Status: Funded - Open
Correction of Mucopolysaccharidosis type 1: Targeting safe harbor loci using genome editing
Natalia Gomez-Ospina, MD, PhD
BACKGROUND: Mucopolysaccharidosis type I (MPSI) is a lysosomal storage disease (LSD) whose manifestations start in early infancy and include relentless neurologic decline, progressive skeletal deformities, and respiratory compromise for which current treatments have limited effectiveness.
GAP: Current interventions for LSDs including MPSI are hematopoietic stem cell transplantation (HSCT), which has high morbidity and mortality due to transplant-related complications, and enzyme replacement therapy (ERT), where the blood-brain barrier limits the usefulness to cases without neurological involvement.
HYPOTHESIS: We hypothesize that the treatment of LSDs, beginning with MPSI, can be improved by modifying the patient’s own hematopoietic stem cells using genome editing to insert the enzymes into well-characterized locations known as “safe harbors.” We predict that human hematopoietic stem cells can be effectively and safely modified without losing their stem cell properties and that the modified human cells should correct a humanized model of the disease.
METHODS The fundamental approach uses CRISPR/Cas9 and AAV6 to introduce functional enzyme into two well-characterized genomic loci into human hematopoietic stem cells, and uses in vitro and in vivo
studies to demonstrate the safety and efficacy of the modification. This study uses human cell lines, human CD34+ hematopoietic cells isolated from cord blood or mobilized peripheral blood from donors, and mice.
IMPACT: If successful the approach would constitute a treatment platform for other LSDs. The next step towards clinical applicability is to perform the optimization necessary to establish a GMP cell manufacturing process and to begin a pre-Investigational New Drug (IND) application.