Early skeletal outcomes after hematopoietic stem and progenitor cell gene therapy for Hurler syndrome

Sci Transl Med. 2024 May;16(745):eadi8214. doi: 10.1126/scitranslmed.adi8214. Epub 2024 May 1.


Mucopolysaccharidosis type I Hurler (MPSIH) is characterized by severe and progressive skeletal dysplasia that is not fully addressed by allogeneic hematopoietic stem cell transplantation (HSCT). Autologous hematopoietic stem progenitor cell-gene therapy (HSPC-GT) provides superior metabolic correction in patients with MPSIH compared with HSCT; however, its ability to affect skeletal manifestations is unknown. Eight patients with MPSIH (mean age at treatment: 1.9 years) received lentiviral-based HSPC-GT in a phase 1/2 clinical trial (NCT03488394). Clinical (growth, measures of kyphosis and genu velgum), functional (motor function, joint range of motion), and radiological [acetabular index (AI), migration percentage (MP) in hip x-rays and MRIs and spine MRI score] parameters of skeletal dysplasia were evaluated at baseline and multiple time points up to 4 years after treatment. Specific skeletal measures were retrospectively compared with an external cohort of HSCT-treated patients. At a median follow-up of 3.78 years after HSPC-GT, all patients treated with HSPC-GT exhibited longitudinal growth within WHO reference ranges and a median height gain greater than that observed in patients treated with HSCT after 3-year follow-up. Patients receiving HSPC-GT experienced complete and earlier normalization of joint mobility compared with patients treated with HSCT. Mean AI and MP showed progressive decreases after HSPC-GT, suggesting a reduction in acetabular dysplasia. Typical spine alterations measured through a spine MRI score stabilized after HSPC-GT. Clinical, functional, and radiological measures suggested an early beneficial effect of HSPC-GT on MPSIH-typical skeletal features. Longer follow-up is needed to draw definitive conclusions on HSPC-GT's impact on MPSIH skeletal dysplasia.

Publication types

  • Research Support, Non-U.S. Gov't
  • Clinical Trial, Phase II
  • Clinical Trial, Phase I
  • Research Support, N.I.H., Extramural

MeSH terms

  • Bone and Bones / pathology
  • Child
  • Child, Preschool
  • Female
  • Genetic Therapy*
  • Hematopoietic Stem Cell Transplantation*
  • Hematopoietic Stem Cells / metabolism
  • Humans
  • Infant
  • Magnetic Resonance Imaging
  • Male
  • Mucopolysaccharidosis I* / genetics
  • Mucopolysaccharidosis I* / pathology
  • Mucopolysaccharidosis I* / therapy
  • Treatment Outcome