Methods and compositions for the treatment of lysosomal storage diseases

A method for expressing and secreting exogenous glucocerbrosidase (GBA), α-galactosidase A (GLA), iduronate sulftase (IDS), iduronidase (IDUA) protein, or α-glucosidase (GAA) in a liver cell in a human with a deficient GLA, GBA, IDS, IDUA, or GAA gene, the method comprising:

• (i) intravenously injecting one or more adeno-associated viral (AAV) vectors encoding a pair of zinc finger nucleases (ZFNs) into the human, wherein the ZFNs target and cleave intron 1 of an endogenous albumin gene in the liver cell;
• and
• (ii) intravenously injecting an AAV vector comprising a donor sequence comprising a transgene encoding:
• (a) an exogenous GBA protein into the human with the deficient GBA gene;
• (b) an exogenous GLA protein into the human with the deficient GLA gene;
• (c) an exogenous IDS protein into the human with the deficient IDS gene;
• (d) an exogenous IDUA protein into the human with the deficient IDUA gene, or
• (e) an exogenous GAA protein into the human with the deficient GAA gene, and
• wherein the transgene is flanked by sequences having homology with the endogenous albumin gene,
• such that the transgene is integrated into the endogenous albumin gene in the liver cell, and the liver cell expresses and secretes the exogenous GBA, GLA, IDS, IDUA, or GAA protein.