857. Intravenous Retroviral Gene Therapy in Neonatal Mucopolysaccharidosis VI Cats

Abstract

Mucopolysaccharidosis (MPS) VI is a lysosomal storage disease caused by deficient activity of N-acetylgalactosamine 4-sulfatase (4S) resulting in an inability to degrade the glycosaminoglycan (GAG) dermatan sulfate, which accumulates in the lysosomes. Clinical features include skeletal abnormalities, growth retardation, facial dysmorphia, and corneal clouding. Two MPS VI cats were injected intravenously at 4 days of age with a Moloney murine leukemia virus-based retroviral vector containing the human alpha-1-antitrypsin promoter, the feline 4S (f4S) cDNA (kindly provided by John J. Hopwood), and the woodchuck hepatitis virus posttranscriptional regulatory element. Both animals received 7.2X10E9 transducing units/kg of body weight. Stable f4S activity has been detected in serum throughout the study and the most recent values from samples taken at 6 months were 23 and 9 times normal. The f4S activities in liver biopsies taken at 5 months were 82 and 38 times normal and the concentration of GAG in the biopsies was reduced to normal levels, 1.2 and 1.8 ug/mg protein, respectively. In comparison, the GAG concentration in liver biopsies from the untreated MPS VI littermates was 34.9 and 20.6 ug/mg. The body weights of the treated cats are 130% and 122% that of their two untreated MPS VI sex-matched control littermates (average of 1.89 kg) and are not different from normal unrelated age- and sex-matched controls. There are profound differences in the appearance of the treated and untreated cats. The MPS VI controls have short ears and tails and their faces are broad and flat. They have joint stiffness and major locomotor difficulties. The treated cats have only mild facial dysmorphia, a much freer range of pelvic motion, near normal gaits, and are more physically active than their MPS VI littermates. The cat with the higher f4S activity is nearly indistinguishable from a phenotypically normal cat except for the eyes, as there was no significant improvement in corneal clouding. MPS VI is particularly suited to liver-directed therapy because unlike other MPS disorders, CNS involvement is minimal. Because MPS VI is a progressive disease, the full extent of the clinical benefit will only become evident over time. We will present a 10-month update, including radiographs comparing the skeletons of normal, treated, and untreated MPS VI cats.