Lysosomal storage disorders (LSDs) are excellent objectives for gene therapy. Target cells for correction are often accessible and for many LSDs a phenomenon called 'metabolic cooperativity' occurs. Here cells that overexpress corrective lysosomai enzymes secrete these hydrolases, which can be functionally utilized by unmodified bystander cells. Thus lower efficiencies or directed gene transfer to single sites can still effect systemic correction. Farber disease (FD) is a very severe LSD due to a deficiency in acid ceramidase. FD presents with debilitating manifestations including painful granulomas and pronounced neurological consequences. Death often occurs in early childhood. Current treatment for FD, like for many LSDs, is only palliative. For some LSDs, BMT using unmodified cells has been partially corrective, although little impact on CNS manifestations has been observed. For only the most prevalent LSDs, enzyme replacement therapy is an option. Gene therapy using a variety of delivery systems has also been tested in vitro and in vivo models of LSDs. A few clinical gene therapy protocols addressing LSDs have also been initiated. No toxicities were reported although clinical improvements have also not been realized. Previously we demonstrated the first conceptual possibility that gene therapy could ameliorate FD. Lately, we have been adapting lentiviruses (LV) for gene augmentation strategies. We have tested successful outcomes using LVs in cell culture and in small animal models for Fabry disease; another LSD. Yet despite this conceptual success, and notwithstanding the growing number of small animal models of LSDs, these experiments are not often predictive of clinical gene therapy outcomes. Thus we have recently initiated gene therapy studies here at the UHN in non-human primates (NHPs) to better predict outcomes in patients and to identify areas wherein more research or protocol development is warranted. This proposed study would thus be the first to fully test LV-mediated correction for an LSD in a more clinically relevant model; that of NHPs.
| Walia, Jagdeep S; Neschadim, Anton; Lopez-Perez, Orlay et al. (2011) Autologous transplantation of lentivector/acid ceramidase-transduced hematopoietic cells in nonhuman primates. Hum Gene Ther 22:679-87 |
| Ramsubir, Shobha; Nonaka, Takahiro; Girbes, Carmen Bedia et al. (2008) In vivo delivery of human acid ceramidase via cord blood transplantation and direct injection of lentivirus as novel treatment approaches for Farber disease. Mol Genet Metab 95:133-41 |
