Stem Cell Transplant Offers Hope for Children With Severe Monogenic IBD

A new retrospective study from The Children’s Hospital of Philadelphia (CHOP) highlights the promising outcomes of allogeneic hematopoietic stem cell transplant (HSCT) in children with monogenic inflammatory bowel disease (IBD), a rare and severe form of IBD driven by genetic mutations causing inborn errors of immunity and intestinal epithelial dysfunction.¹

The study, which evaluated 25 pediatric patients who underwent allogeneic HSCT between 2012 and 2022, found that 92% of patients achieved sustained, IBD medication–free remission after transplant. Remarkably, the cohort also experienced a 100% survival rate—a critical milestone given the severity of disease among this population.

“The younger the patient, the more likely we are to find a single gene driving their IBD,” said first study author Alyssa Baccarella, MD, MS, an attending physician with the Division of Gastroenterology, Hepatology, and Nutrition at CHOP, in a statement.² “By identifying these genes through genetic sequencing, we can truly personalize therapy for patients with identified defects. Stem cell transplant has become safer and more effective with protocol advances made over the last couple of decades.”

Monogenic IBD, which often presents before the age of 6 years and is classified as very early-onset IBD (VEO-IBD), follows a more aggressive and treatment-resistant course than polygenic IBD.³ More than 90 genes have been identified as causative in monogenic IBD, many of which are tied to inborn errors of immunity.⁴ Traditional IBD therapies, including immunosuppressive and biologic medications, are often ineffective in these patients, leaving them vulnerable to serious complications, including infections, growth failure, and multi-organ involvement.³

In this single-center study at CHOP, researchers identified causative gene mutations in 11 different genes among the 25 patients, 72% of whom were diagnosed with Crohn disease.¹ The majority (92%) had VEO-IBD, and more than half presented before the age of 1 year. These findings underscore the severity and early onset characteristic of monogenic IBD, often requiring timely and decisive interventions.

The primary outcome of the study was defined as sustained IBD medication-free remission following transplant, assessed using a standardized disease activity index. Secondary outcomes included mucosal healing observed via endoscopy, successful donor engraftment, improved growth metrics, reduced hospitalizations, fewer infections related to immune dysfunction, and assessment of transplant-related adverse events.

In this cohort, 8 patients had macroscopic ileal disease and 12 had upper gastrointestinal (GI) involvement; 44% had perianal disease. Before HSCT, 5 patients underwent luminal IBD surgery and 2 had permanent ileostomies. Most (76%) received IBD immunosuppressive therapy pre-transplant, including steroids (56%) and biologics/small molecules/immunomodulators (64%). Six patients, including 3 infants and 3 with CGD, did not receive IBD-specific therapy—patients with CGD were managed with antibiotics instead of anti-tumor necrosis factor α. At transplant, 7 had moderate/severe disease despite treatment, while 7 (mostly CGD) were in remission. None were in sustained medication-free remission pre-HSCT.

Researchers found that 92% of patients achieved sustained, IBD medication-free remission after transplant. Remarkably, the cohort also experienced a 100% survival rate—a critical milestone given the severity of disease among this population. | Image credit: pinkeyes - stock.adobe.com

Extraintestinal manifestations were common: 10 had symptoms like arthritis (n = 2), fevers (n = 5), oral ulcers (n = 6), and uveitis (n = 2). Four had autoimmune comorbidities. One developed diffuse large B cell lymphoma (IL-10R deficiency) and another HLH (STXBP2); both resolved pre-HSCT.

Median transplant age was 6.2 years with a 3-year median follow-up (range, 1-10); no deaths occurred. At last follow-up, 92% (n = 23/25) achieved sustained medication-free IBD remission. Among patients who didn’t have ileostomies, 80% were in remission at 1 year vs 0% at baseline. All 5 patients with ileostomies achieved remission—2 had successful re-anastomosis, 1 had colectomy with ileorectal anastomosis, and 2 retained permanent ostomies in remission.

Two patients had mild disease activity: 1 remained medication-free (STXBP2), and the other (STXBP3) required immunotherapy and diversion. Post-HSCT endoscopy (n=8) showed mucosal healing in 6; the remaining 2 had diversion colitis but were in remission after re-anastomosis.

Pre-transplant, 22/25 had serious infections. In the first post-HSCT year, 76% had infections (mostly viremia [52%] and bacteremia [28%]). By 18 months, 75% were infection-free. Hospital stays dropped from 23 days/year pre-HSCT to 1 day by year 2. Growth improved significantly: height Z-scores increased, and enteral nutrition dependence declined (average change, 10-4); no patients required TPN post-HSCT.

Donor chimerism exceeded 97% in 23/25 patients; 2 had stable mixed chimerism without symptoms. Two needed repeat HSCT for chimerism loss and reached over 99% engraftment. Acute GVHD occurred in 3 (n = 1 with chronic skin GVHD); 1 had transient multiorgan GVHD. Four developed veno-occlusive disease, but they all recovered. One had a GI bleed post-repeat transplant, successfully treated.

These results could have significant implications for the management of patients with severe monogenic IBD, particularly those unresponsive to conventional therapies. By targeting the root cause of disease—genetic defects affecting the immune system—HSCT offers a transformative approach that goes beyond symptom management to true disease modification and even potential cure.

Although further studies are needed to evaluate long-term outcomes, optimize transplant timing, and identify the most appropriate candidates, this research solidifies the role of HSCT as a powerful tool in the therapeutic arsenal for pediatric patients with monogenic IBD. It also underscores the importance of early genetic diagnosis and multidisciplinary care in managing this challenging condition.

“Our experience clearly indicates that a multidisciplinary collaborative team approach is essential for identifying appropriate transplant candidates…. While HSCT is currently indicated for only a subset of patients with monogenic IBD, insights gained from studying these cases may inform the development of novel therapeutic targets for the broader IBD population,” commented senior study author Judith R. Kelsen, MD, Program Director of the VEO-IBD Clinic and the Richard and Ann Frankel Chair in Gastroenterology Research at CHOP.²

Building on the promise that stem cell transplantation offered as a curative approach for children with severe monogenic IBD—by resetting the immune system at its root—emerging drug delivery innovations also transformed how inflammatory bowel disease was managed across broader patient populations. A recent review in Frontiers in Bioscience-Landmark highlighted how advanced systems such as nanoparticles, hydrogels, and microrobotics addressed long-standing challenges in gastrointestinal drug delivery.⁵

Whereas stem cell transplant offered curative potential for select patients, these novel delivery systems advanced precision medicine for many others by improving drug stability, targeting, and treatment adherence—offering new hope in the evolving landscape of IBD care.

References

1. Baccarella A, Patel T, Conrad MA, et al. Outcomes of allogeneic hematopoietic stem cell transplant in monogenic inflammatory bowel disease. Clin Gastroenterol Hepatol. Published online May 14, 2025. doi:10.1016/j.cgh.2025.03.018

2. Children’s Hospital of Philadelphia researchers show stem cell transplant offers potentially curative therapy in pediatric patients with monogenic inflammatory bowel disease. Press release. CHOP. May 20, 2025. Accessed June 2, 2025. https://www.newswise.com/articles/children-s-hospital-of-philadelphia-researchers-show-stem-cell-transplant-offers-potentially-curative-therapy-in-pediatric-patients-with-monogenic-inflammatory-bowel-disease

3. Nambu R, Warner N, Mulder DJ, et al. A systematic review of monogenic inflammatory bowel disease. Clin Gastroenterol Hepatol. 2022;20:e653-e663. doi:10.1016/j.cgh.2021.03.021
4. Bolton C, Smillie CS, Pandey S, et al. An integrated taxonomy for monogenic inflammatory bowel disease. Gastroenterology. 2022;162:859-876. doi:10.1053/j.gastro.2021.11.014

5. Jeremias S. The future of GI drug delivery in managing IBD. AJMC^®. April 10, 2025. Accessed June 2, 2025. https://www.ajmc.com/view/the-future-of-gi-drug-delivery-in-managing-ibd