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Enhanced secretion and uptake of beta-glucuronidase improves adeno-associated viral-mediated gene therapy of

Susan S Elliger¹, Carl A Elliger, Chen Lang

¹Children's Hospital Oakland Research Institute, Oakland, California 94609, USA. selliger@chori.org

Molecular Therapy : the Journal of the American Society of Gene Therapy

|May 7, 2002

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Gene therapy for Sly syndrome (mucopolysaccharidosis type VII) using enhanced AAV vectors significantly boosted beta-glucuronidase (GUS) enzyme levels, improving overall health and enabling treated mice to breed. Offspring were unaffected but showed resistance to subsequent intravenous gene therapy.

Area of Science:

Genetics
Molecular Biology
Biochemistry

Background:

Mucopolysaccharidosis type VII (Sly syndrome) is a genetic disorder characterized by the accumulation of glycosaminoglycans due to beta-glucuronidase (GUS) deficiency.
Previous AAV vector treatments showed limited GUS enzyme distribution and health improvements in affected mice.
Enhancing AAV vectors with secretion and uptake signals may improve gene therapy efficacy for lysosomal storage diseases.

Purpose of the Study:

To evaluate the efficacy of an enhanced AAV vector carrying GUS with secretion and uptake signals for treating Sly syndrome in mice.
To assess the distribution of GUS enzyme and therapeutic effects in various tissues following combined intrathecal and intravenous administration.
To determine the long-term health benefits and reproductive capacity of treated mice and the impact on their offspring.

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Main Methods:

Development of an AAV vector encoding a modified GUS gene with Igkappa and HIV-1 TAT signals for enhanced secretion and cellular uptake.
Administration of the enhanced AAV vector intrathecally and intravenously to newborn Sly syndrome mice.
Measurement of GUS enzyme levels, glycosaminoglycan storage, AAV GUS DNA, and phenotypic improvements in treated mice and their offspring.
Assessment of immune response in offspring to subsequent AAV GUS treatments.

Main Results:

Significantly increased GUS enzyme levels in multiple tissues, including serum, heart, and aorta, leading to reduced glycosaminoglycan storage.
Therapeutic GUS levels in serum reduced storage in non-transduced tissues like the spleen.
Treated mice exhibited improved health, increased activity, reduced skeletal growth stunting, and successful breeding.
Offspring did not inherit the therapeutic benefits but developed resistance to intravenous AAV GUS treatment due to maternal antibodies.

Conclusions:

Enhanced AAV vectors with secretion and uptake signals represent a promising strategy for treating Sly syndrome, improving enzyme distribution and overall health.
Combined intrathecal and intravenous delivery in newborns can achieve widespread therapeutic effects, even in non-transduced tissues.
Maternal antibodies can confer resistance to subsequent intravenous gene therapy in offspring, highlighting the importance of treatment timing and route.