28 Targeted Delivery of Glycine Receptors to Peripheral Neurons as Treatment for Pain 26 Correction of Brain Lesions in MPS I Dogs after Neonatal Systemic Gene Therapy May Involve Migration of Blood C[.]
26 Correction of Brain Lesions in MPS I Dogs after Neonatal Systemic Gene Therapy May Involve Migration of Blood Cells into the Brain 27 Analysis of the Transduction and Biodistribution Patterns of Alternative AAV Vector Serotypes in the CNS of Adult Rhesus Macaques Mark E Haskins,' Anne M Traas,' Ping Wang,' Xiucui Ma,2 Mindy Tiuiger,' Patricia O'Donnell,' Charles Vite,' Katherine P Ponder.' Bruce A Bunnell,I Jason Dufour,' Mette Flaat,' Jeanne Fisher, I Xavier Alvarez,' Kate Baker,' Pete Didier,' Andrew Lackner,' John H Wolfe.2 'School of Veterinary Medicine University a/Pennsylvania Philadelphia PA; 2/m em al Medicine Washington University School a/Medicine, St LOllis Mo 'Gene Therapy Comparative Pathology, Veterinary Medicine Tulane National Primate Research Center; Covington, LA; 2Division a/Neurology, Children s Hospital 0/Philadelphia Philadelphia, PA Neurologicaldisease is a major manifestationof many lysosomal storage diseases (LSD) MucopolysaccharidosisI (MPS I) is due to deficient activity ofa-L-iduronidase (IDUA) and results in cognitive dysfunction in the severe form known as Hurler syndrome Gene therapy approaches to prevent storage in the brain have included direct injection of a viral vector or hematopoietic stem cell (HSC)-directed gene therapy The goal of this study was to determine ifsystemic gene therapy could treat neurologicaldisease in MPS I dogs, and to define the mechanism by which this occurs An amphotropic retroviral vector (RV) expressing canine IDUA from the human n l-antitrypsin promoter was generated This can also express IDUA in non-hepatic cells from the long-terminal repeat (LTR) MPS I dogs that were injected IV at days of age with 4x I 09 transducing units/kg of RV achieved stable expression at 366±344 units/ml (28-fold normal) of IDUA activity in serum At -I year after transduction, RV-treated dogs had 6.8±6 Ulmg of IDUA activity in brain, which was 80% of normal and 19-foldthat in untreated MPS I dogs Untreated MPS I dogs had 13.9±6.1 ug glycosaminoglycan/mgprotein in brain This was reduced to 1±0.5 in RV-treated dogs, which was similar to normal (0.8±0.3) In the frontal cortex of untreated MPS I dogs, 79±9% (N=5) of large pyramidal neurons had;;::5 granules consistent with lysosomalstorage, which was higher than the values of 14±3% and 11±8%in normal and RV-treated dogs, respectively (p