Hematopoietic stem cell mediated gene therapy for Gaucher disease

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Gaucher disease, an autosomal recessive lysosomal storage disorder caused by a deficiency of glucocerebrosidase (GC), is an important target for human somatic cell gene therapy. In order to achieve the efficient gene transfer strategy for Gaucher disease, we attempted to optimize the conditions for retroviral mediated gene transfer into hematopoietic stem cells. Approximately 50 % of hematopoietic progenitor cells could be transduced by retroviral vectors using various cytokines, stroma cells, and fibronectin. However, this efficiency is still inadequate for genetic correction of the real hematopoietic stem cells. A major limitation of retroviral vectors appears to be their inability to infect growth arrested cells. To overcome this intrinsic problem, a retroviral vector derived from human immune-deficiency virus (HIV) that is able to infect terminally differentiated cells has been newly developed. We demonstrated that HIV vectors were capable of efficient gene transfer into non-dividing or rarely dividing cells such as hematopoietic cells, neurological cells, and muscle cells. HIV based vectors should be useful for gene therapy of type I Gaucher disease targeting hematopoietic stem cells. We have also shown that bone marrow contains multipotential stem cells that differentiate into neurological cells. Autologous bone marrow cells may be useful as carriers for ex vivo gene therapy for neurological symptoms of type II Gaucher disease.