How Does Hematopoietic Stem Cell Gene Therapy Affect Hip Dysplasia in Mucopolysaccharidosis Type I Hurler Syndrome? Radiological Outcomes at a Minimum 4-year Follow-up

BACKGROUND: Mucopolysaccharidosis type I (MPS IH), or Hurler syndrome, is a lysosomal disorder caused by glycosaminoglycan accumulation due to an α-L-iduronidase deficiency. It is characterized by progressive skeletal impairment and impaired cognitive development. Hip dysplasia is a major skeletal manifestation for which conventional treatments (allogeneic hematopoietic stem cell transplantation with or without enzyme replacement therapy) does not prevent progression. QUESTIONS/PURPOSES: Among patients with MPS IH, does hematopoietic stem cell gene therapy (HSC-GT) result in (1) longitudinal improvement in bony measurements of hip dysplasia, specifically the acetabular index (the angle between the Hilgenreiner line and the line drawn from the Y-cartilage to the lateral edge of the acetabular roof) and migration percentage (the proportion of the femoral head lateral to a Perkins line drawn from the lateral edge of the acetabular roof); (2) improvement in the cartilaginous acetabular index and migration percentage, accounting for the cartilaginous components of the acetabular roof and femoral head; and (3) an increase in the proportion of patients with an acetabular index and cartilaginous acetabular index within published norms? METHODS: Between 2018 and 2019, 8 patients (6 males, 2 females) with MPS IH received OTL-203, an HSC-GT, in a Phase I/II clinical trial. All patients met the trial eligibility criteria, including absence of a suitable allogeneic donor and a Developmental Quotient or Intelligence Quotient score ≥ 70. Median (range) age at treatment was 23.5 months (14 to 34). All patients had dysplastic hip morphology at baseline, with abnormal acetabular index values and reduced femoral head coverage. This secondary analysis used prospectively collected orthopaedic and skeletal data from the same trial cohort, including hip radiographs and MRIs obtained during multidisciplinary follow-up. All patients completed the 5-year follow-up and entered the approved long-term follow-up program (up to 15 years after HSC-GT); no patients were lost to follow-up. One patient with pretreatment bilateral hip dislocation underwent hip surgery and was excluded from the subsequent longitudinal analysis, with radiological data retained up to surgery. One additional patient had missing radiographic assessments because behavioral difficulties precluded imaging; all other patients had 4-year assessments available. Hip dysplasia was assessed at baseline and 1, 2, 3, and 4 years after HSC-GT using acetabular index and migration percentage on radiographs and MRIs, as well as cartilaginous acetabular index and cartilaginous migration percentage on MRI. Radiological measurements were compared with published age- and sex-specific normative values. Mean ± SD age at last follow-up was 5.8 ± 0.5 years. RESULTS: Radiographic acetabular index and migration percentage decreased longitudinally (acetabular index: fixed effect estimate = -2.7° per year [95% CI -3.5° to -1.9°]; p < 0.001; migration percentage: fixed effect estimate = -8.1% per year [95% CI -9.8% to -6.3%]; p < 0.001). MRI acetabular index, migration percentage, and cartilaginous acetabular index decreased longitudinally (acetabular index: fixed effect estimate = -2.2° per year [95% CI -3.1° to -1.2°]; p < 0.001; migration percentage: fixed effect estimate = -2.6% per year [95% CI -4.4% to -0.9%]; p = 0.003; cartilaginous acetabular index: fixed effect estimate = -0.8° per year [95% CI -1.6° to -0.1°]; p = 0.02). However, there was no overall longitudinal change in cartilaginous migration percentage when all timepoints were considered (fixed effect estimate = -0.8% per year [95% CI -1.8% to 0.3%]; p = 0.15). The proportion of hips with acetabular measurements within published normative ranges increased during follow-up: acetabular index consistent with hip dysplasia decreased from 12 of 14 hips at baseline to 6 of 12 hips at 4 years, and severe hip dysplasia decreased from 11 of 14 hips to 1 of 12 hips within the same time frame. MRI measurements showed a similar shift toward published normative values from individuals without MPS IH. Radiographic and MRI measurements were positively correlated across examinations obtained at the same timepoints (acetabular index: r = 0.61 [95% CI 0.42 to 0.75]; p < 0.001; migration percentage: r = 0.54 [95% CI 0.32 to 0.70]; p < 0.001). Variations between baseline and 4-year follow-up in bony and cartilaginous measurements were also positively correlated (acetabular index and cartilaginous acetabular index: r = 0.53 [95% CI 0.001 to 0.83]; p = 0.05; migration percentage and cartilaginous femoral head coverage: r = 0.61 [95% CI 0.06 to 0.88]; p = 0.03). CONCLUSION: These findings suggest that hip dysplasia may stabilize or improve after OTL-203 treatment, supporting continued radiological surveillance in young children after HSC-GT. Longer-term prospective multicenter studies are needed to assess durability and clinical relevance and to compare outcomes with bone marrow transplantation. LEVEL OF EVIDENCE: Level IV, therapeutic study.