RARE DISEASE
Congenital isolated hyperinsulinism
Congenital isolated hyperinsulinism
Congenital isolated hyperinsulinism
Synonyms: PHHI, Persistent hyperinsulinemic hypoglycemia of infancy
Synonyms: PHHI, Persistent hyperinsulinemic hypoglycemia of infancy
Synonyms: PHHI, Persistent hyperinsulinemic hypoglycemia of infancy
Drug discovery
19
drugs
With orphan designations
Overview
Congenital isolated hyperinsulinism (CHI) is a rare genetic disorder causing persistent hypoglycemia due to dysregulated insulin secretion from pancreatic β-cells. It is the most common cause of severe, recurrent hypoglycemia in neonates and infants, with up to 50% risk of permanent neurocognitive impairment if untreated. Genetic mutations (e.g., ABCC8, KCNJ11) disrupt insulin regulation, leading to excessive secretion independent of blood glucose levels [1][4][7].
Burden
Up to 25–50% risk of brain injury without prompt treatment [4][9].
High morbidity: Long-term neurodevelopmental delays, diabetes post-pancreatectomy, and pancreatic exocrine dysfunction in surgically treated cases [9][16].
Resource-intensive care: Requires frequent glucose monitoring, specialized centers, and multidisciplinary management [1][7].
Therapies
First-line: Diazoxide (KATP channel agonist) for diazoxide-responsive cases [4][16].
Second-line: Somatostatin analogs (octreotide, lanreotide) or glucagon for unresponsive cases; surgery (focal lesionectomy or subtotal pancreatectomy) for focal/diffuse forms [3][8][16].
Emergency: IV dextrose and glucagon to stabilize acute hypoglycemia [3][6].
Categories: rare endocrine diseases, rare genetic diseases, rare inborn errors of metabolism
Research Papers
702 drug discovery papers about Congenital isolated hyperinsulinism, with 1 first-in-class and 20 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
702 drug discovery papers about Congenital isolated hyperinsulinism, with 1 first-in-class and 20 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
proteins
2026-05-13 | Somatostatin and Its Analogues as Second-Line Treatments in Non-Neoplastic Conditions.
Somatostatin is a potent endocrine regulator and neurotransmitter, exerting predominantly inhibitory effects in different tissues of the body, via G-protein coupled receptors. Five such specific receptors have been identified, with different effects and tissue distribution. The multifaceted actions and effects of somatostatin make it useful as a potential therapeutical means in various pathologies; however, in clinical practice, somatostatin analogues, namely octreotide, lanreotide and pasireotide, are commonly used instead, due to their increased half-life and increased receptor selectivity, with pasireotide showing a more extensive receptor binding profile and high affinity for somatotastin receptor (SSTR) 5, which may prove effective in cases of resistance to first-generation analogues. Apart from their many uses in neoplastic pathologies, somatostatin analogues represent viable treatment choices in some ocular pathologies, congenital hyperinsulinism, gastrointestinal bleedings and portal hypertension, acute pancreatitis, and dumping syndrome. They have also been used in some cases, with varying degrees of success, in patients with post-surgical gastrointestinal and lymphatic fistulas, refractory chronic diarrhoea and polycystic kidney disease; many applications in paediatric patients have also been documented. The aim of this review is to present the applications of somatostatin and its analogues as alternative or second-line therapies, along with insights into their effectiveness and future potential.
2025-11-07 | Advances in Pharmacotherapy for Congenital Hyperinsulinism.
Congenital hyperinsulinism (CHI) is a rare disorder causing persistent hypoglycaemia in infants due to excessive insulin secretion from pancreatic β-cells. It has genetic causes, primarily mutations in ATP-sensitive potassium channel genes (ABCC8, KCNJ11). CHI manifests in three forms-focal, diffuse, and atypical-distinguished by histology and genetics, influencing treatment strategies. Early diagnosis and tailored management are vital to prevent neurological damage. While transient CHI resolves spontaneously, permanent CHI often requires complex medical and/or surgical intervention. Despite advances, long-term neurodisability remains high, highlighting increased need to improve monitoring as well as better therapies with lesser side effects. Acute treatment aims to rapidly normalize glucose levels and long-term treatments include diazoxide (KATP channel agonist) to suppress insulin secretion, though its effectiveness depends on genetic mutation type. Other therapies include somatostatin analogues. Newer emerging therapies include novel glucagon analogues, monoclonal antibodies targeting insulin receptors, GLP-1 receptor antagonist, and selective somatostatin receptor agonist, currently under clinical trials. Along with medical treatment, children may require additional feeding support with carbohydrate supplementation using glucose polymers and special formulas. Continuous glucose monitoring aids detection but has limitations. Surgery is preferred for focal lesions to potentially cure CHI.
2025-10-13 | Treatment of Congenital Hyperinsulinism With a Novel, Long-acting Glucagon Analogue.
Congenital hyperinsulinism (HI) is a disorder of insulin regulation that results in hypoketotic hypoglycemia and is associated with a high risk of neurological sequalae from hypoglycemia-induced brain damage. There is only 1 Food and Drug Administration-approved drug for the treatment of HI, and up to 60% of patients do not respond to it; thus, there is a significant unmet need for new treatments. We report a case of a 29-year-old female with HI due to an activating glucokinase pathogenic variant, who was diagnosed as an adult and continued to have persistent hypoglycemia despite standard-of-care therapy. The patient was enrolled in the phase II clinical trial evaluating efpegerglucagon, a novel long-acting glucagon analog. She has continued treatment with efpegerglucagon through a single-patient Investigational New Drug Expanded Access Program and has demonstrated improved glycemic control throughout 10 months of treatment. Efpegerglucagon may be a viable treatment option or adjunct therapy for patients with HI who are unresponsive or partially responsive to currently available therapies.
2025-04-29 | Necrolytic migratory erythema following prolonged continuous subcutaneous dasiglucagon administration: a rare dermatologic adverse event.
Clinical management of congenital hyperinsulinism (CHI) remains a significant challenge due to its complex pathophysiology and the limitations of available therapies. Dasiglucagon, a synthetic glucagon analog, represents a novel approach to managing CHI, particularly in patients where conventional therapies fail. This report discusses a rare case of prolonged continuous subcutaneous dasiglucagon use in a neonate with CHI. Despite initial stabilization of glycemic levels, the patient developed necrolytic migratory erythema (NME), a rare dermatological condition associated with hyperglucagonemia, during dasiglucagon therapy. The patient further experienced severe malnutrition, zinc and amino acid deficiencies, and sepsis. Following the discontinuation of dasiglucagon therapy due to these severe side effects, the patient's skin and nutritional status improved markedly. However, glycemic control required subtotal pancreatectomy. This report underscores the potential of dasiglucagon in CHI management but highlights the importance of close monitoring during prolonged therapy. NME, a rare but severe condition, appears to be associated with prolonged continuous subcutaneous dasiglucagon therapy, requiring early recognition and intervention. Close monitoring is essential during prolonged continuous subcutaneous dasiglucagon therapy to detect potential adverse effects, focusing on dermatological conditions, nutrient deficiencies or signs of infection. Multidisciplinary care is crucial to manage CHI with dasiglucagon, ensuring a comprehensive approach that addresses both glycemic control and potential side effects.
2023-03-29 | Hyperinsulinism Gateway Between Diabetes and Cancer: New Roles for Bifunctional Antidiabetic - Anticancer Active Somatostatins, IGF - 1 Inhibitors and Insulin Sensitizers
Hyperinsulinism refers to a condition of abnormally high concentration of circulating insulin in the body commonly seen in obese and type 2 diabetic patients due to insulin resistance. Elevated circulating insulin is the main factor linking obesity, diabetes and cancer and an important mechanism of cancer therapeutic resistance and failure. The insulin receptor subfamily which is made up of the insulin receptor (IR), the type 1 IGF receptor (IGF-1) which binds insulin-like growth factors I and II, and the orphan insulin receptor-related receptor (IRRR) have been identified and linked to the process of carcinogenesis, as cancer cells require insulin for growth. IR receptors are overexpressed in various cancers and insulin activates growth mostly through these receptors and their interplays through mainly the PI3K/AKT/mTOR, MAPK and RAS signal transduction pathways. Estrogens and androgens synergistic effects worsen hyperinsulinism and accelerates its carcinogenesis properties while progesterone and Sex Hormone Binding Globulins exert modulatory effects. This review examined the various factor interplays in hyperinsulinism that links diabetes with cancer and the biomarkers involved. It equally identified the potentials and therapeutic roles for Somatostatins, IGF – 1 inhibitors and Insulin sensitizing antidiabetics in preventing and reversing the cancer linked trends.
small molecules
2026-08-06 | Ghrelin and relamorelin counteract hypoglycemia in mice engrafted with congenital hyperinsulinism stem cell-derived islets.
KATP-channel-related hyperinsulinism (KATPHI) is a rare genetic disorder of the pancreatic beta cells, manifesting as life-threatening hypoglycemia in neonates due to excessive insulin secretion. Management of the severe diffuse form of KATPHI currently lacks treatment options, as the first-line therapy octreotide is often insufficiently effective, necessitating radical pancreatectomy in many patients. In this study, we differentiated stem cells carrying the KATPHI-causing mutation KCNJ11-/- to stem cell-derived islets (SC-islets) to develop new pharmaceutical therapies for KATPHI. We tested seven candidate molecules in vitro and the most effective ones in vivo in immunocompromised mice that were transplanted with the human KCNJ11-/- SC-islets. KCNJ11 -/- SC-islets inappropriately secreted 3.9 times more insulin in low glucose than KCNJ11+/+ controls. Transplanted KCNJ11-/- SC-islets caused persistent hyperinsulinemia and hypoglycemia to the recipient mice. We tested acyl-ghrelin identified in our in vitro experiments and its long-acting analogue relamorelin in these mice. Acyl-ghrelin and relamorelin alone increased fasting blood glucose. Combining relamorelin with octreotide increased blood glucose synergistically, ie, more than the sum of each drug alone, reverting hypoglycemia to normoglycemia while reducing the excessive insulin secretion. We show that ghrelin-receptor agonists have acute anti-hypoglycemic effects in a humanized mouse model of KATPHI, especially when combined with octreotide. Relamorelin has been tested in >650 diabetic adults with little side effects, leading us to propose relamorelin-octreotide combination for further development as a therapeutic candidate for severe KATPHI patients.
2026-07-23 | Indocyanine green fluorescence cholangiography enables safe laparoscopic near-total pancreatectomy for diffuse congenital hyperinsulinism.
Laparoscopic near-total pancreatectomy (NTP) for diffuse congenital hyperinsulinism (CHI) may reduce morbidity compared with open surgery. However, it is technically limited by uncertainty regarding the intrapancreatic common bile duct (CBD) course, risking bile duct injury or inadequate resection. We evaluated whether near-infrared indocyanine green fluorescence cholangiography (NIR ICG FC) improves intraoperative identification of the intrapancreatic CBD and supports laparoscopic NTP for medically-refractory diffuse CHI. We performed a retrospective single-centre review of consecutive infants undergoing laparoscopic NTP with NIR ICG FC for diffuse CHI (2021-2025). Intravenous ICG (0.5 mg/kg) was administered 10-15 h preoperatively. Outcomes included feasibility of CBD visualisation, extent of resection, biliary complications, postoperative recovery, persistence of hyperinsulinism and medium-term endocrine/exocrine function. Five infants underwent laparoscopic NTP at a median age of 3 months (range 2-6). The intrapancreatic CBD was visualised in all cases, enabling a consistent 95% resection without conversion to open surgery. There were no bile duct injuries. Enteral feeding commenced at a median of 3 postoperative days (range 2-4). One patient developed transient obstructive jaundice on postoperative day 13 that resolved with conservative management. At a median follow-up of 30 months (range 20-51), three infants had residual hyperinsulinism (managed by feeding strategies in two and medication in one), and one had exocrine insufficiency requiring enzyme supplementation; no child had diabetes at latest follow up. NIR ICG fluorescence cholangiography provides real time delineation of the intrapancreatic CBD and can support a safe minimally invasive approach to near-total pancreatectomy for diffuse CHI.
2026-07-23 | Indocyanine green fluorescence-guided intraoperative biliary mapping during pediatric laparoscopic duodenum-preserving pancreatic head resection: a standardized operative approach.
Laparoscopic duodenum-preserving pancreatic head resection (LDPPHR) for focal congenital hyperinsulinism (CHI) poses a specific intraoperative challenge: reliable, continuous identification of the intrapancreatic common bile duct (CBD) in an anatomically diminutive, tactile-feedback-free operative field. We describe a standardized indocyanine green (ICG) fluorescence-guided biliary visualization workflow for pediatric LDPPHR and report its initial implementation experience. In this retrospective case series, we summarized the application of this standardized workflow in seven consecutive children with focal CHI who underwent ICG fluorescence-guided LDPPHR at Beijing Children's Hospital from February 2025 to March 2026. The workflow comprised seven sequential steps: exposure and preparation, first-dose ICG administration, initial biliary mapping, boundary-guided pancreatic head dissection, repeated fluorescence assessment and reinjection when required, post-resection perfusion assessment, and reconstruction with final intraoperative checking. The workflow was completed as planned in all seven cases, with full workflow adherence in 7/7 procedures. Continuous visualization of the intrapancreatic CBD under near-infrared (NIR) illumination was achieved in 7/7 procedures. Repeated white-light/NIR correlation was feasible throughout dissection in all cases. The fluorescence-guided workflow was implemented without intraoperative abandonment. No bile leak, clinically relevant postoperative pancreatic fistula (ISGPS 2016 criteria), or duodenal ischemia was observed. Median operative time was 310 min (range 229-570 min). This stepwise ICG biliary visualization workflow was technically feasible and was implemented without biliary adverse events in this initial retrospective case series. As a workflow description with feasibility observations rather than an efficacy study, this report suggests that repeated real-time delineation of the intrapancreatic CBD may facilitate duct-sparing dissection; whether it reduces bile duct injury requires validation in larger comparative studies.
2026-07-15 | Two threats in early life: congenital hyperinsulinemic hypoglycemia and thrombosis.
Congenital persistent hyperinsulinemic hypoglycemia (HH) is a rare disorder that can lead to severe and recurrent hypoglycemic episodes in neonates and infants. Management often requires intensive glucose infusion via central venous catheters (CVCs), which may increase the risk of thrombosis. While case reports suggest thrombosis can occur in HH, the incidence, risk factors, severity, and outcomes remain poorly understood. This study aimed to determine the incidence of thrombosis in children with persistent HH and to evaluate potential risk factors associated with thrombotic complications. A descriptive, retrospective cohort study of patients with persistent HH followed at a university pediatric endocrinology clinic between January 2000 and December 2025. Twenty patients with persistent HH were included. Data on demographics, clinical characteristics, laboratory results, treatment protocols, CVC use, timing and location of thrombosis were collected. Patients who developed thrombosis were compared with those who did not to identify risk factors. Among 20 patients, 55% were male, with a median age at diagnosis of 1 day. A total of 23 CVCs were placed in 15 patients, with a median dwell time of 38 days. Thrombosis occurred in nine patients (45%), including six catheter-related and three catheter-independent intracranial thrombosis. Median age at thrombosis detection was 74 days. Patients who developed thrombosis experienced significantly more hypoglycemic episodes and more days with hypoglycemia (p < 0.05). No association was found between genetic mutations (ABCC8, KCNJ11, etc.) and thrombosis development. All four patients treated with enoxaparin achieved complete resolution without complications. Thrombosis is a frequent and clinically significant complication in persistent HH. Recurrent and severe hypoglycemic episodes are major risk factors. Routine thrombosis screening, particularly in patients with CVCs, may allow early detection and treatment even in asymptomatic cases.
2026-06-10 | Structural basis of insulin receptor antagonism by bivalent site 1-site 2 ligands S961 and Ins-AC-S2.
Congenital hyperinsulinism is a rare genetic disease characterized by overproduction of insulin. One class of potential treatments is insulin receptor antagonists like S961 and Ins-AC-S2, which comprise segments for binding each of the two insulin-binding sites (site 1 and site 2) on the receptor. Notably, S597 - containing the same receptor binding segments as S961 but in the opposite order (site 2-site 1) - is an insulin receptor agonist rather than an antagonist. Using cryo-EM, we show how both S961 and Ins-AC-S2 bind an inactive conformation of the receptor, thereby explaining their antagonism. Furthermore, our structures reveal how agonist vs. antagonist activity is influenced by the order of site 1- and site 2-binding modules in bivalent ligands. Additionally, we show subtle differences between the receptor-binding mechanisms of S961 and Ins-AC-S2, which include displacement or engagement of αCT, and a binding interface between the Ins-AC-S2 insulin and the receptor FnIII-2/insert domains. These structural insights may inform development of next generation insulin receptor antagonists for treatment of congenital hyperinsulinism.
gene therapies
2025-05-18 | Comprehensive clinical and molecular characterization with long-term outcomes in 40 patients with congenital hyperinsulinism.
Congenital hyperinsulinism (CHI) represents the most frequent cause of recurrent hypoglycemia in neonates and infants, stemming from defects in the regulatory pathways of insulin secretion from pancreatic beta cells. This study aims to assess the clinical and genetic characteristics of a CHI cohort and to discuss the complexities involved in managing this heterogeneous disorder. Forty patients (23 girls) with CHI were included in the study. Data on the diagnosis and treatment of CHI were obtained from the medical records. The median age at diagnosis was 1.4 months (range 0.1-30 months). The mean gestational age was 37.8 ± 2.4 weeks, and the birth weight was 1.1 ± 2.0 SDS. The consanguinity ratio was 35.0%. Median glucose, insulin, and C-peptide concentrations at diagnosis were 34.0 mg/dl (IQR 25.2-41.7), 12.4µU/ml (IQR 4.4-27.1), and 1.5 ng/ml (IQR 0.7-3.8), respectively. Molecular genetic diagnosis could be established in 62.5% (n = 25). Pathogenic variants were predominantly identified in the KATP channel genes (17/25, 68%), with the ABCC8 being the most frequent (n = 15; biallelic: 8, monoallelic: 7). KCNJ11 variants were identified in two (5.0%), GLUD1 variants in three (7.5%), and HADH variants in five patients (12.5%). Pancreatectomy was performed in 10 patients, with a mean age at the time of surgery of 3.9 ± 3.2 months. The genetic etiology was identified in all patients who underwent pancreatectomy, all of whom had defects in the KATP channel. ABCC8 variants were detected in nine (biallelic: 5, monoallelic: 4), while a biallelic variant in the KCNJ11 was identified in one case. A molecular genetic diagnosis was identified in approximately two-thirds of our cohort, underscoring the significance of genetic testing in the management of CHI. Ongoing advances in genetic technologies are anticipated to enhance our understanding of the etiopathogenesis of CHI and support the development of more personalized therapeutic strategies. Although the genotype-phenotype correlation remains only partially elucidated, specific genetic variants may provide predictive insights into treatment resistance, thereby informing more targeted treatment approaches.
2025-04-11 | The genetics of low and high birthweight and their relationship with cardiometabolic disease.
Low birthweight infants are at increased risk not only of mortality, but also of type 2 diabetes mellitus and CVD in later life. At the opposite end of the spectrum, high birthweight infants have increased risk of birth complications, such as shoulder dystocia, neonatal hypoglycaemia and obesity, and similarly increased risk of type 2 diabetes mellitus and CVD. However, previous genome-wide association studies (GWAS) of birthweight in the UK Biobank have primarily focused on individuals within the 'normal' range and have excluded individuals with high and low birthweight (<2.5 kg or >4.5 kg). The aim of this study was to investigate genetic variation associated within the tail ends of the birthweight distribution, to: (1) see whether the genetic factors operating in these regions were different from those that explained variation in birthweight within the normal range; (2) explore the genetic correlation between extremes of birthweight and cardiometabolic disease; and (3) investigate whether analysing the full distribution of birthweight values, including the extremes, improved the ability to detect genuine loci in GWAS. We performed case-control GWAS analysis of low (<2.5 kg) and high (>4.5 kg) birthweight in the UK Biobank using REGENIE software (Nlow=20,947; Nhigh=12,715; Ncontrols=207,506) and conducted three continuous GWAS of birthweight, one including the full range of birthweights, one involving a truncated GWAS including only individuals with birthweights between 2.5 and 4.5 kg and a third GWAS that winsorised birthweight values <2.5 kg and >4.5 kg. Additionally, we performed bivariate linkage disequilibrium (LD) score regression to estimate the genetic correlation between low/normal/high birthweight and cardiometabolic traits. Bivariate LD score regression analyses suggested that high birthweight had a mostly similar genetic aetiology to birthweight within the normal range (genetic correlation coefficient [rG]=0.91, 95% CI 0.83, 0.99), whereas there was more evidence for a separate set of genes underlying low birthweight (rG=-0.74, 95% CI 0.66, 0.82). Low birthweight was also significantly positively genetically correlated with most cardiometabolic traits and diseases we examined, whereas high birthweight was mostly positively genetically correlated with adiposity and anthropometric-related traits. The winsorisation strategy performed best in terms of locus detection, with the number of independent genome-wide significant associations (p<5×10-8) increasing from 120 genetic variants at 94 loci in the truncated GWAS to 270 genetic variants at 178 loci, including 27 variants at 25 loci that had not been identified in previous birthweight GWAS. This included a novel low-frequency missense variant in the ABCC8 gene, a gene known to be involved in congenital hyperinsulinism, neonatal diabetes mellitus and MODY, that was estimated to be responsible for a 170 g increase in birthweight amongst carriers. Our results underscore the importance of genetic factors in the genesis of the phenotypic correlation between birthweight and cardiometabolic traits and diseases.
2024-12-25 | Case report: Duplication of the GCK gene is a novel cause of nesidioblastosis: evidence from a case with Silver-Russell syndrome-like phenotype related to chromosome 7.
Silver-Russell syndrome (SRS) is a syndrome characterized by prenatal and postnatal growth retardation, facial features, and body asymmetry. SRS is often complicated with hypoglycemia, whose etiology is unclear. We describe the clinical course of 25-year-old man with hypoglycemia. We diagnosed him with hyperinsulinemic hypoglycemia (HH) and treated him with laparoscopic distal pancreatectomy. Histological examination led to a diagnosis of nesidioblastosis. The juvenile onset of his nesidioblastosis and its slowly progressive course suggested a genetic etiology. Whole-exome sequencing (WES) identified the heterozygous NR0B2 Ala195Ser variant, which alone was unlikely to cause nesidioblastosis because this variant is sometimes detected in the Japanese population. Copy number analysis using WES data suggested duplication in chromosome 7, and subsequent G-banding chromosome analysis confirmed mos dup(7)(p11.2p14). We determined that the patient had SRS-like phenotype based on his clinical features and this duplication. Furthermore, we found that the duplicated region contained the GCK gene, whose gain-of function variants could cause HH. Taken together, the patient's HH may have been caused by duplication of the GCK gene, which could be a novel cause of nesidioblastosis.
2023-07-20 | A novel mutation in the KCNJ11 gene (p.Val36Glu), predisposes to congenital hyperinsulinemia.
The hypoglycemia induced by insulin hypersecretion in congenital hyperinsulinemia (CHI), a rare life-threatening condition can lead to irreversible brain damage in neonates. Inactivating mutations in the genes encoding KATP channel (ABCC8 and KCNJ11) as well as HNF4A, HNF1A, HADH, UCP2, and activating mutations in GLUD1, GCK, and SLC16A1 have been identified as causal. A 3-month-old male infant presenting tonic-clonic seizures and hyperinsulinemia was clinically assessed and subjected to genetic analysis. Besides the index patient, his parents were clinically investigated, and a detailed family history was also recorded. The laboratory investigations and the genetic test results of the parents were compared with the index patient. The biochemical and hormonal profile of the patient confirmed his suffering from CHI and did not respond to diazoxide treatment. The genetic testing revealed that the subject harbored a novel homozygous missense mutation in the KCNJ11 gene, (c.107T>A, p.Val36Glu.). The bioinformatic analysis revealed that valine is highly conserved and predicted that the variant allele (p.Val36Glu) is likely pathogenic and causal for CHI. Parents were heterozygous carriers and did not report any abnormal metabolic profile. Identification of such mutations is critical and likely to change the therapeutic interventions for such patients in the future.
2022-11-08 | Integration of genomic analysis and transcript expression of ABCC8 and KCNJ11 in focal form of congenital hyperinsulinism.
The focal form of CHI is caused by an autosomal recessive pathogenic variant affecting the paternal homologue of genes ABCC8 or KCNJ11 and a second somatic event specifically occurring in the affected islet of Langerhans. The approach of this study was to integrate the genetic changes occurring in pancreatic focal lesions of CHI at the genomic and transcriptional level. Patients receiving therapeutic surgery and with proven ABCC8 or KCNJ11 pathogenic variants were selected and analyzed for loss of heterozygosity (LOH), changes in copy number and uniparental disomy (UPD) on the short am of chromosome 11 by molecular microarray analysis and methylation-specific MLPA. Gene expression was analyzed by RT-PCR and Massive Analysis of cDNA Ends (MACE). Both genes, ABCC8 and KCNJ11, are located in proximity to the Beckwith-Wiedemann (BWS) imprinting control region on chromosome 11p15. Somatic paternal uniparental isodisomy (UPD) at chromosome 11p was identified as second genetic event in focal lesions resulting in LOH and monoallelic expression of the mutated ABCC8/KCNJ11 alleles. Of five patients with samples available for microarray analysis, the breakpoints of UPD on chromosome 11p were different. Samples of two patients were analyzed further for changes in gene expression. Profound downregulation of growth suppressing genes CDKN1 and H19 was detected in focal lesions whereas growth promoting gene ASCL2 and pancreatic transcription factors of the endocrine cell lineage were upregulated. Paternal UPD on the short arm of chromosome 11 appears to be the major second genetic event specifically within focal lesions of CHI but no common breakpoint for UDP can be delineated. We show for the first time upregulation of growth promoting ASCL2 (achaete-scute homolog 2) suggestive of a driving factor in postnatal focal expansion in addition to downregulation of growth suppressing genes CDKN1C and H19.
cell therapies
2026-01-31 | Robotic versus Open Pancreatectomy for Focal Congenital Hyperinsulinism in Infants: A Single-Center Study.
Focal forms of congenital hyperinsulinism (FoCHI) are rare pediatric conditions managed using established metabolic and surgical protocols. To date, the use of a robotic approach for this surgery in children has not been described. We present our initial experience with robotic pancreatectomy, compared with the open approach, for the management of FoCHI. We conducted a retrospective, single-center study involving 25 children who underwent pancreatectomy for CHI between 2011 and 2024. Collected data included patient demographics, surgical details, complications, and post-operative outcomes. The Da Vinci Xi robotic system was used for all robotic procedures. Ten patients underwent robotic pancreatectomy, and 10 underwent open surgery; five children treated laparoscopically were excluded. There were no significant differences between the robotic and open groups in median weight at surgery (7.7 kg vs. 7.3 kg, p = 0.7), median age (7 months vs. 5.9 months, p = 0.48), median operative time (298 minutes vs. 285 minutes, p = 0.5), length of stay (14 days vs. 14.5 days, p = 0.26), or time to postoperative feeding resumption (4 days vs. 4.5 days, p = 0.68). Intraoperatively, 80% of lesions were visible on the pancreatic surface. Two cases of incomplete resection occurred in each group; after multidisciplinary review, both patients in the robotic group required a second procedure. No intraoperative bleeding or conversions were reported. The overall cure rate was 90% in the robotic group and 80% in the open surgery group. This preliminary study suggests that robotic pancreatectomy for congenital hyperinsulinism may be both safe and feasible. The robotic approach provides enhanced visualization of small vessels, enabling limited dissection and safe resection. Given the sample size, further studies are required to confirm these findings.
2025-09-23 | A rare case of congenital hyperinsulinism in a child — when morphology determines treatment tactics
Background. A clinical case of an encapsulated focal form of congenital hyperinsulinism in a young child is presented. A comprehensive examination was performed, including molecular genetic analysis, radionuclide diagnostics (PET-CT with 18F-DOPA) and intraoperative histological examination. During morphological analysis, an encapsulated focus of β-cell adenomatous hyperplasia was verified, located in the head of the pancreas. This finding necessitated an extended organ resection. It is particularly noteworthy that there is a clear fibrous capsule around the pathological focus, which presents a diagnostic challenge in differentiating this pathology from an insulinoma. The postoperative period was uneventful, and stable normoglycemia was achieved, which ultimately confirmed the positive outcome of the treatment and the patient's recovery. The unique feature of this clinical case is that it represents the first recorded example of the focal form of congenital hyperinsulinism, characterized by a well-defined fibrous capsule combined with adenomatosis lacking visible boundaries. As of today, similar observations have not been found in available publications from domestic medical centers, which highlights the rarity of the described case and its significance for expanding knowledge about the spectrum of focal forms of this disease. Analysis of this morphological variant highlights the importance of performing a rapid histological examination of tissues during surgery, which in this clinical case was a key factor in determining the extent of the resection. This decision allowed us not to be limited to just the encapsulated formation and ultimately led to the patient's full recovery. Conclusion. This case demonstrates the importance of a multidisciplinary approach in the diagnosis of rare forms of congenital hyperinsulinism and highlights the need for a thorough histopathological examination of the surgical material to achieve correct clinical decision.
2025-04-14 | Successful Management of an Infant with Congenital Focal Hyperinsulinism with No Apparent Lesion During Surgery.
Congenital hyperinsulinism (HI) is the leading cause of persistent hypoglycemia in infants and children. Focal pancreatic lesions account for 30-40% of cases with congenital HI. With early diagnosis, these patients can be treated by resection of the lesion, making long-term medical care unnecessary. In this case, a 5-day-old newborn boy presented with convulsion due to severe and persistent hypoglycemia at his hospitalization in neonatal intensive care unit. Laboratory studies revealed very low levels of ketone bodies with inappropriately normal insulin levels during hypoglycemia. The patient was unresponsive to diazoxide treatment. The molecular genetic analysis revealed a heterozygous pathogenic variant in the ABCC8 gene. 18F-DOPA-PET/CT scan showed increased uptake of 18F-DOPA consistent with focal lesion at the tail of the pancreas. A focal pancreatectomy operation was performed when he was three months old. Histopathological evaluation confirmed focal endocrine cell hyperplasia. Hypoglycemia did not recur after the operation. CHI patients with ABCC8 / KCNJ11 mutation are not easy to manage with pharmacotheraphy. In the case of an identifiable focal lesion associated with CHI, surgery is the most preferred option. In focal CHI, as in our case, the lesion may not be visually evident and requires a surgeon experienced in CHI.
2025-03-17 | Surgical treatment of congenital hyperinsulinism
Objectives: This study aims to analyze the details of surgical techniques performed in various types of congenital hyperinsulinism (CHI) and review our experience. Patients and methods: Six children with CHI (3 males, 3 females) treated between January 2013 and January 2024 were retrospectively reviewed. Results: Four patients had diffuse type CHI, and two had focal type CHI. The median age at diagnosis was 18.5 days (range, 1 to 54 days). The diagnosis involved 18F-DOPA (18-fluoro-dihydroxyphenylalanine) positron emission tomography (PET)/computed tomography (CT) in two patients and 68Ga-NODAGA-exendin-4 PET/CT in one patient. Mutations in ABCC8/KCNJ1 were detected in five patients. Ultrasonography (n=2), frozen biopsy (n=2), and indocyanine green-guided identification (n=1) were used introperatively. Near total pancreatectomy (95 to 98%) and gastrostomy were performed in four patients with diffuse CHI. Among the two patients with focal lesions, distal pancreatectomy was performed in one patient, and enucleation was performed in the other patient. Conclusion: Knowing the technical details of the surgery, preparation for different surgical approaches to various types of CHI, and being aware of the risky major complications achieve successful outcomes in pancreatic surgery.
2024-12-17 | Congenital hyperinsulinism in the Ukraine: a 10-year national study.
Congenital Hyperinsulinism (CHI) has not been previously studied in Ukraine. We therefore aimed to elucidate the genetics, clinical phenotype, histological subtype, treatment and long-term outcomes of Ukrainian patients with CHI. Forty-one patients with CHI were recruited to the Ukrainian national registry between the years 2014-2023. Genetic testing (n=40), 18F-fluorodihydroxyphenylalanin and 68Ga-DOTANOC PET/CT imaging followed by surgical treatment and subsequent histological analysis (n=19) was performed through international collaboration. Pathogenic variants were identified in 19/22 (86.3%) individuals with persistent CHI (p-CHI) and 8/18 (44.4%) with early remission CHI (er-CHI). Pathogenic variants in the K-ATP channel genes were the only identified genetic cause of p-CHI (ABCC8 (n=17) and KCNJ11 (n=2)) with greater genetic heterogeneity observed in those with er-CHI (ABCC8 (n=3), KMT2D (Kabuki Syndrome, n=1), Beckwith-Wiedemann syndrome (n=2) and INSR (Donohue syndrome (n=2)). Histological analysis performed on 19 children with persistent CHI confirmed focal disease in 14 (73.7%), diffuse disease in two (10.5%) and atypical histology in three (15.8%). After surgery, complete recovery was observed in all 14 with focal disease, while relapse occurred in three patients with diffuse or atypical histology. A genetic diagnosis was achieved for 67.5% (27/40) of the cohort with a higher pick-up rate observed in those with p-CHI. The genetics and imaging studies enabled subtype-targeted treatment with surgical cure achieved in all individuals with focal disease.
other
2023-06-26 | Optimization of a Glucagon-Like Peptide 1 Receptor Antagonist Antibody for Treatment of Hyperinsulinism
Congenital hyperinsulinism (HI) is a genetic disorder in which pancreatic β-cell insulin secretion is excessive and results in hypoglycemia that, without treatment, can cause brain damage or death. Most patients with loss-of-function mutations in ABCC8 and KCNJ11, the genes encoding the β-cell ATP-sensitive potassium channel (KATP), are unresponsive to diazoxide, the only U.S. Food and Drug Administration–approved medical therapy and require pancreatectomy. The glucagon-like peptide 1 receptor (GLP-1R) antagonist exendin-(9-39) is an effective therapeutic agent that inhibits insulin secretion in both HI and acquired hyperinsulinism. Previously, we identified a highly potent antagonist antibody, TB-001-003, which was derived from our synthetic antibody libraries that were designed to target G protein–coupled receptors. Here, we designed a combinatorial variant antibody library to optimize the activity of TB-001-003 against GLP-1R and performed phage display on cells overexpressing GLP-1R. One antagonist, TB-222-023, is more potent than exendin-(9-39), also known as avexitide. TB-222-023 effectively decreased insulin secretion in primary isolated pancreatic islets from a mouse model of hyperinsulinism, Sur1−/− mice, and in islets from an infant with HI, and increased plasma glucose levels and decreased the insulin to glucose ratio in Sur1−/− mice. These findings demonstrate that targeting GLP-1R with an antibody antagonist is an effective and innovative strategy for treatment of hyperinsulinism. Article Highlights Patients with the most common and severe form of diazoxide-unresponsive congenital hyperinsulinism (HI) require a pancreatectomy. Other second-line therapies are limited in their use because of severe side effects and short half-lives. Therefore, there is a critical need for better therapies. Studies with the glucagon-like peptide 1 receptor (GLP-1R) antagonist, avexitide (exendin-(9-39)), have demonstrated that GLP-1R antagonism is effective at lowering insulin secretion and increasing plasma glucose levels. We have optimized a GLP-1R antagonist antibody with more potent blocking of GLP-1R than avexitide. This antibody therapy is a potential novel and effective treatment for HI.
2022-11-01 | Non-coding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism
Gene expression is tightly regulated, with many genes exhibiting cell-specific silencing when their protein product would disrupt normal cellular function1. This silencing is largely controlled by non-coding elements, and their disruption might cause human disease2. We performed gene-agnostic screening of the non-coding regions to discover new molecular causes of congenital hyperinsulinism. This identified 14 non-coding de novo variants affecting a 42-bp conserved region encompassed by a regulatory element in intron 2 of the hexokinase 1 gene (HK1). HK1 is widely expressed across all tissues except in the liver and pancreatic beta cells and is thus termed a ‘disallowed gene’ in these specific tissues. We demonstrated that the variants result in a loss of repression of HK1 in pancreatic beta cells, thereby causing insulin secretion and congenital hyperinsulinism. Using epigenomic data accessed from public repositories, we demonstrated that these variants reside within a regulatory region that we determine to be critical for cell-specific silencing. Importantly, this has revealed a disease mechanism for non-coding variants that cause inappropriate expression of a disallowed gene. De novo variants altering a conserved region in an intron of HK1 cause congenital hyperinsulinism by perturbing the activity of a putative cell type-specific regulatory element.
proteins
2026-05-13 | Somatostatin and Its Analogues as Second-Line Treatments in Non-Neoplastic Conditions.
Somatostatin is a potent endocrine regulator and neurotransmitter, exerting predominantly inhibitory effects in different tissues of the body, via G-protein coupled receptors. Five such specific receptors have been identified, with different effects and tissue distribution. The multifaceted actions and effects of somatostatin make it useful as a potential therapeutical means in various pathologies; however, in clinical practice, somatostatin analogues, namely octreotide, lanreotide and pasireotide, are commonly used instead, due to their increased half-life and increased receptor selectivity, with pasireotide showing a more extensive receptor binding profile and high affinity for somatotastin receptor (SSTR) 5, which may prove effective in cases of resistance to first-generation analogues. Apart from their many uses in neoplastic pathologies, somatostatin analogues represent viable treatment choices in some ocular pathologies, congenital hyperinsulinism, gastrointestinal bleedings and portal hypertension, acute pancreatitis, and dumping syndrome. They have also been used in some cases, with varying degrees of success, in patients with post-surgical gastrointestinal and lymphatic fistulas, refractory chronic diarrhoea and polycystic kidney disease; many applications in paediatric patients have also been documented. The aim of this review is to present the applications of somatostatin and its analogues as alternative or second-line therapies, along with insights into their effectiveness and future potential.
2025-11-07 | Advances in Pharmacotherapy for Congenital Hyperinsulinism.
Congenital hyperinsulinism (CHI) is a rare disorder causing persistent hypoglycaemia in infants due to excessive insulin secretion from pancreatic β-cells. It has genetic causes, primarily mutations in ATP-sensitive potassium channel genes (ABCC8, KCNJ11). CHI manifests in three forms-focal, diffuse, and atypical-distinguished by histology and genetics, influencing treatment strategies. Early diagnosis and tailored management are vital to prevent neurological damage. While transient CHI resolves spontaneously, permanent CHI often requires complex medical and/or surgical intervention. Despite advances, long-term neurodisability remains high, highlighting increased need to improve monitoring as well as better therapies with lesser side effects. Acute treatment aims to rapidly normalize glucose levels and long-term treatments include diazoxide (KATP channel agonist) to suppress insulin secretion, though its effectiveness depends on genetic mutation type. Other therapies include somatostatin analogues. Newer emerging therapies include novel glucagon analogues, monoclonal antibodies targeting insulin receptors, GLP-1 receptor antagonist, and selective somatostatin receptor agonist, currently under clinical trials. Along with medical treatment, children may require additional feeding support with carbohydrate supplementation using glucose polymers and special formulas. Continuous glucose monitoring aids detection but has limitations. Surgery is preferred for focal lesions to potentially cure CHI.
2025-10-13 | Treatment of Congenital Hyperinsulinism With a Novel, Long-acting Glucagon Analogue.
Congenital hyperinsulinism (HI) is a disorder of insulin regulation that results in hypoketotic hypoglycemia and is associated with a high risk of neurological sequalae from hypoglycemia-induced brain damage. There is only 1 Food and Drug Administration-approved drug for the treatment of HI, and up to 60% of patients do not respond to it; thus, there is a significant unmet need for new treatments. We report a case of a 29-year-old female with HI due to an activating glucokinase pathogenic variant, who was diagnosed as an adult and continued to have persistent hypoglycemia despite standard-of-care therapy. The patient was enrolled in the phase II clinical trial evaluating efpegerglucagon, a novel long-acting glucagon analog. She has continued treatment with efpegerglucagon through a single-patient Investigational New Drug Expanded Access Program and has demonstrated improved glycemic control throughout 10 months of treatment. Efpegerglucagon may be a viable treatment option or adjunct therapy for patients with HI who are unresponsive or partially responsive to currently available therapies.
2025-04-29 | Necrolytic migratory erythema following prolonged continuous subcutaneous dasiglucagon administration: a rare dermatologic adverse event.
Clinical management of congenital hyperinsulinism (CHI) remains a significant challenge due to its complex pathophysiology and the limitations of available therapies. Dasiglucagon, a synthetic glucagon analog, represents a novel approach to managing CHI, particularly in patients where conventional therapies fail. This report discusses a rare case of prolonged continuous subcutaneous dasiglucagon use in a neonate with CHI. Despite initial stabilization of glycemic levels, the patient developed necrolytic migratory erythema (NME), a rare dermatological condition associated with hyperglucagonemia, during dasiglucagon therapy. The patient further experienced severe malnutrition, zinc and amino acid deficiencies, and sepsis. Following the discontinuation of dasiglucagon therapy due to these severe side effects, the patient's skin and nutritional status improved markedly. However, glycemic control required subtotal pancreatectomy. This report underscores the potential of dasiglucagon in CHI management but highlights the importance of close monitoring during prolonged therapy. NME, a rare but severe condition, appears to be associated with prolonged continuous subcutaneous dasiglucagon therapy, requiring early recognition and intervention. Close monitoring is essential during prolonged continuous subcutaneous dasiglucagon therapy to detect potential adverse effects, focusing on dermatological conditions, nutrient deficiencies or signs of infection. Multidisciplinary care is crucial to manage CHI with dasiglucagon, ensuring a comprehensive approach that addresses both glycemic control and potential side effects.
2023-03-29 | Hyperinsulinism Gateway Between Diabetes and Cancer: New Roles for Bifunctional Antidiabetic - Anticancer Active Somatostatins, IGF - 1 Inhibitors and Insulin Sensitizers
Hyperinsulinism refers to a condition of abnormally high concentration of circulating insulin in the body commonly seen in obese and type 2 diabetic patients due to insulin resistance. Elevated circulating insulin is the main factor linking obesity, diabetes and cancer and an important mechanism of cancer therapeutic resistance and failure. The insulin receptor subfamily which is made up of the insulin receptor (IR), the type 1 IGF receptor (IGF-1) which binds insulin-like growth factors I and II, and the orphan insulin receptor-related receptor (IRRR) have been identified and linked to the process of carcinogenesis, as cancer cells require insulin for growth. IR receptors are overexpressed in various cancers and insulin activates growth mostly through these receptors and their interplays through mainly the PI3K/AKT/mTOR, MAPK and RAS signal transduction pathways. Estrogens and androgens synergistic effects worsen hyperinsulinism and accelerates its carcinogenesis properties while progesterone and Sex Hormone Binding Globulins exert modulatory effects. This review examined the various factor interplays in hyperinsulinism that links diabetes with cancer and the biomarkers involved. It equally identified the potentials and therapeutic roles for Somatostatins, IGF – 1 inhibitors and Insulin sensitizing antidiabetics in preventing and reversing the cancer linked trends.
small molecules
2026-08-06 | Ghrelin and relamorelin counteract hypoglycemia in mice engrafted with congenital hyperinsulinism stem cell-derived islets.
KATP-channel-related hyperinsulinism (KATPHI) is a rare genetic disorder of the pancreatic beta cells, manifesting as life-threatening hypoglycemia in neonates due to excessive insulin secretion. Management of the severe diffuse form of KATPHI currently lacks treatment options, as the first-line therapy octreotide is often insufficiently effective, necessitating radical pancreatectomy in many patients. In this study, we differentiated stem cells carrying the KATPHI-causing mutation KCNJ11-/- to stem cell-derived islets (SC-islets) to develop new pharmaceutical therapies for KATPHI. We tested seven candidate molecules in vitro and the most effective ones in vivo in immunocompromised mice that were transplanted with the human KCNJ11-/- SC-islets. KCNJ11 -/- SC-islets inappropriately secreted 3.9 times more insulin in low glucose than KCNJ11+/+ controls. Transplanted KCNJ11-/- SC-islets caused persistent hyperinsulinemia and hypoglycemia to the recipient mice. We tested acyl-ghrelin identified in our in vitro experiments and its long-acting analogue relamorelin in these mice. Acyl-ghrelin and relamorelin alone increased fasting blood glucose. Combining relamorelin with octreotide increased blood glucose synergistically, ie, more than the sum of each drug alone, reverting hypoglycemia to normoglycemia while reducing the excessive insulin secretion. We show that ghrelin-receptor agonists have acute anti-hypoglycemic effects in a humanized mouse model of KATPHI, especially when combined with octreotide. Relamorelin has been tested in >650 diabetic adults with little side effects, leading us to propose relamorelin-octreotide combination for further development as a therapeutic candidate for severe KATPHI patients.
2026-07-23 | Indocyanine green fluorescence cholangiography enables safe laparoscopic near-total pancreatectomy for diffuse congenital hyperinsulinism.
Laparoscopic near-total pancreatectomy (NTP) for diffuse congenital hyperinsulinism (CHI) may reduce morbidity compared with open surgery. However, it is technically limited by uncertainty regarding the intrapancreatic common bile duct (CBD) course, risking bile duct injury or inadequate resection. We evaluated whether near-infrared indocyanine green fluorescence cholangiography (NIR ICG FC) improves intraoperative identification of the intrapancreatic CBD and supports laparoscopic NTP for medically-refractory diffuse CHI. We performed a retrospective single-centre review of consecutive infants undergoing laparoscopic NTP with NIR ICG FC for diffuse CHI (2021-2025). Intravenous ICG (0.5 mg/kg) was administered 10-15 h preoperatively. Outcomes included feasibility of CBD visualisation, extent of resection, biliary complications, postoperative recovery, persistence of hyperinsulinism and medium-term endocrine/exocrine function. Five infants underwent laparoscopic NTP at a median age of 3 months (range 2-6). The intrapancreatic CBD was visualised in all cases, enabling a consistent 95% resection without conversion to open surgery. There were no bile duct injuries. Enteral feeding commenced at a median of 3 postoperative days (range 2-4). One patient developed transient obstructive jaundice on postoperative day 13 that resolved with conservative management. At a median follow-up of 30 months (range 20-51), three infants had residual hyperinsulinism (managed by feeding strategies in two and medication in one), and one had exocrine insufficiency requiring enzyme supplementation; no child had diabetes at latest follow up. NIR ICG fluorescence cholangiography provides real time delineation of the intrapancreatic CBD and can support a safe minimally invasive approach to near-total pancreatectomy for diffuse CHI.
2026-07-23 | Indocyanine green fluorescence-guided intraoperative biliary mapping during pediatric laparoscopic duodenum-preserving pancreatic head resection: a standardized operative approach.
Laparoscopic duodenum-preserving pancreatic head resection (LDPPHR) for focal congenital hyperinsulinism (CHI) poses a specific intraoperative challenge: reliable, continuous identification of the intrapancreatic common bile duct (CBD) in an anatomically diminutive, tactile-feedback-free operative field. We describe a standardized indocyanine green (ICG) fluorescence-guided biliary visualization workflow for pediatric LDPPHR and report its initial implementation experience. In this retrospective case series, we summarized the application of this standardized workflow in seven consecutive children with focal CHI who underwent ICG fluorescence-guided LDPPHR at Beijing Children's Hospital from February 2025 to March 2026. The workflow comprised seven sequential steps: exposure and preparation, first-dose ICG administration, initial biliary mapping, boundary-guided pancreatic head dissection, repeated fluorescence assessment and reinjection when required, post-resection perfusion assessment, and reconstruction with final intraoperative checking. The workflow was completed as planned in all seven cases, with full workflow adherence in 7/7 procedures. Continuous visualization of the intrapancreatic CBD under near-infrared (NIR) illumination was achieved in 7/7 procedures. Repeated white-light/NIR correlation was feasible throughout dissection in all cases. The fluorescence-guided workflow was implemented without intraoperative abandonment. No bile leak, clinically relevant postoperative pancreatic fistula (ISGPS 2016 criteria), or duodenal ischemia was observed. Median operative time was 310 min (range 229-570 min). This stepwise ICG biliary visualization workflow was technically feasible and was implemented without biliary adverse events in this initial retrospective case series. As a workflow description with feasibility observations rather than an efficacy study, this report suggests that repeated real-time delineation of the intrapancreatic CBD may facilitate duct-sparing dissection; whether it reduces bile duct injury requires validation in larger comparative studies.
2026-07-15 | Two threats in early life: congenital hyperinsulinemic hypoglycemia and thrombosis.
Congenital persistent hyperinsulinemic hypoglycemia (HH) is a rare disorder that can lead to severe and recurrent hypoglycemic episodes in neonates and infants. Management often requires intensive glucose infusion via central venous catheters (CVCs), which may increase the risk of thrombosis. While case reports suggest thrombosis can occur in HH, the incidence, risk factors, severity, and outcomes remain poorly understood. This study aimed to determine the incidence of thrombosis in children with persistent HH and to evaluate potential risk factors associated with thrombotic complications. A descriptive, retrospective cohort study of patients with persistent HH followed at a university pediatric endocrinology clinic between January 2000 and December 2025. Twenty patients with persistent HH were included. Data on demographics, clinical characteristics, laboratory results, treatment protocols, CVC use, timing and location of thrombosis were collected. Patients who developed thrombosis were compared with those who did not to identify risk factors. Among 20 patients, 55% were male, with a median age at diagnosis of 1 day. A total of 23 CVCs were placed in 15 patients, with a median dwell time of 38 days. Thrombosis occurred in nine patients (45%), including six catheter-related and three catheter-independent intracranial thrombosis. Median age at thrombosis detection was 74 days. Patients who developed thrombosis experienced significantly more hypoglycemic episodes and more days with hypoglycemia (p < 0.05). No association was found between genetic mutations (ABCC8, KCNJ11, etc.) and thrombosis development. All four patients treated with enoxaparin achieved complete resolution without complications. Thrombosis is a frequent and clinically significant complication in persistent HH. Recurrent and severe hypoglycemic episodes are major risk factors. Routine thrombosis screening, particularly in patients with CVCs, may allow early detection and treatment even in asymptomatic cases.
2026-06-10 | Structural basis of insulin receptor antagonism by bivalent site 1-site 2 ligands S961 and Ins-AC-S2.
Congenital hyperinsulinism is a rare genetic disease characterized by overproduction of insulin. One class of potential treatments is insulin receptor antagonists like S961 and Ins-AC-S2, which comprise segments for binding each of the two insulin-binding sites (site 1 and site 2) on the receptor. Notably, S597 - containing the same receptor binding segments as S961 but in the opposite order (site 2-site 1) - is an insulin receptor agonist rather than an antagonist. Using cryo-EM, we show how both S961 and Ins-AC-S2 bind an inactive conformation of the receptor, thereby explaining their antagonism. Furthermore, our structures reveal how agonist vs. antagonist activity is influenced by the order of site 1- and site 2-binding modules in bivalent ligands. Additionally, we show subtle differences between the receptor-binding mechanisms of S961 and Ins-AC-S2, which include displacement or engagement of αCT, and a binding interface between the Ins-AC-S2 insulin and the receptor FnIII-2/insert domains. These structural insights may inform development of next generation insulin receptor antagonists for treatment of congenital hyperinsulinism.
gene therapies
2025-05-18 | Comprehensive clinical and molecular characterization with long-term outcomes in 40 patients with congenital hyperinsulinism.
Congenital hyperinsulinism (CHI) represents the most frequent cause of recurrent hypoglycemia in neonates and infants, stemming from defects in the regulatory pathways of insulin secretion from pancreatic beta cells. This study aims to assess the clinical and genetic characteristics of a CHI cohort and to discuss the complexities involved in managing this heterogeneous disorder. Forty patients (23 girls) with CHI were included in the study. Data on the diagnosis and treatment of CHI were obtained from the medical records. The median age at diagnosis was 1.4 months (range 0.1-30 months). The mean gestational age was 37.8 ± 2.4 weeks, and the birth weight was 1.1 ± 2.0 SDS. The consanguinity ratio was 35.0%. Median glucose, insulin, and C-peptide concentrations at diagnosis were 34.0 mg/dl (IQR 25.2-41.7), 12.4µU/ml (IQR 4.4-27.1), and 1.5 ng/ml (IQR 0.7-3.8), respectively. Molecular genetic diagnosis could be established in 62.5% (n = 25). Pathogenic variants were predominantly identified in the KATP channel genes (17/25, 68%), with the ABCC8 being the most frequent (n = 15; biallelic: 8, monoallelic: 7). KCNJ11 variants were identified in two (5.0%), GLUD1 variants in three (7.5%), and HADH variants in five patients (12.5%). Pancreatectomy was performed in 10 patients, with a mean age at the time of surgery of 3.9 ± 3.2 months. The genetic etiology was identified in all patients who underwent pancreatectomy, all of whom had defects in the KATP channel. ABCC8 variants were detected in nine (biallelic: 5, monoallelic: 4), while a biallelic variant in the KCNJ11 was identified in one case. A molecular genetic diagnosis was identified in approximately two-thirds of our cohort, underscoring the significance of genetic testing in the management of CHI. Ongoing advances in genetic technologies are anticipated to enhance our understanding of the etiopathogenesis of CHI and support the development of more personalized therapeutic strategies. Although the genotype-phenotype correlation remains only partially elucidated, specific genetic variants may provide predictive insights into treatment resistance, thereby informing more targeted treatment approaches.
2025-04-11 | The genetics of low and high birthweight and their relationship with cardiometabolic disease.
Low birthweight infants are at increased risk not only of mortality, but also of type 2 diabetes mellitus and CVD in later life. At the opposite end of the spectrum, high birthweight infants have increased risk of birth complications, such as shoulder dystocia, neonatal hypoglycaemia and obesity, and similarly increased risk of type 2 diabetes mellitus and CVD. However, previous genome-wide association studies (GWAS) of birthweight in the UK Biobank have primarily focused on individuals within the 'normal' range and have excluded individuals with high and low birthweight (<2.5 kg or >4.5 kg). The aim of this study was to investigate genetic variation associated within the tail ends of the birthweight distribution, to: (1) see whether the genetic factors operating in these regions were different from those that explained variation in birthweight within the normal range; (2) explore the genetic correlation between extremes of birthweight and cardiometabolic disease; and (3) investigate whether analysing the full distribution of birthweight values, including the extremes, improved the ability to detect genuine loci in GWAS. We performed case-control GWAS analysis of low (<2.5 kg) and high (>4.5 kg) birthweight in the UK Biobank using REGENIE software (Nlow=20,947; Nhigh=12,715; Ncontrols=207,506) and conducted three continuous GWAS of birthweight, one including the full range of birthweights, one involving a truncated GWAS including only individuals with birthweights between 2.5 and 4.5 kg and a third GWAS that winsorised birthweight values <2.5 kg and >4.5 kg. Additionally, we performed bivariate linkage disequilibrium (LD) score regression to estimate the genetic correlation between low/normal/high birthweight and cardiometabolic traits. Bivariate LD score regression analyses suggested that high birthweight had a mostly similar genetic aetiology to birthweight within the normal range (genetic correlation coefficient [rG]=0.91, 95% CI 0.83, 0.99), whereas there was more evidence for a separate set of genes underlying low birthweight (rG=-0.74, 95% CI 0.66, 0.82). Low birthweight was also significantly positively genetically correlated with most cardiometabolic traits and diseases we examined, whereas high birthweight was mostly positively genetically correlated with adiposity and anthropometric-related traits. The winsorisation strategy performed best in terms of locus detection, with the number of independent genome-wide significant associations (p<5×10-8) increasing from 120 genetic variants at 94 loci in the truncated GWAS to 270 genetic variants at 178 loci, including 27 variants at 25 loci that had not been identified in previous birthweight GWAS. This included a novel low-frequency missense variant in the ABCC8 gene, a gene known to be involved in congenital hyperinsulinism, neonatal diabetes mellitus and MODY, that was estimated to be responsible for a 170 g increase in birthweight amongst carriers. Our results underscore the importance of genetic factors in the genesis of the phenotypic correlation between birthweight and cardiometabolic traits and diseases.
2024-12-25 | Case report: Duplication of the GCK gene is a novel cause of nesidioblastosis: evidence from a case with Silver-Russell syndrome-like phenotype related to chromosome 7.
Silver-Russell syndrome (SRS) is a syndrome characterized by prenatal and postnatal growth retardation, facial features, and body asymmetry. SRS is often complicated with hypoglycemia, whose etiology is unclear. We describe the clinical course of 25-year-old man with hypoglycemia. We diagnosed him with hyperinsulinemic hypoglycemia (HH) and treated him with laparoscopic distal pancreatectomy. Histological examination led to a diagnosis of nesidioblastosis. The juvenile onset of his nesidioblastosis and its slowly progressive course suggested a genetic etiology. Whole-exome sequencing (WES) identified the heterozygous NR0B2 Ala195Ser variant, which alone was unlikely to cause nesidioblastosis because this variant is sometimes detected in the Japanese population. Copy number analysis using WES data suggested duplication in chromosome 7, and subsequent G-banding chromosome analysis confirmed mos dup(7)(p11.2p14). We determined that the patient had SRS-like phenotype based on his clinical features and this duplication. Furthermore, we found that the duplicated region contained the GCK gene, whose gain-of function variants could cause HH. Taken together, the patient's HH may have been caused by duplication of the GCK gene, which could be a novel cause of nesidioblastosis.
2023-07-20 | A novel mutation in the KCNJ11 gene (p.Val36Glu), predisposes to congenital hyperinsulinemia.
The hypoglycemia induced by insulin hypersecretion in congenital hyperinsulinemia (CHI), a rare life-threatening condition can lead to irreversible brain damage in neonates. Inactivating mutations in the genes encoding KATP channel (ABCC8 and KCNJ11) as well as HNF4A, HNF1A, HADH, UCP2, and activating mutations in GLUD1, GCK, and SLC16A1 have been identified as causal. A 3-month-old male infant presenting tonic-clonic seizures and hyperinsulinemia was clinically assessed and subjected to genetic analysis. Besides the index patient, his parents were clinically investigated, and a detailed family history was also recorded. The laboratory investigations and the genetic test results of the parents were compared with the index patient. The biochemical and hormonal profile of the patient confirmed his suffering from CHI and did not respond to diazoxide treatment. The genetic testing revealed that the subject harbored a novel homozygous missense mutation in the KCNJ11 gene, (c.107T>A, p.Val36Glu.). The bioinformatic analysis revealed that valine is highly conserved and predicted that the variant allele (p.Val36Glu) is likely pathogenic and causal for CHI. Parents were heterozygous carriers and did not report any abnormal metabolic profile. Identification of such mutations is critical and likely to change the therapeutic interventions for such patients in the future.
2022-11-08 | Integration of genomic analysis and transcript expression of ABCC8 and KCNJ11 in focal form of congenital hyperinsulinism.
The focal form of CHI is caused by an autosomal recessive pathogenic variant affecting the paternal homologue of genes ABCC8 or KCNJ11 and a second somatic event specifically occurring in the affected islet of Langerhans. The approach of this study was to integrate the genetic changes occurring in pancreatic focal lesions of CHI at the genomic and transcriptional level. Patients receiving therapeutic surgery and with proven ABCC8 or KCNJ11 pathogenic variants were selected and analyzed for loss of heterozygosity (LOH), changes in copy number and uniparental disomy (UPD) on the short am of chromosome 11 by molecular microarray analysis and methylation-specific MLPA. Gene expression was analyzed by RT-PCR and Massive Analysis of cDNA Ends (MACE). Both genes, ABCC8 and KCNJ11, are located in proximity to the Beckwith-Wiedemann (BWS) imprinting control region on chromosome 11p15. Somatic paternal uniparental isodisomy (UPD) at chromosome 11p was identified as second genetic event in focal lesions resulting in LOH and monoallelic expression of the mutated ABCC8/KCNJ11 alleles. Of five patients with samples available for microarray analysis, the breakpoints of UPD on chromosome 11p were different. Samples of two patients were analyzed further for changes in gene expression. Profound downregulation of growth suppressing genes CDKN1 and H19 was detected in focal lesions whereas growth promoting gene ASCL2 and pancreatic transcription factors of the endocrine cell lineage were upregulated. Paternal UPD on the short arm of chromosome 11 appears to be the major second genetic event specifically within focal lesions of CHI but no common breakpoint for UDP can be delineated. We show for the first time upregulation of growth promoting ASCL2 (achaete-scute homolog 2) suggestive of a driving factor in postnatal focal expansion in addition to downregulation of growth suppressing genes CDKN1C and H19.
cell therapies
2026-01-31 | Robotic versus Open Pancreatectomy for Focal Congenital Hyperinsulinism in Infants: A Single-Center Study.
Focal forms of congenital hyperinsulinism (FoCHI) are rare pediatric conditions managed using established metabolic and surgical protocols. To date, the use of a robotic approach for this surgery in children has not been described. We present our initial experience with robotic pancreatectomy, compared with the open approach, for the management of FoCHI. We conducted a retrospective, single-center study involving 25 children who underwent pancreatectomy for CHI between 2011 and 2024. Collected data included patient demographics, surgical details, complications, and post-operative outcomes. The Da Vinci Xi robotic system was used for all robotic procedures. Ten patients underwent robotic pancreatectomy, and 10 underwent open surgery; five children treated laparoscopically were excluded. There were no significant differences between the robotic and open groups in median weight at surgery (7.7 kg vs. 7.3 kg, p = 0.7), median age (7 months vs. 5.9 months, p = 0.48), median operative time (298 minutes vs. 285 minutes, p = 0.5), length of stay (14 days vs. 14.5 days, p = 0.26), or time to postoperative feeding resumption (4 days vs. 4.5 days, p = 0.68). Intraoperatively, 80% of lesions were visible on the pancreatic surface. Two cases of incomplete resection occurred in each group; after multidisciplinary review, both patients in the robotic group required a second procedure. No intraoperative bleeding or conversions were reported. The overall cure rate was 90% in the robotic group and 80% in the open surgery group. This preliminary study suggests that robotic pancreatectomy for congenital hyperinsulinism may be both safe and feasible. The robotic approach provides enhanced visualization of small vessels, enabling limited dissection and safe resection. Given the sample size, further studies are required to confirm these findings.
2025-09-23 | A rare case of congenital hyperinsulinism in a child — when morphology determines treatment tactics
Background. A clinical case of an encapsulated focal form of congenital hyperinsulinism in a young child is presented. A comprehensive examination was performed, including molecular genetic analysis, radionuclide diagnostics (PET-CT with 18F-DOPA) and intraoperative histological examination. During morphological analysis, an encapsulated focus of β-cell adenomatous hyperplasia was verified, located in the head of the pancreas. This finding necessitated an extended organ resection. It is particularly noteworthy that there is a clear fibrous capsule around the pathological focus, which presents a diagnostic challenge in differentiating this pathology from an insulinoma. The postoperative period was uneventful, and stable normoglycemia was achieved, which ultimately confirmed the positive outcome of the treatment and the patient's recovery. The unique feature of this clinical case is that it represents the first recorded example of the focal form of congenital hyperinsulinism, characterized by a well-defined fibrous capsule combined with adenomatosis lacking visible boundaries. As of today, similar observations have not been found in available publications from domestic medical centers, which highlights the rarity of the described case and its significance for expanding knowledge about the spectrum of focal forms of this disease. Analysis of this morphological variant highlights the importance of performing a rapid histological examination of tissues during surgery, which in this clinical case was a key factor in determining the extent of the resection. This decision allowed us not to be limited to just the encapsulated formation and ultimately led to the patient's full recovery. Conclusion. This case demonstrates the importance of a multidisciplinary approach in the diagnosis of rare forms of congenital hyperinsulinism and highlights the need for a thorough histopathological examination of the surgical material to achieve correct clinical decision.
2025-04-14 | Successful Management of an Infant with Congenital Focal Hyperinsulinism with No Apparent Lesion During Surgery.
Congenital hyperinsulinism (HI) is the leading cause of persistent hypoglycemia in infants and children. Focal pancreatic lesions account for 30-40% of cases with congenital HI. With early diagnosis, these patients can be treated by resection of the lesion, making long-term medical care unnecessary. In this case, a 5-day-old newborn boy presented with convulsion due to severe and persistent hypoglycemia at his hospitalization in neonatal intensive care unit. Laboratory studies revealed very low levels of ketone bodies with inappropriately normal insulin levels during hypoglycemia. The patient was unresponsive to diazoxide treatment. The molecular genetic analysis revealed a heterozygous pathogenic variant in the ABCC8 gene. 18F-DOPA-PET/CT scan showed increased uptake of 18F-DOPA consistent with focal lesion at the tail of the pancreas. A focal pancreatectomy operation was performed when he was three months old. Histopathological evaluation confirmed focal endocrine cell hyperplasia. Hypoglycemia did not recur after the operation. CHI patients with ABCC8 / KCNJ11 mutation are not easy to manage with pharmacotheraphy. In the case of an identifiable focal lesion associated with CHI, surgery is the most preferred option. In focal CHI, as in our case, the lesion may not be visually evident and requires a surgeon experienced in CHI.
2025-03-17 | Surgical treatment of congenital hyperinsulinism
Objectives: This study aims to analyze the details of surgical techniques performed in various types of congenital hyperinsulinism (CHI) and review our experience. Patients and methods: Six children with CHI (3 males, 3 females) treated between January 2013 and January 2024 were retrospectively reviewed. Results: Four patients had diffuse type CHI, and two had focal type CHI. The median age at diagnosis was 18.5 days (range, 1 to 54 days). The diagnosis involved 18F-DOPA (18-fluoro-dihydroxyphenylalanine) positron emission tomography (PET)/computed tomography (CT) in two patients and 68Ga-NODAGA-exendin-4 PET/CT in one patient. Mutations in ABCC8/KCNJ1 were detected in five patients. Ultrasonography (n=2), frozen biopsy (n=2), and indocyanine green-guided identification (n=1) were used introperatively. Near total pancreatectomy (95 to 98%) and gastrostomy were performed in four patients with diffuse CHI. Among the two patients with focal lesions, distal pancreatectomy was performed in one patient, and enucleation was performed in the other patient. Conclusion: Knowing the technical details of the surgery, preparation for different surgical approaches to various types of CHI, and being aware of the risky major complications achieve successful outcomes in pancreatic surgery.
2024-12-17 | Congenital hyperinsulinism in the Ukraine: a 10-year national study.
Congenital Hyperinsulinism (CHI) has not been previously studied in Ukraine. We therefore aimed to elucidate the genetics, clinical phenotype, histological subtype, treatment and long-term outcomes of Ukrainian patients with CHI. Forty-one patients with CHI were recruited to the Ukrainian national registry between the years 2014-2023. Genetic testing (n=40), 18F-fluorodihydroxyphenylalanin and 68Ga-DOTANOC PET/CT imaging followed by surgical treatment and subsequent histological analysis (n=19) was performed through international collaboration. Pathogenic variants were identified in 19/22 (86.3%) individuals with persistent CHI (p-CHI) and 8/18 (44.4%) with early remission CHI (er-CHI). Pathogenic variants in the K-ATP channel genes were the only identified genetic cause of p-CHI (ABCC8 (n=17) and KCNJ11 (n=2)) with greater genetic heterogeneity observed in those with er-CHI (ABCC8 (n=3), KMT2D (Kabuki Syndrome, n=1), Beckwith-Wiedemann syndrome (n=2) and INSR (Donohue syndrome (n=2)). Histological analysis performed on 19 children with persistent CHI confirmed focal disease in 14 (73.7%), diffuse disease in two (10.5%) and atypical histology in three (15.8%). After surgery, complete recovery was observed in all 14 with focal disease, while relapse occurred in three patients with diffuse or atypical histology. A genetic diagnosis was achieved for 67.5% (27/40) of the cohort with a higher pick-up rate observed in those with p-CHI. The genetics and imaging studies enabled subtype-targeted treatment with surgical cure achieved in all individuals with focal disease.
other
2023-06-26 | Optimization of a Glucagon-Like Peptide 1 Receptor Antagonist Antibody for Treatment of Hyperinsulinism
Congenital hyperinsulinism (HI) is a genetic disorder in which pancreatic β-cell insulin secretion is excessive and results in hypoglycemia that, without treatment, can cause brain damage or death. Most patients with loss-of-function mutations in ABCC8 and KCNJ11, the genes encoding the β-cell ATP-sensitive potassium channel (KATP), are unresponsive to diazoxide, the only U.S. Food and Drug Administration–approved medical therapy and require pancreatectomy. The glucagon-like peptide 1 receptor (GLP-1R) antagonist exendin-(9-39) is an effective therapeutic agent that inhibits insulin secretion in both HI and acquired hyperinsulinism. Previously, we identified a highly potent antagonist antibody, TB-001-003, which was derived from our synthetic antibody libraries that were designed to target G protein–coupled receptors. Here, we designed a combinatorial variant antibody library to optimize the activity of TB-001-003 against GLP-1R and performed phage display on cells overexpressing GLP-1R. One antagonist, TB-222-023, is more potent than exendin-(9-39), also known as avexitide. TB-222-023 effectively decreased insulin secretion in primary isolated pancreatic islets from a mouse model of hyperinsulinism, Sur1−/− mice, and in islets from an infant with HI, and increased plasma glucose levels and decreased the insulin to glucose ratio in Sur1−/− mice. These findings demonstrate that targeting GLP-1R with an antibody antagonist is an effective and innovative strategy for treatment of hyperinsulinism. Article Highlights Patients with the most common and severe form of diazoxide-unresponsive congenital hyperinsulinism (HI) require a pancreatectomy. Other second-line therapies are limited in their use because of severe side effects and short half-lives. Therefore, there is a critical need for better therapies. Studies with the glucagon-like peptide 1 receptor (GLP-1R) antagonist, avexitide (exendin-(9-39)), have demonstrated that GLP-1R antagonism is effective at lowering insulin secretion and increasing plasma glucose levels. We have optimized a GLP-1R antagonist antibody with more potent blocking of GLP-1R than avexitide. This antibody therapy is a potential novel and effective treatment for HI.
2022-11-01 | Non-coding variants disrupting a tissue-specific regulatory element in HK1 cause congenital hyperinsulinism
Gene expression is tightly regulated, with many genes exhibiting cell-specific silencing when their protein product would disrupt normal cellular function1. This silencing is largely controlled by non-coding elements, and their disruption might cause human disease2. We performed gene-agnostic screening of the non-coding regions to discover new molecular causes of congenital hyperinsulinism. This identified 14 non-coding de novo variants affecting a 42-bp conserved region encompassed by a regulatory element in intron 2 of the hexokinase 1 gene (HK1). HK1 is widely expressed across all tissues except in the liver and pancreatic beta cells and is thus termed a ‘disallowed gene’ in these specific tissues. We demonstrated that the variants result in a loss of repression of HK1 in pancreatic beta cells, thereby causing insulin secretion and congenital hyperinsulinism. Using epigenomic data accessed from public repositories, we demonstrated that these variants reside within a regulatory region that we determine to be critical for cell-specific silencing. Importantly, this has revealed a disease mechanism for non-coding variants that cause inappropriate expression of a disallowed gene. De novo variants altering a conserved region in an intron of HK1 cause congenital hyperinsulinism by perturbing the activity of a putative cell type-specific regulatory element.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
19 orphan drug designations for Congenital isolated hyperinsulinism.
19 orphan drug designations for Congenital isolated hyperinsulinism.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
solution stable glucagon analog | peptides | FDA | 2024-06-17 | — | AmideBio, Inc. |
Pegylated Glucagon Receptor Agonist | peptides | FDA | 2021-05-17 | — | Pegbio Co. Ltd. |
Zavolosotine | small molecules | EMA | 2020-12-09 | — | Crinetics Pharmaceuticals Europe GmbH |
solution stable glucagon analog | peptides | FDA | 2020-04-20 | — | AmideBio |
Exendin (9-39) | peptides | EMA | 2019-11-13 | — | Amylyx Pharmaceuticals EMEA B.V. |
Glucagon analogue linked to a human immunoglobulin Fc fragment | proteins | EMA | 2018-05-25 | — | JVM Europe B.V. |
glucagon analog conjugated with human immunoglobulin G4 fragment | proteins | FDA | 2018-02-01 | — | Hanmi Pharmaceutical Company, Ltd. |
glucagon (ready-to-use) | peptides | FDA | 2018-01-24 | — | Xeris Pharmaceuticals, Inc. |
dihydroxyphenylalanine F 18/Fluorodopa (F18) | small molecules | FDA | 2018-01-22 | — | Society of Nuclear Medicine and Molecular Imaging |
dasiglucagon | peptides | FDA | 2017-08-10 | — | Zealand Pharma A/S |
Synthetic glucagon analogue modified to contain 7 amino acid substitutions | peptides | EMA | 2017-06-20 | — | Zealand Pharma A/S |
avexitide | peptides | FDA | 2016-12-08 | — | Amylyx Pharmaceuticals, Inc. |
Recombinant human monoclonal antibody to insulin receptor | antibodies | EMA | 2016-07-14 | — | Rezolute (Bio) Ireland Limited |
fully human IgG2 monoclonal antibody that binds insulin receptors | antibodies | FDA | 2015-06-09 | — | Rezolute, Inc. |
Glucagon | peptides | EMA | 2014-10-15 | — | S-cubed Pharmaceutical Services ApS |
glucagon infusion | peptides | FDA | 2014-09-25 | — | Xeris Pharmaceuticals, Inc. |
glucagon | peptides | FDA | 2012-12-05 | — | Biodel, Inc. |
Glucagon | peptides | EMA | 2012-03-05 | — | Biodel UK Limited |
exendin-(9-39) | peptides | FDA | 2011-06-01 | — | The Children's Hospital of Philadelphia |
Let's accelerate rare disease drug discovery
Let's accelerate drug discovery
Get access to Explority AI’s forecasts to outperform average preclinical success rates. Whether you’re expanding your R&D pipeline, evaluating a partnership, or simply have a question — we’d love to hear from you.