Beyond the CNS and Skeleton: HSPC-Gene Therapy (OTL-203) Demonstrates Superior Multi-System Efficacy in Hurler Syndrome

Introduction: The Evolving Landscape of MPSIH Treatment

Mucopolysaccharidosis type I Hurler (MPSIH) represents the most severe phenotype of alpha-L-iduronidase (IDUA) deficiency. This lysosomal storage disorder is characterized by the progressive accumulation of glycosaminoglycans (GAGs), leading to a devastating cascade of multi-organ dysfunction. For decades, allogeneic hematopoietic stem cell transplantation (allo-HSCT) has stood as the gold standard of care, primarily for its ability to preserve cognitive function when administered early in life. However, while allo-HSCT provides a life-saving source of functional IDUA, it remains a sub-optimal solution for many non-neurological manifestations of the disease. Residual disease in the skeletal, ocular, auditory, and cardiovascular systems often persists, necessitating frequent surgical interventions and diminishing the quality of life for survivors.

In a landmark study published in Molecular Therapy, Tucci et al. (2026) present findings from a Phase I/II clinical trial (NCT03488394) evaluating OTL-203, an autologous hematopoietic stem and progenitor cell-gene therapy (HSPC-GT). This treatment utilizes a lentiviral vector to deliver a functional IDUA gene into the patient’s own stem cells. The results suggest that by achieving supraphysiological enzyme levels, HSPC-GT may address the unmet clinical needs that allo-HSCT leaves behind.

Highlighting Clinical Advancements

– HSPC-GT (OTL-203) achieved stable engraftment and supraphysiological IDUA activity in all treated patients, with no evidence of insertional oncogenesis or immune-mediated transgene rejection over a 4-year follow-up.
– Compared to a retrospective allo-HSCT cohort, patients receiving gene therapy showed superior outcomes in corneal clouding resolution and hearing preservation.
– OTL-203 appears to mitigate the progression of carpal tunnel syndrome and valvular heart disease, reducing the long-term surgical burden typically associated with Hurler syndrome.

The Clinical Burden and Limitations of Allogeneic HSCT

MPSIH is a multisystemic disease. While the neurological benefits of allo-HSCT are well-documented—stemming from the replacement of host microglia with donor-derived cells that secrete enzyme within the central nervous system—the peripheral manifestations are less responsive. Allogeneic transplantation often fails to provide sufficient enzyme levels to poorly vascularized tissues such as the cornea, heart valves, and tendons. Furthermore, allo-HSCT carries significant risks, including graft-versus-host disease (GvHD), graft failure, and the need for prolonged immunosuppression. These limitations underscored the need for a more potent, autologous solution that could deliver higher, more consistent levels of the missing enzyme.

Study Design and Patient Population

The study evaluated eight patients with MPSIH who underwent treatment with OTL-203. These patients were followed for up to 4 years post-infusion. The primary objective was to assess safety and engraftment, while secondary endpoints focused on multisystemic clinical outcomes, specifically those that are historically resistant to allo-HSCT. To provide context, the researchers utilized a retrospective external cohort of nine MPSIH patients who had undergone traditional allo-HSCT.

The intervention involved the mobilization of autologous CD34+ cells, followed by ex vivo transduction with a lentiviral vector carrying the human IDUA cDNA under the control of a high-expression promoter. Patients received busulfan-based conditioning prior to the re-infusion of the gene-modified cells.

Key Findings: A New Paradigm for Multisystemic Recovery

Ophthalmologic Outcomes: Clearing the Vision

One of the most striking findings of the study was the impact on corneal clouding. In the HSPC-GT cohort, 3 out of 8 patients experienced complete resolution of corneal clouding at the last follow-up. In contrast, all patients in the allo-HSCT cohort maintained moderate corneal clouding throughout the study period. This suggests that the supraphysiological levels of circulating IDUA achieved via gene therapy are better able to penetrate the avascular corneal stroma and clear accumulated GAGs.

Auditory Preservation and Improvement

Sensorineural and conductive hearing loss are nearly universal in untreated MPSIH. The study found that 4 out of 8 HSPC-GT patients maintained normal hearing function at their last follow-up. This was due to either the stabilization of baseline hearing or significant improvement in pre-existing deficits. Conversely, the allo-HSCT cohort showed a higher prevalence of persistent mild-to-moderate hearing loss, highlighting a potential advantage for OTL-203 in preserving the delicate structures of the inner and middle ear.

Orthopedic and Neuropathic Benefits: Carpal Tunnel Syndrome

Carpal tunnel syndrome (CTS) is a major cause of morbidity in MPSIH, often requiring multiple surgical releases. Remarkably, no patients in the HSPC-GT group required surgery for CTS that developed post-treatment. In the allo-HSCT cohort, 7 out of 9 patients required surgical intervention for CTS during the follow-up period. This suggests that gene therapy may more effectively reduce the thickening of the transverse carpal ligament and the surrounding synovial tissue.

Cardiovascular Stability

Cardiac involvement, particularly valvular thickening and insufficiency, is a leading cause of mortality in aging MPSIH patients. In the OTL-203 group, no patients developed severe cardiomyopathy or required valve replacement. While valvular disease did not entirely disappear, it remained stable. In the HSCT cohort, 4 out of 9 patients showed a clear progression of valvular insufficiency, suggesting that the higher enzyme levels provided by OTL-203 may offer better protection for the endocardium and heart valves.

Safety and Biological Plausibility

Safety is a paramount concern in any gene therapy trial. All eight patients in the OTL-203 trial were alive at the last follow-up with stable hematopoietic engraftment. There were no reports of graft failure, GvHD, or insertional oncogenesis—a risk historically associated with older gamma-retroviral vectors. Furthermore, none of the patients developed inhibitory antibodies (immune responses) against the IDUA transgene, which is a common complication in enzyme replacement therapy (ERT).

The biological plausibility for these superior results lies in the “over-expression” strategy. By using a lentiviral vector with a strong promoter, the gene-modified stem cells and their progeny (monocytes, macrophages, etc.) produce IDUA at levels significantly higher than those found in healthy donors. This creates a more robust concentration gradient, allowing the enzyme to reach “sanctuary sites” like the cornea and heart valves more effectively than the donor cells in a standard allo-HSCT, which only produce enzyme at normal physiological levels.

Expert Commentary and Clinical Implications

Clinical experts note that these findings could redefine the treatment algorithm for MPSIH. While allo-HSCT has been the cornerstone of therapy for decades, the metabolic “correction” it provides is often incomplete. The data from Tucci et al. suggest that OTL-203 provides a more comprehensive metabolic rescue.

However, limitations must be acknowledged. The study size is small (n=8), and the comparison to the allo-HSCT group was retrospective. Long-term monitoring remains essential to ensure the continued safety of the lentiviral integration and the durability of the enzyme expression. Additionally, while the non-neurological outcomes are promising, the skeletal system (dysostosis multiplex) remains a challenge for both allo-HSCT and HSPC-GT, likely requiring earlier intervention or adjunctive therapies.

Conclusion

The OTL-203 trial represents a significant leap forward in the treatment of Hurler syndrome. By demonstrating superior efficacy in clearing corneal clouding, preserving hearing, and preventing surgical complications like carpal tunnel syndrome, this gene therapy approach addresses the chronic morbidities that allo-HSCT cannot. As we move toward a future of personalized genomic medicine, OTL-203 stands as a potent example of how autologous gene-modified stem cells can outperform traditional donor transplantation in complex, multisystemic metabolic diseases.

Funding and ClinicalTrials.gov

This study was supported by Orchard Therapeutics and conducted at the San Raffaele Telethon Institute for Gene Therapy (SR-Tiget). Clinical trial registration: NCT03488394.

References

1. Tucci F, Uria Oficialdegui ML, Consiglieri G, et al. Non-neurological, non-skeletal outcomes after hematopoietic stem and progenitor cell-gene therapy (OTL-203) for Hurler syndrome. Mol Ther. 2026;34(1):443-454.
2. Aldenhoven M, Boelens JJ, de Koning TJ. The clinical outcome of Hurler syndrome after bone marrow transplantation. Biol Blood Marrow Transplant. 2008;14(4):485-498.
3. Gentner B, Tucci F, Castagnaro S, et al. Hematopoietic Stem-and-Progenitor-Cell Gene Therapy for Hurler Syndrome. N Engl J Med. 2021;385(21):1929-1940.