RARE DISEASE
Hirschsprung disease
Hirschsprung disease
Hirschsprung disease
Synonyms: Aganglionic megacolon, Colonic aganglionosis, Congenital intestinal aganglionosis, HSCR
Synonyms: Aganglionic megacolon, Colonic aganglionosis, Congenital intestinal aganglionosis, HSCR
Synonyms: Aganglionic megacolon, Colonic aganglionosis, Congenital intestinal aganglionosis, HSCR
Drug discovery
3
drugs
With orphan designations
Overview
Hirschsprung disease (HSCR) is a congenital disorder caused by the absence of ganglion cells in the distal colon, leading to functional obstruction and impaired peristalsis. It occurs in ~1 in 5,000 live births, with male predominance (3–4:1), and is associated with genetic conditions like Down syndrome (5–10% of cases) [1][9][14]. Diagnosis involves rectal biopsy and imaging. Treatment requires surgical resection of the aganglionic bowel segment, typically via pull-through procedures, with favorable long-term outcomes in most patients [1][7][12][15].
Burden
Acute complications: Enterocolitis (10–30% of cases), intestinal perforation, and sepsis [5][13][15].
Chronic morbidity: Persistent constipation (20–40%), fecal incontinence (5–10%), and growth delays [1][12][15].
Economic impact: Extended hospitalizations, need for reoperations (up to 10% of cases), and lifelong multidisciplinary care [1][12][13].
Therapies
Primary surgery: Laparoscopic or transanal pull-through (Swenson, Soave, Duhamel techniques) to excise aganglionic bowel [1][12][19].
Staged repair: Colostomy/ileostomy followed by delayed pull-through in complex cases (e.g., enterocolitis, long-segment disease) [3][7][13].
Adjuvant care: Preoperative rectal irrigation, antibiotics for enterocolitis, and postoperative bowel management protocols [3][7][11].
Categories: rare gastroenterological diseases, rare genetic diseases, rare transplant-related disorders
Research Papers
1,808 drug discovery papers about Hirschsprung disease, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
1,808 drug discovery papers about Hirschsprung disease, with 1 first-in-class and 2 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-13 | Ex vivo fluorescence confocal microscopy combined with rapid immunofluorescence for intraoperative intestinal mapping in near-total intestinal aganglionosis: a pediatric proof-of-concept case report.
In Hirschsprung disease (HD), intraoperative identification of ganglionated bowel remains central to surgical planning, particularly in extensive or near-total intestinal aganglionosis (nTIA), where bowel preservation is critical. Frozen-section histopathology remains the intraoperative standard. Ex-vivo fluorescence confocal microscopy (FCM) provides microscopic assessment of fresh tissue, while rapid immunofluorescence (rIF) has the potential to add targeted visualization of enteric neural structures. We describe a single pediatric proof-of-concept case in which FCM combined with selected rIF was integrated into intraoperative intestinal mapping. A full-term newborn, diagnosed at birth with nTIA, underwent tube stoma formation at 40 cm from the Treitz ligament without bowel resection. At 4-years, surgery was scheduled to remove aganglionic segments and lengthen the remaining bowel. During surgery the small bowel segment proximal to the ostomy measured 70 cm. Twenty-four full-thickness biopsies were collected every 20 cm from sigmoid colon to presumed ganglionic areas at stoma level. All samples underwent FCM for morphological assessment of fresh tissue. rIF was applied to four selected samples, two from presumed ganglionated bowel and two from presumed aganglionic bowel, as an adjunct to enhance visualization of S100B-positive neural and glial structures. Fresh tissue was incubated for 30 min with a primary anti-S100B antibody followed by an Alexa Fluor 647-conjugated secondary antibody, then rinsed and counterstained with acridine orange. Under fluorescence laser visualization ganglion cells were identified in functional segments while hypertrophic nerve fibers were detected in aganglionic regions. Surgical planning relied on integrated intraoperative assessment, with final confirmation by conventional histopathology. The simultaneous application of a longitudinal intestinal lengthening (LILT) ensured maximization of functional bowel. This single-case experience demonstrates the technical feasibility of integrating ex vivo FCM and rIF into intraoperative intestinal mapping for complex Hirschsprung disease. The approach should be regarded as exploratory and complementary to established histopathological assessment.
2026-08-02 | RNA methylation and the potential role of folate supplementation in preventing Hirschsprung disease.
To determine whether folate supplementation may reduce the incidence of Hirschsprung disease (HSCR) by regulating the methylation level of growth arrest-specific 5 (GAS5). The m6A methylation deficiency model and folate supplementation model were created using the m6A inhibitor 3-Deazaadenosine (DAZ) and folate, respectively. The effects of folate on the morphology, mortality, and number of HuC/D positive neurons in zebrafish were observed. The methylation level and proliferation ability of mouse enteric neural crest stem cells (ENCSCs) were detected by m6A ELISA and EdU assay respectively. Human HSCR cases and control tissues were collected. The expression level of GAS5 in intestinal tissues was detected by qRT-PCR. M6A ELISA, actinomycin D, and MeRIP qRT-PCR were used to detect the effect of folate on m6A methylation levels, GAS5 stability, and the content of m6A-modified GAS5 in N2a cells. The RIP assay was used to detect the content of GAS5 bound to YTH N6-methyladenosine RNA binding protein F2 (YTHDF2) under different folate concentrations. Supplementation of folate can ameliorate the decreased ENCSC proliferation ability caused by low m6A methylation level, reduce embryonic mortality of zebrafish and increase the number of HuC/D positive neurons at 96 hpf. Furthermore, folate may reduce the expression of the demethylase alkB homologue 5 (ALKBH5), weaken ALKBH5's demethylation effect on GAS5, promote the degradation of GAS5 by YTHDF2, and subsequently reduce the expression of GAS5. Additional folate supplementation during early embryonic development may serve as a strategy for preventing HSCR.
2026-07-21 | Extracellular vesicles in perinatal conditions: A minimally invasive approach to regenerative medicine.
Extracellular vesicles (EVs) are lipid bilayer-delimited nanoparticles released by cells to act as mediators of intercellular communication during organ development, injury, and repair. EVs carry cargo (bioactive proteins, lipids, and nucleic acids) that reflects the status of the parent cell and is transferred to recipient cells to regulate biological processes, such as inflammation, immune responses, and tissue regeneration. These properties have made EVs promising tools for investigating disease pathogenesis, improving diagnostic and prognostic accuracy, and developing cell-free regenerative therapies for conditions characterized by dysregulation of multiple biological pathways. EVs are particularly relevant in diseases that affect the pediatric population where pathogenesis often remains poorly understood, access to affected tissues is limited, and treatment options are frequently inadequate. This review summarizes current evidence on EV applications in fetal and neonatal disorders, including necrotizing enterocolitis, congenital diaphragmatic hernia, and bronchopulmonary dysplasia, and highlights emerging data in biliary atresia, spina bifida, short bowel syndrome, and Hirschsprung's disease. In this age group, human milk and amniotic fluid represent particularly attractive biologically accessible sources of EVs, combining therapeutic potential with feasibility of clinical application. Building on robust preclinical evidence, the field is now advancing toward clinical translation, but several aspects still need to be addressed such as cargo heterogeneity, scalability of production, dosing, biodistribution, safety, and regulatory standardization. Herein, we discuss the translational challenges and future directions that will shape the clinical application of EVs in perinatal conditions.
2026-07-17 | Thymic Stromal Lymphopoietin-Driven B-Cell Hyperactivation Impairs Intestinal Epithelial Homeostasis Predisposing to Enterocolitis in Hirschsprung Disease.
Hirschsprung-associated enterocolitis, a lethal complication of Hirschsprung's disease-a prevalent congenital disorder with high morbidity-has a poorly understood pathogenesis. We investigated how aberrant immune-stromal crosstalk drives mucosal injury in Hirschsprung's disease. Integrated single-cell RNA sequencing, spatial transcriptomics, bulk RNA sequencing, and proteomics were performed using human Hirschsprung's disease tissues. Validation was conducted using murine Hirschsprung-associated enterocolitis (Ednrb-/-) models, flow cytometry, multiplex immunohistochemistry, in vitro B-cell stimulation, epithelial coculture, rescue experiments with the thymic stromal lymphopoietin inhibitor baicalein, and ex vivo intestinal organoid assays. We identified significant expansion and hyperactivation of B cells that colocalized with epithelial barrier defects in Hirschsprung's disease segments. Multiomics analysis revealed an activated phenotype in these naive and memory B cells, characterized by the upregulation of B lymphocyte kinase, B cell linker, and proliferating cell nuclear antigen, which may contribute to impaired epithelial homeostasis. Crucially, we identified profibrotic thymic stromal lymphopoietin+ fibroblasts enriched in Hirschsprung's disease. Spatial mapping and in vitro assays demonstrated that thymic stromal lymphopoietin potently activated B cells, synergizing with classical stimuli to enhance proliferation. Activated B cells, in turn, secreted proinflammatory factors, such as, ICAM1 and CCL5, which induced epithelial apoptosis, suppressed proliferation, and disrupted tight junctions-effects that were amplified by thymic stromal lymphopoietin costimulation. Activated B cells and epithelial dysfunction were conserved in Hirschsprung-associated enterocolitis (Ednrb-/-) mouse models. Coculture and ex vivo organoid experiments confirmed that thymic stromal lymphopoietin-activated B cells directly destabilized epithelial homeostasis; crucially, baicalein treatment rescued epithelial proliferation, attenuated apoptosis, and reduced inflammation-associated gene expression. Our study reveals a novel pathogenic mechanism whereby thymic stromal lymphopoietin instigates pathogenic B-cell hyperactivation, thereby disrupting epithelial integrity and increasing susceptibility to Hirschsprung-associated enterocolitis. Inhibition of thymic stromal lymphopoietin signaling with baicalein ameliorates epithelial injury, highlighting this axis as a promising therapeutic target for Hirschsprung-associated enterocolitis prevention in patients with Hirschsprung's disease.
2026-07-17 | Sacral Neuromodulation in Pediatric Gastrointestinal Motility Disorders: An Exploratory Prospective Cohort Analysis of Clinical Outcomes Based on Different Approaches.
To evaluate the efficacy and safety of minimally invasive sacral neuromodulation (SNM) and noninvasive enteral neuromodulation (ENM) in children with refractory gastrointestinal motility disorders (GMD). This prospective exploratory trial enrolled pediatric patients with GMD between 2019 and 2024 at a single tertiary referral center. Children with inflammatory bowel disease or mechanical causes of GMD were excluded. Participants received either SNM through an implanted device or ENM through surface electrodes. Stimulation was delivered at 14 Hz, 210 μs pulse width, with individualized intensity (median 1.0 mA for SNM; 6.0 mA for ENM). Primary outcomes were abdominal pain, fecal incontinence, defecation frequency, and stool consistency. Treatment success was defined as clinically significant improvement in at least two of these four domains. Quality of life was assessed at baseline and 12 weeks. Safety outcomes were monitored over a 12-month follow-up. Of 70 eligible patients, 48 completed the study (18 SNM; 30 ENM). Diagnoses included Hirschsprung disease, functional constipation, and congenital neuronal malformations. Severe comorbidities were more frequent in the SNM group (45%) than the ENM group (3%; p = 0.0018). Treatment success was observed in 80% (24/30) of the ENM cohort and 83% (15/18) of SNM cohort. No significant differences were found between groups for individual outcomes. No major complications occurred. Minor adverse events were comparable (ENM 27%; SNM 17%). Both SNM and ENM are effective and safe options for treating pediatric GMD and may be considered within a multimodal therapeutic approach. This trial is registered at clinicaltrials.gov (ID NCT04713085, title "Sacral Neuromodulation in Children and Adolescents"). Web link: https://clinicaltrials.gov/study/NCT04713085.
2026-08-13 | Ex vivo fluorescence confocal microscopy combined with rapid immunofluorescence for intraoperative intestinal mapping in near-total intestinal aganglionosis: a pediatric proof-of-concept case report.
In Hirschsprung disease (HD), intraoperative identification of ganglionated bowel remains central to surgical planning, particularly in extensive or near-total intestinal aganglionosis (nTIA), where bowel preservation is critical. Frozen-section histopathology remains the intraoperative standard. Ex-vivo fluorescence confocal microscopy (FCM) provides microscopic assessment of fresh tissue, while rapid immunofluorescence (rIF) has the potential to add targeted visualization of enteric neural structures. We describe a single pediatric proof-of-concept case in which FCM combined with selected rIF was integrated into intraoperative intestinal mapping. A full-term newborn, diagnosed at birth with nTIA, underwent tube stoma formation at 40 cm from the Treitz ligament without bowel resection. At 4-years, surgery was scheduled to remove aganglionic segments and lengthen the remaining bowel. During surgery the small bowel segment proximal to the ostomy measured 70 cm. Twenty-four full-thickness biopsies were collected every 20 cm from sigmoid colon to presumed ganglionic areas at stoma level. All samples underwent FCM for morphological assessment of fresh tissue. rIF was applied to four selected samples, two from presumed ganglionated bowel and two from presumed aganglionic bowel, as an adjunct to enhance visualization of S100B-positive neural and glial structures. Fresh tissue was incubated for 30 min with a primary anti-S100B antibody followed by an Alexa Fluor 647-conjugated secondary antibody, then rinsed and counterstained with acridine orange. Under fluorescence laser visualization ganglion cells were identified in functional segments while hypertrophic nerve fibers were detected in aganglionic regions. Surgical planning relied on integrated intraoperative assessment, with final confirmation by conventional histopathology. The simultaneous application of a longitudinal intestinal lengthening (LILT) ensured maximization of functional bowel. This single-case experience demonstrates the technical feasibility of integrating ex vivo FCM and rIF into intraoperative intestinal mapping for complex Hirschsprung disease. The approach should be regarded as exploratory and complementary to established histopathological assessment.
2026-08-02 | RNA methylation and the potential role of folate supplementation in preventing Hirschsprung disease.
To determine whether folate supplementation may reduce the incidence of Hirschsprung disease (HSCR) by regulating the methylation level of growth arrest-specific 5 (GAS5). The m6A methylation deficiency model and folate supplementation model were created using the m6A inhibitor 3-Deazaadenosine (DAZ) and folate, respectively. The effects of folate on the morphology, mortality, and number of HuC/D positive neurons in zebrafish were observed. The methylation level and proliferation ability of mouse enteric neural crest stem cells (ENCSCs) were detected by m6A ELISA and EdU assay respectively. Human HSCR cases and control tissues were collected. The expression level of GAS5 in intestinal tissues was detected by qRT-PCR. M6A ELISA, actinomycin D, and MeRIP qRT-PCR were used to detect the effect of folate on m6A methylation levels, GAS5 stability, and the content of m6A-modified GAS5 in N2a cells. The RIP assay was used to detect the content of GAS5 bound to YTH N6-methyladenosine RNA binding protein F2 (YTHDF2) under different folate concentrations. Supplementation of folate can ameliorate the decreased ENCSC proliferation ability caused by low m6A methylation level, reduce embryonic mortality of zebrafish and increase the number of HuC/D positive neurons at 96 hpf. Furthermore, folate may reduce the expression of the demethylase alkB homologue 5 (ALKBH5), weaken ALKBH5's demethylation effect on GAS5, promote the degradation of GAS5 by YTHDF2, and subsequently reduce the expression of GAS5. Additional folate supplementation during early embryonic development may serve as a strategy for preventing HSCR.
2026-07-21 | Extracellular vesicles in perinatal conditions: A minimally invasive approach to regenerative medicine.
Extracellular vesicles (EVs) are lipid bilayer-delimited nanoparticles released by cells to act as mediators of intercellular communication during organ development, injury, and repair. EVs carry cargo (bioactive proteins, lipids, and nucleic acids) that reflects the status of the parent cell and is transferred to recipient cells to regulate biological processes, such as inflammation, immune responses, and tissue regeneration. These properties have made EVs promising tools for investigating disease pathogenesis, improving diagnostic and prognostic accuracy, and developing cell-free regenerative therapies for conditions characterized by dysregulation of multiple biological pathways. EVs are particularly relevant in diseases that affect the pediatric population where pathogenesis often remains poorly understood, access to affected tissues is limited, and treatment options are frequently inadequate. This review summarizes current evidence on EV applications in fetal and neonatal disorders, including necrotizing enterocolitis, congenital diaphragmatic hernia, and bronchopulmonary dysplasia, and highlights emerging data in biliary atresia, spina bifida, short bowel syndrome, and Hirschsprung's disease. In this age group, human milk and amniotic fluid represent particularly attractive biologically accessible sources of EVs, combining therapeutic potential with feasibility of clinical application. Building on robust preclinical evidence, the field is now advancing toward clinical translation, but several aspects still need to be addressed such as cargo heterogeneity, scalability of production, dosing, biodistribution, safety, and regulatory standardization. Herein, we discuss the translational challenges and future directions that will shape the clinical application of EVs in perinatal conditions.
2026-07-17 | Thymic Stromal Lymphopoietin-Driven B-Cell Hyperactivation Impairs Intestinal Epithelial Homeostasis Predisposing to Enterocolitis in Hirschsprung Disease.
Hirschsprung-associated enterocolitis, a lethal complication of Hirschsprung's disease-a prevalent congenital disorder with high morbidity-has a poorly understood pathogenesis. We investigated how aberrant immune-stromal crosstalk drives mucosal injury in Hirschsprung's disease. Integrated single-cell RNA sequencing, spatial transcriptomics, bulk RNA sequencing, and proteomics were performed using human Hirschsprung's disease tissues. Validation was conducted using murine Hirschsprung-associated enterocolitis (Ednrb-/-) models, flow cytometry, multiplex immunohistochemistry, in vitro B-cell stimulation, epithelial coculture, rescue experiments with the thymic stromal lymphopoietin inhibitor baicalein, and ex vivo intestinal organoid assays. We identified significant expansion and hyperactivation of B cells that colocalized with epithelial barrier defects in Hirschsprung's disease segments. Multiomics analysis revealed an activated phenotype in these naive and memory B cells, characterized by the upregulation of B lymphocyte kinase, B cell linker, and proliferating cell nuclear antigen, which may contribute to impaired epithelial homeostasis. Crucially, we identified profibrotic thymic stromal lymphopoietin+ fibroblasts enriched in Hirschsprung's disease. Spatial mapping and in vitro assays demonstrated that thymic stromal lymphopoietin potently activated B cells, synergizing with classical stimuli to enhance proliferation. Activated B cells, in turn, secreted proinflammatory factors, such as, ICAM1 and CCL5, which induced epithelial apoptosis, suppressed proliferation, and disrupted tight junctions-effects that were amplified by thymic stromal lymphopoietin costimulation. Activated B cells and epithelial dysfunction were conserved in Hirschsprung-associated enterocolitis (Ednrb-/-) mouse models. Coculture and ex vivo organoid experiments confirmed that thymic stromal lymphopoietin-activated B cells directly destabilized epithelial homeostasis; crucially, baicalein treatment rescued epithelial proliferation, attenuated apoptosis, and reduced inflammation-associated gene expression. Our study reveals a novel pathogenic mechanism whereby thymic stromal lymphopoietin instigates pathogenic B-cell hyperactivation, thereby disrupting epithelial integrity and increasing susceptibility to Hirschsprung-associated enterocolitis. Inhibition of thymic stromal lymphopoietin signaling with baicalein ameliorates epithelial injury, highlighting this axis as a promising therapeutic target for Hirschsprung-associated enterocolitis prevention in patients with Hirschsprung's disease.
2026-07-17 | Sacral Neuromodulation in Pediatric Gastrointestinal Motility Disorders: An Exploratory Prospective Cohort Analysis of Clinical Outcomes Based on Different Approaches.
To evaluate the efficacy and safety of minimally invasive sacral neuromodulation (SNM) and noninvasive enteral neuromodulation (ENM) in children with refractory gastrointestinal motility disorders (GMD). This prospective exploratory trial enrolled pediatric patients with GMD between 2019 and 2024 at a single tertiary referral center. Children with inflammatory bowel disease or mechanical causes of GMD were excluded. Participants received either SNM through an implanted device or ENM through surface electrodes. Stimulation was delivered at 14 Hz, 210 μs pulse width, with individualized intensity (median 1.0 mA for SNM; 6.0 mA for ENM). Primary outcomes were abdominal pain, fecal incontinence, defecation frequency, and stool consistency. Treatment success was defined as clinically significant improvement in at least two of these four domains. Quality of life was assessed at baseline and 12 weeks. Safety outcomes were monitored over a 12-month follow-up. Of 70 eligible patients, 48 completed the study (18 SNM; 30 ENM). Diagnoses included Hirschsprung disease, functional constipation, and congenital neuronal malformations. Severe comorbidities were more frequent in the SNM group (45%) than the ENM group (3%; p = 0.0018). Treatment success was observed in 80% (24/30) of the ENM cohort and 83% (15/18) of SNM cohort. No significant differences were found between groups for individual outcomes. No major complications occurred. Minor adverse events were comparable (ENM 27%; SNM 17%). Both SNM and ENM are effective and safe options for treating pediatric GMD and may be considered within a multimodal therapeutic approach. This trial is registered at clinicaltrials.gov (ID NCT04713085, title "Sacral Neuromodulation in Children and Adolescents"). Web link: https://clinicaltrials.gov/study/NCT04713085.
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
3 orphan drug designations for Hirschsprung disease.
3 orphan drug designations for Hirschsprung disease.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Glial cell line-derived neurotrophic factor, sodium butyrate | small molecules | EMA | 2025-10-22 | — | CATS Consultants GmbH |
glial cell derived neurotrophic factor and sodium butyrate | other | FDA | 2025-03-03 | — | Neurenati Therapeutics |
autologous neurospheres containing enteric neural stem cells, enteric neurons, and glia | cell therapies | FDA | 2024-09-26 | — | Mass General Brigham |
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.