Human genome-edited hematopoietic stem cells phenotypically correct Mucopolysaccharidosis type I

Area of Science:

• Biotechnology
• Genetic Engineering
• Hematology

Background:

• Lysosomal enzyme deficiencies are genetic disorders with limited treatment options.
• Hematopoietic stem cell engineering offers a potential therapeutic strategy by enabling enzyme expression.

Purpose of the Study:

• To develop an ex vivo genome editing approach for treating Mucopolysaccharidosis type I (MPS I).
• To utilize the CCR5 safe harbor locus for targeted expression of the iduronidase enzyme.

Main Methods:

• CRISPR-Cas9 gene editing was employed to modify human CD34+ hematopoietic stem and progenitor cells.
• Targeting the CCR5 safe harbor locus for stable expression of the iduronidase enzyme.
• Evaluation of modified cells' engraftment, differentiation potential, and therapeutic efficacy in an MPS I mouse model.

Main Results:

• Engineered cells secreted supra-endogenous levels of the iduronidase enzyme.
• Modified cells demonstrated long-term repopulation and multi-lineage differentiation capacity.
• Significant improvement in biochemical and phenotypic abnormalities was observed in the MPS I mouse model.

Conclusions:

• Genome-edited CD34+ hematopoietic stem and progenitor cells show potential as a treatment for MPS I.
• The safe harbor targeting approach is a flexible platform applicable to other lysosomal storage disorders.