of thyroid dysgenesis. SUBJECTS AND METHODS: Characterization of patients with congenital hypothyroidism into specific subtypes of thyroid dysgenesis with hormone levels (TT4 and TSH), thyroid ultrasound and scintigraphy. DNA was extracted from peripheral blood leukocytes and the genetic analysis was realized by investigating the presence of mutations in the transcription factor genes involved in thyroid development. RESULTS: No mutations were detected in any of the candidate genes. In situ thyroid gland represented 71.1% of all cases of permanent primary congenital hypothyroidism, followed by hypoplasia (9.6%), ectopia (78%), hemiagenesis (6.0%) and agenesis (5.5%). The highest neonatal screening TSH levels were in the agenesis group (p < 0.001). CONCLUSIONS: Thyroid dysgenesis is possibly a polygenic disorder and epigenetic factors could to be implicated in these pathogeneses.
Open Journal of Biological Sciences · 2016 · 6 citations · open access
Advances and Perspectives in Genetics of Congenital Thyroid Disorders Associated with Thyroglobulin Gene Mutations
AbstractDyshormonogenesis due to thyroglobulin (TG) gene mutations is a rare cause of congenital hypothyroidism with an estimated incidence of approximately 1 in 100,000 newborns. The TG gene is organized in 48 exons, spanning over 270 kb on human chromosome 8q24. The human TG mRNA is 8.5 Kb long and the preprotein monomer is composed of a 19 amino acids signal peptide followed by a 2749 residues polypeptide. Until now, one hundred seventeen deleterious mutations in the human TG gene have been identified and characterized, originating structural changes in the protein that alter the normal protein folding, assembly and biosynthesis of thyroid hormones: 19 splice site mutations, 23 nonsense mutations, 57 missense mutations, 13 deletions (9 single nucleotide deletions, 2 multiple nucleotide deletions and 2 involving a large number of nucleotides), 4 single nucleotide insertions or duplication and 1 imperfect DNA inversion. The p.R277*, p.R1511*, p.A2215D, p.R2223H and p.R2317* mutations are the most frequently identified TG mutations in Caucasian population, whereas c.274+2T>G, p.C1058R, p.C1245R and p.C1977S are the most common mutations in Asian population. TG mutations are inherited in an autosomal recessive manner and affected individuals are either homozygous or compound heterozygous for gene mutations and the parents should be carriers of one the TG mutation. New approaches including the use of new sequencing technology, will eclipse traditional methods of detecting mutations and will allow the quick identification of mutations in remote regions as well as the detection of coexistence of multiple mutations in the same gene or in different thyroid genes.
Congenital Hypothyroidism due to Thyroid Dysgenesis: From Epidemiology to Molecular Mechanisms
AbstractThyroid dyshormonogenesis results from a defect in any one of the steps involved in the biosynthesis of thyroid hormone, from the transport of iodine across the apical membrane to its intracellular recycling from monoand di-iodotyrosines. These defects are inherited as autosomal recessive traits and occur at higher frequency in consanguineous families. In population-based studies, mutations inactivating the thyroperoxidase gene (TPO)1-4 and the dual oxidase-like domains 2 gene (DUOX2; see www.endocrine-abstracts.org/ea/ 0020/ea0020s14.2.htm) seem to be the most commonly involved.
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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