Dr. Candotti's laboratory studies the molecular basis of inherited disorders of the immune system with the aim of developing better treatments for these conditions. For many inherited immune deficiency disorders, the only available therapeutic option is hematopoietic cell transplantation (HCT), currently an intensive procedure that carries a number of risks. Dr. Candotti is seeking treatment alternatives to HCT, with a particular interest in gene replacement approaches. His laboratory is developing gene therapies for two rare immune deficiency syndromes: adenosine deaminase (ADA) deficiency and Wiskott-Aldrich syndrome (WAS).
ADA is a key enzyme in the purine salvage pathway that catalyzes the deamination of adenosine and deoxyadenosine to inosine and deoxyinosine, respectively. Genetic loss of ADA causes a significant increase in adenosine and deoxyadenosine levels, with toxic effects on lymphocytes. Most individuals with this disorder develop severe combined immune deficiency (SCID) soon after birth due to the absence of T and B lymphocytes and consequent lack of immune protection. Left untreated, individuals with ADA-deficient SCID usually die within the first two years of life from multiple opportunistic infections. Some patients have enough residual enzyme activity to prevent toxic adenosine metabolites from accumulating. Their immune deficiency is therefore milder, and may not be diagnosed until later in childhood or even adulthood. Although HCT from a matching sibling donor can cure ADA deficiency, most patients do not have a matched donor; HCT for them carries increased risks. Genetic correction of a patient's own hematopoietic stem cells, therefore, could be a beneficial therapeutic alternative.
Dr. Candotti's laboratory is evaluating novel viral vectors as gene transfer tools for correcting ADA deficiency. A major obstacle to this approach has been the low efficiency of the procedure due to the complex steps necessary in the collection, genetic manipulation and administration of adequate numbers of gene-corrected hematopoietic stem cells. Results from current trials carried out by Dr. Candotti's group using murine retroviral vectors are promising. With the goal of improving the timing and quality of immune reconstitution, Dr. Candotti's laboratory is evaluating the use of vectors based on human lentiviruses that should be available for human experimentation in late 2011.
WAS is an X-linked recessive disorder characterized by very low numbers of platelets that are unusually small. It is associated with eczema of the skin and immune deficiency. WAS patients have an increased chance of developing a malignancy and, in as many as 40% of cases, also have an autoimmune disorder. As with ADA deficiency, most WAS patients do not have an ideal donor for HCT and development of alternative therapeutic approaches is therefore needed. Dr. Candotti's group is building on n vitro and in vivo studies indicating that retroviral-mediated gene transfer can correct the biological defects observed in cells from patients with WAS and in animal models of the disease. In addition, observations in WAS patients with spontaneous correction of their genetic defects have confirmed that gene-corrected cells have a selective advantage over their mutated counterparts. These findings provide a positive outlook for the prospects of gene therapy in this disease.
Dr. Candotti's laboratory has demonstrated that WAS patients carry defective regulatory T-cells, an important subset of T-lymphocytes responsible for the maintenance of immune tolerance. These findings may explain the autoimmune problems that develop in this disease and may allow development of new therapeutic avenues. Other research efforts by Dr. Candotti's group have demonstrated that novel gene transfer vectors based on Foamy virus can be used to correct the constellation of immunological problems characteristic of WAS mouse models. Because of their safety profile, these new vectors are good candidates for clinical development, which could provide new alternative therapeutic options in the near future.
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Last Reviewed: June 26, 2013