Gene Therapy in 2003: Breadth and Vigor
Authors: Don B. Kohn
Journal: Molecular Therapy (2003)

A year has passed since the first patient in a trial of gene transfer to treat XSCID was deter-mined to have developed a lymphoproliferative disease as a result of insertional onco-genesis. I became heavily involved in the response to this event, both as an officer of theASGT, and as an investigator on one of the other clinical trials using retroviral vectors totransfer genes to hematopoietic stem cells that was subsequently placed on “clinical hold."In retrospect, my involvement in this response seems to have clouded my view of the con-tinuing advance in the prospects of the field of gene transfer technology. However, the Sixth Annual Meeting of the ASGT, which took place in June 2003 did agreat job of reminding me of the vast potential of gene therapy as a therapeutic modality.The work presented at the meeting provided many examples of the breadth and vigor ofthe field and the ongoing advances in basic techniques and therapeutic applications. Ourunderstanding of the biology of AAV continues to expand, and new viral serotypes prom-ise to advance the efficacy of AAV vectors for diverse new applications. Lentiviral vectorsare being developed to greater degrees of sophistication and may be less prone to causeinsertional oncogenesis than oncoretroviral vectors. New viral, nonviral and hybrid vectorsand innovative techniques are being exploited, such as trans-splicing, siRNA, and the useof genetic insulators, for example. There was abundant evidence of continued advancesagainst many of the diseases that have been targeted by gene therapists for years, includ-ing cystic fibrosis, hemophilia, sickle cell disease, cancer, AIDS, neurological disorders, andmusculoskeletal diseases. Moreover, new results presented from other studies for XSCID inLondon and for ADA-deficient SCID in Milan make absolutely clear that the curative effectsof gene therapy for XSCID by the Paris group are generally reproducible and consistent. Certainly, an important theme that recurred throughout the meeting was analysis of thechromosomal integration sites of gene transfer vectors. The question of how random isretroviral integration has been addressed numerous times in prior years, but we are learn-ing that the answer depends on what the meaning of “how random is” is. New techniquesfor integration site recovery and genomic analysis are producing a wealth of informationon integration patterns of retroviral, lentiviral, and AAV-based vectors, as well as trans-posons. We are learning about the relative frequency of vector integration, the category ofpreferred integration sites (random, gene-rich regions, actively transcribed genes, exons ver-sus introns, promoter regions, etc.), and the interactions between genetic elements of thevector and juxtaposed cellular sequences. Understanding these properties of each specificgene transfer vector should allow more informed estimations of their relative risks and ben-efits in clinical applications. The way in which Alain Fischer, Marina Cavazzana-Calvo and their collaborators actedupon the discovery of the tragic complication seen in two of their patients has been exem-plary. Their willingness to share in real time with scientific colleagues as well as regulatoryagencies and advisory boards in multiple countries meets the standard to which all med-ical scientists should strive: placing the health, safety and rights of the human subjects ofgene therapy research as an unwavering primary consideration. But, we also must keep inmind the basic reason for the research we do: to develop gene therapy as a new and moreeffective way to alleviate the suffering of people with diseases. The science presented at therecent meeting showed that we are continuing to do both. It is now our duty to continueto find better ways to develop these therapeutic modalities to achieve maximum efficacyand safety.