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. Â We hope that transfer of the normal gene will replace the missing function of the mutant gene, and thus treat the disease. Â 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. Â 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. Â Importantly, such mice never develop the characteristic microscopic pathology of mucopolysaccharidosis disease in tissues, including the brain. Â 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. Â 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. Â If funded, future work will determine whether this dramatic response can be achieved in mice afflicted with Sanfilippo syndrome. Â 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.
