HomeResearchIntramural ResearchResearch Branches at NHGRIGenetics and Molecular Biology Branch Candotti Lab

Fabio Candotti, M.D. Senior Investigator Genetics and Molecular Biology Branch Head Disorders of Immunity Section M.D. University of Brescia, Italy, 1987 (301) 435-2944 (301) 480-3678 fabio@nhgri.nih.gov Building 49, Room 3A04 49 Convent Dr, MSC 4442 Bethesda, MD 20892-4442 Selected Publications Gene therapy brings hope to young CC isolation room patient

Dr. Candotti's laboratory studies the molecular basis of inherited disorders of the immune system in order to develop better treatments for these conditions. For many inherited immune deficiency disorders, the only available therapeutic option is hematopoietic stem cell transplantation (HSCT), currently an intensive procedure that carries a number of risks. Dr. Candotti is seeking treatment alternatives to HSCT, 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 do have enough residual enzyme activity to prevent the toxic adenosine metabolites from accumulating. They, therefore, have a milder form of immune deficiency, which may not be diagnosed until later in childhood or even adulthood. Although HSCT from a matching sibling donor can cure ADA deficiency, most patients do not have a matched donor and, thus, face substantial risks from HSCT. Genetic correction of a patient's own hematopoietic stem cells, therefore, could be a beneficial therapeutic alternative.

Dr. Candotti's laboratory is evaluating novel retroviral vectors as gene transfer tools for correcting ADA deficiency. A major obstacle to this approach has been the low level of expression of the inserted genes and often eventual loss of expression. To overcome this problem, his group has constructed improved retroviral vectors that provide a higher level of transgene expression in human lymphoid cells, as compared with previously used vectors. They currently are conducting a clinical trial to determine whether these improved vectors will provide better reconstitution of the immune system.

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 also have an increased chance of developing a malignancy and, in as many as 40 percent of cases suffer from an autoimmune disorder. However, WAS is associated with a milder form of immune deficiency than that observed in ADA deficiency. Thus, WAS patients usually do not develop overwhelming infections at an early age. As with ADA deficiency, however, most WAS patients do not have an ideal donor for HSCT. Dr. Candotti's group is building on in vitro studies indicating that retroviral-mediated gene transfer can correct the biological defects observed in cell lines from patients with WAS. In addition, observations in WAS patients with spontaneous in vivo correction of their genetic defects have confirmed that gene-corrected cells have a selective advantage over their mutated counterparts. These findings suggest that the prospects for the success of gene therapy in this disease are relatively good.

Finally, Dr. Candotti's group is evaluating T cell and hematopoietic stem cell-directed gene therapy for a rare form of immune deficiency caused by a genetic mutation of the β1 chain of the interleukin12 receptor (IL12Rβ1). This disease is characterized by increased vulnerability to weakly pathogenic organisms. Even with aggressive treatment, IL12Rβ1- deficient patients can succumb to such infections. Experiments with retroviral- mediated gene correction of T cells from IL12Rβ1-deficient patients have shown restored expression of IL12Rβ1 and a reconstituted, functional IL-12 signaling pathway. As with ADA deficiency and WAS, these results indicate that the biological defects of T cells caused by IL12Rβ1 deficiency can be corrected by gene transfer.

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Last Reviewed: July 15, 2008