Lysosomal storage disease: Gene therapy on both sides of the blood–brain barrier

Highlights

• Gene therapy for LSD using LV-HSC and AAV9 or rh.10 vectors is ready for translation to the clinic.

• Liver-directed gene therapy can ameliorate neurologic disease.

• Efficiency of liver-directed gene therapy can be increased.

• The major challenge for non-viral vectors is their delivery to large animals.

• Evaluation of neurologic correction in animal models is inadequate.

Abstract

Most lysosomal storage disorders affect the nervous system as well as other tissues and organs of the body. Previously, the complexities of these diseases, particularly in treating neurologic abnormalities, were too great to surmount. However, based on recent developments there are realistic expectations that effective therapies are coming soon. Gene therapy offers the possibility of affordable, comprehensive treatment associated with these diseases currently not provided by standards of care. With a focus on correction of neurologic disease by systemic gene therapy of mucopolysaccharidoses types I and IIIA, we review some of the major recent advances in viral and non-viral vectors, methods of their delivery and strategies leading to correction of both the nervous and somatic tissues as well as evaluation of functional correction of neurologic manifestations in animal models. We discuss two questions: what systemic gene therapy strategies work best for correction of both somatic and neurologic abnormalities in a lysosomal storage disorder and is there evidence that targeting peripheral tissues (e.g., in the liver) has a future for ameliorating neurologic disease in patients?