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<p>Hirschsprungʼs disease (HD) is a&#xa0;congenital developmental disorder of the enteric nervous system characterized by the absence of enteric ganglion cells in a distal bowel segment, usually the rectosigmoid colon. This lack of peristalsis leads to functional obstruction, manifesting in neonates typically as delayed meconium passage, abdominal distension and vomiting. The current standard of care is surgical resection of the aganglionic segment and connection of the healthy segment to the anal channel with a&#xa0;pull-through procedure. Despite initial success, many patients experience long-term complications such as chronic constipation, fecal incontinence and Hirschsprung-associated enterocolitis (HAEC), which underlines the need for innovative treatment options. Recent research has increasingly focused on organoid technology and cell-based therapies. Intestinal organoids can be derived from patient-specific biopsies or induced pluripotent stem cells (iPSC) and subsequently populated with enteric neural crest cells (ENCC) to simulate essential features of the enteric nervous system (ENS). These “mini-guts” enable personalized modelling of HD pathophysiology, enabling drug screening and exploration of genetic interventions (e.g., CRISPR/Cas9-mediated correction of RET mutations).</p><p>Simultaneously, various approaches to reinnervate aganglionic bowel segments using cell transplantation are being tested. By transplantation of ENS precursor cells into the aganglionic bowel segment, functional ganglionic structures can be reconstituted and the motility can therefore be causally improved. Animal experimental studies have shown initial success including a&#xa0;partial restoration of peristalsis and support the formation of functional neural networks; however, the technical and biological complexity of such procedures, such as the scaling of cell numbers, the exact integration of neural cells and long-term safety, have not yet finally been solved.</p><p>Nevertheless, these areas of research offer promising prospects: within the next 5–10&#xa0;years organoid-based diagnostics, e.g., for functional characterization of patient-derived organoids or in vitro testing of pharmacological compounds as well as cell-based therapeutic interventions, could complement conventional surgery or even replace it in certain high-risk groups. Clinical trials will be needed to determine whether targeted causative treatment can lead to long-term improvements in the prognosis, particularly with respect to chronic constipation and the risk of enterocolitis. The close collaboration between basic research and clinical practice will be essential to translate these new treatment options into pediatric care practice and to offer affected patients a&#xa0;sustainable improvement in the quality of life.</p>

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Morbus Hirschsprung (MH): Organoide und Zelltherapien als wegweisende Ansätze für Diagnostik und Therapie

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月25日

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  • Konrad Reinshagen,
  • Johanna Hagens,
  • Christian Tomuschat

摘要

Hirschsprungʼs disease (HD) is a congenital developmental disorder of the enteric nervous system characterized by the absence of enteric ganglion cells in a distal bowel segment, usually the rectosigmoid colon. This lack of peristalsis leads to functional obstruction, manifesting in neonates typically as delayed meconium passage, abdominal distension and vomiting. The current standard of care is surgical resection of the aganglionic segment and connection of the healthy segment to the anal channel with a pull-through procedure. Despite initial success, many patients experience long-term complications such as chronic constipation, fecal incontinence and Hirschsprung-associated enterocolitis (HAEC), which underlines the need for innovative treatment options. Recent research has increasingly focused on organoid technology and cell-based therapies. Intestinal organoids can be derived from patient-specific biopsies or induced pluripotent stem cells (iPSC) and subsequently populated with enteric neural crest cells (ENCC) to simulate essential features of the enteric nervous system (ENS). These “mini-guts” enable personalized modelling of HD pathophysiology, enabling drug screening and exploration of genetic interventions (e.g., CRISPR/Cas9-mediated correction of RET mutations).

Simultaneously, various approaches to reinnervate aganglionic bowel segments using cell transplantation are being tested. By transplantation of ENS precursor cells into the aganglionic bowel segment, functional ganglionic structures can be reconstituted and the motility can therefore be causally improved. Animal experimental studies have shown initial success including a partial restoration of peristalsis and support the formation of functional neural networks; however, the technical and biological complexity of such procedures, such as the scaling of cell numbers, the exact integration of neural cells and long-term safety, have not yet finally been solved.

Nevertheless, these areas of research offer promising prospects: within the next 5–10 years organoid-based diagnostics, e.g., for functional characterization of patient-derived organoids or in vitro testing of pharmacological compounds as well as cell-based therapeutic interventions, could complement conventional surgery or even replace it in certain high-risk groups. Clinical trials will be needed to determine whether targeted causative treatment can lead to long-term improvements in the prognosis, particularly with respect to chronic constipation and the risk of enterocolitis. The close collaboration between basic research and clinical practice will be essential to translate these new treatment options into pediatric care practice and to offer affected patients a sustainable improvement in the quality of life.