ZFN-Mediated In Vivo Genome Editing Corrects Murine Hurler Syndrome.

Area of Science:

• Genetics
• Biotechnology
• Lysosomal Storage Diseases

Background:

• Mucopolysaccharidosis type I (MPS I) is a severe inherited lysosomal storage disease caused by alpha-L-iduronidase (IDUA) deficiency.
• Accumulation of glycosaminoglycans (GAGs) leads to progressive systemic pathology and reduced lifespan.
• Current treatments like stem cell transplantation and enzyme replacement therapy have limitations and risks.

Purpose of the Study:

• To evaluate a novel in vivo genome-editing strategy for treating MPS I.
• To establish a proof-of-concept for a platform-based gene therapy approach for monogenic diseases.

Main Methods:

• Utilized a murine model of Hurler syndrome (MPS I).
• Inserted a functional IDUA gene copy into the albumin locus of hepatocytes.
• Assessed sustained enzyme expression, systemic secretion, and therapeutic efficacy.

Main Results:

• Achieved sustained expression and secretion of IDUA enzyme from hepatocytes into circulation.
• Demonstrated correction of GAG substrate accumulation, reversing metabolic disease.
• Prevented neurobehavioral deficits in MPS I mice, indicating systemic therapeutic effects.

Conclusions:

• In vivo genome editing at the albumin locus is a viable strategy for MPS I treatment.
• This platform-based approach shows broad applicability for treating various monogenic disorders.
• The study provides a promising new therapeutic avenue for MPS I and other genetic diseases.