Summary of Current Clinical Trials

Currently, there are over 600 approved clinical protocols worldwide. Detailed information is available from the RAC on the 545 protocols that were approved in the US as of the end of 2002, and helpful statistical summaries are available on the website of the Journal of Gene Medicine (http:// The original ADA

Table 2 Gene Delivery Strategies

1. Ex vivo

Cells are removed from body and incubated with vector; engineered cells are then returned (e.g., T lymphocytes for anti-HIV therapy)

2. In situ

Vector or producer cells are placed directly into the tissues to be transduced (e.g., TK vectors in brain tumors)

3. In vivo

Vector would be directly injected into the bloodstream and would home in on its target cells (no examples yet)

deficiency gene therapy trial (2) was begun in 1990, giving gene-corrected autologous T lymphocytes to 2 girls suffering from this disease. ADA deficiency is a rare genetic disorder that produces severe immunodeficiency in children. Patient 1 (A.D.) received a total of 11 infusions, the last being in the summer of 1992. Her total T cell level and her level of transduced T cells have remained essentially constant since then, at approximately 20% and at considerably higher levels than patient 2 (C.C.) (<0.01%). Due to differences in cell harvest and transduction efficiencies, patient 1 received greater than 2 logs more vector-transduced cells than patient 2, who also developed persisting antibodies against components of the gene transfer system. These 2 factors likely resulted in the large discrepancy in the frequency of modified T cells seen in the 2 patients. Although patient 1 in particular may have benefited from gene therapy, because both patients continue to receive PEG-ADA treatment in addition to their gene therapy treatments, no final conclusion can be drawn as to the relative roles of PEG-ADA and gene therapy in their excellent clinical course. More recently, Aiuti et al. (99) reported successful results for ADA gene therapy following transduction of hema-topoietic stem cells (HSC) without PEG-ADA treatment.

Only 1 large phase III clinical trial using retroviral vectors has been conducted for the treatment of glioblastoma multi-forma. This approach was based on the in situ production of amphotropic retroviral vectors expressing TK from a mouse producer cell line, inoculated into the residual tumor and surrounding areas following tumor resection. The phase III trial included a total of more than 40 centers in North America and Europe and was scheduled to enroll a total of 250 patients, but has been abandoned due to lack of therapeutic effect (79).

In 2000, great excitement was generated by the announcement from Alain Fischer's group in France that gene therapy had been used to effectively cure patients undergoing gene therapy for SCID-XI (75). This is an X-linked disorder where the yc cytokine receptor subunit is missing, and is characterized by early blocks in T and NK cell development. The vector used was based on MFG, expressing the yc subunit under the control of the vector LTR. However, great concern has now been raised by the announcement that two patients have developed leukemia. At the present time, gene therapy trials in the U.S. using retroviral vectors are on clinical hold.

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