University of Minnesota – Dr. Chester Whitley
Our overall objective is to assess and optimize the transfer and expression of a therapeutic gene using a third-generation lentiviral gene therapy system. We hope that transfer of the normal gene will replace the missing function of the mutant gene, and thus treat the disease. In our laboratory, we recently observed that a single intravenous injection on the first day of life “cures” virtually all features of mucopolysaccharidosis disease in mice with Hurler syndrome. When receiving this treatment, enzyme-deficient mice exhibit long-term expression of normal enzyme, achieving blood levels that are sometimes many-fold above normal levels. Importantly, such mice never develop the characteristic microscopic pathology of mucopolysaccharidosis disease in tissues, including the brain. We hope that the same strategy will prove effective in replacing the alpha-N-acetylglucosaminidase (NAGLU) enzyme that is missing in Sanfilippo syndrome type B. To date, we have constructed the NAGLU lentiviral vector and have used this to transduce the normal NAGLU gene into mouse cells grown in tissue culture; this procedure yielded normal NAGLU enzyme activity, and would therefore seem to predict a “cure” in affected mice analogous to results in Hurler syndrome. If funded, future work will determine whether this dramatic response can be achieved in mice afflicted with Sanfilippo syndrome. Special attention will be focused on attaining metabolic correction in the central nervous system, and preventing the neurologic deterioration that is characteristic of Sanfilippo syndrome.