This proposal will develop a clinical trial to treat patients with purine nucleoside phosphorylase (PNP) deficiency with gene transfer of the normal PNP gene into hematopoietic stems cells of affected patients. After 20 years of research in the gene therapy field, there are two clinical trials for inherited immunodeficiency that have yielded an efficacious outcome. The first was a French trial of retroviral gene therapy for X-linked severe combined immunodeficiency (SCID), in which bone marrow cells from children deficient in the common gamma-chain for several cytokine receptors were exposed to a retrovirus encoding the missing gene and then reinfused into the patient. The second trial yielding an efficacious outcome was conducted in Italy, also using retroviral transduction of marrow cells, but in this case for introduction of the gene encoding adenosine deaminase (ADA) for treatment of SCID associated with deficiency of ADA. As for X-linked SCID, several patients have responded to the treatment with restored cellular and humoral immunity. We propose to treat a disease that is similar to ADA-deficiency; immunodeficiency associated with the absence of purine nucleoside phosphorylase (PNP). Both are diseases of aberrant purine metabolism resulting in accumulation of deoxynucleosides that are toxic for lymphocytes. PNP deficient patients suffer from deficient cellular immunity and aberrant humoral immunity. There is no medical therapy available for this disease, so patients who lack a matched donor for allogeneic hematopoietic cell transplant have no clinical options. We have previously generated retroviral vector encoding the human PNP gene and demonstrated correction of metabolic deficiency and restored immunoproliferative function in T-cells obtained from a PNP-deficient patient. By analogy to the clinical results generated in the Italian trial for ADA-deficiency, we predict that PNP-deficiency can also be treated by retroviral transduction of the PNP gene into hematopoietic stem cells obtained from PNP-deficient patients. Results from this clinical trial will have implications not only for the treatment of PNP deficiency but for the treatment of other immunodeficiencies as well. Gene therapy provides a new form of therapy for patients with life threatening diseases for which there are lacking safe and effective treatments. Purine nucleoside phosphorylase (PNP) deficiency is a prematurely lethal immunodeficiency with limited treatment options in the majority of patients. The primary importance of this proposed clinical trial will be providing a treatment option for these patients; and more importantly, the knowledge that gained in the use of gene therapy to safely and effectively treat human disease will have implications for the treatment of many other potentially life threatening diseases. ? ? ?
