Shunji Tomatsu, Adriana Montano-Suarez, Carlos J. Almeciga-Diaz and Luis Barrera
This invention relates to compositions and methods of delivering therapeutic agents to bone. More specifically, the invention relates to endowing a large molecule vectors i.e., adeno virus, retrovirus, liposomes, micelles, natural and synthetic polymers, or combinations thereof, with the ability to target bone tissue in vivo and with improved stability in the blood, by attaching multiple copies of acid amino acid peptides. One preferred embodiment of the invention relates to endowing an adeno-associated virus (AAV) vector with the ability to target bone-tissue in vivo and improve its stability, by the addition of multiple acidic amino acid peptides attached to the capsid of the viral vector.
Mucopolysaccharidosis IVA (MPS IVA) is an autosomal recessive disorder caused by deficiency of N-acetylgalactosamine-6-sulfate-sulfatase (GALNS), leading to accumulation of glycosaminoglycans (GAGs), keratan sulfate (KS) and chondroitin-6-sulfate. Clinical manifestations vary from severe to an attenuated form characterized by systemic skeletal dysplasia, laxity of joints, hearing loss, corneal clouding, and heart valvular disease, with normal intelligence. Currently, no effective therapies exist for MPS IVA. Surgical interventions are used to treat some manifestations of the disease. Although other tissues are affected in MPS IVA patients, an ideal therapeutic agent would be efficiently distributed to bone and bone marrow. Other diseases also exist for which delivery of therapeutic agents to bone would be beneficial. One example is hypophosphotasia, for which the targeted delivery of tissue non-specific alkaline phosphatase (TNSALP) would be highly beneficial. Another example is type VII mucopolysaccharidosis, which would benefit greatly from the targeted delivery of .beta.-glucuronidase (GUS). Gene and enzyme replacement therapy are promising treatments for bone related diseases.