DNA Integration in Human Gene Therapy

cell

The methods we developed for analyzing large populations of HIV integration sites are ideal for tracking outcome in human gene therapy, and so we have collaborated extensively to analyze gene therapy trials. Initially we began work with Marina Cavazzana-Calvo and Alain Fischer to characterize the outcome of their SCID-X1 trial, the first successful human gene therapy of any kind. We helped characterize some of the adverse events in their trials, and developed novel sequencing and bioinformatic methods for tracking cell populations using integration site information. We also have been helping Dr. Carl June in his trials to treat HIV and cancer using gene-based therapy. A history of work from the Bushman laboratory in the gene therapy area was published in association with a “Pioneer in Human Gene Therapy” award (Bushman, 2014; see below).

Wang GP, Ciuffi A, Leipzig J, Berry CC, Bushman FD. 2007. HIV integration site selection: analysis by massively parallel pyrosequencing reveals association with epigenetic modifications. Genome Research 17:1186-1194.

Hacein-Bey-Abina S, Pai SY, Gaspar HB, Armant M, Berry CC, Blanche S, Bleesing J, Blondeau J, de Boer H, Buckland KF, Caccavelli L, Cros G, De Oliveira S, Fernández KS, Guo D, Harris CE, Hopkins G, Lehmann LE, Lim A, London WB, van der Loo JC, Malani N, Male F, Malik P, Marinovic MA, McNicol AM, Moshous D, Neven B, Oleastro M, Picard C, Ritz J, Rivat C, Schambach A, Shaw KL, Sherman EA, Silberstein LE, Six E, Touzot F, Tsytsykova A, Xu-Bayford J, Baum C, Bushman FD, Fischer A, Kohn DB, Filipovich AH, Notarangelo LD, Cavazzana M, Williams DA, Thrasher AJ. 2014. A modified gamma-retrovirus vector for X-linked severe combined immunodeficiency. NEJM 371:1407-1417. PMCID: PMC4274995

Bushman FD. 2014. Engineering the human genome: reflections on the beginning. Human Gene Therapy 25:395-400.

Morris EC, Fox T, Chakraverty R, Tendeiro R, Snell K, Rivat C, Grace S, Gilmour K, Workman S, Buckland K, Butler K, Chee R, Salama AD, Ibrahim H, Hara H, Duret C, Mavilio F, Male F, Bushman FD, Galy A, Burns SO, Gaspar HB, Thrasher AJ. Gene therapy for Wiskott-Aldrich syndrome in a severely affected adult. Blood. 2017 Sep 14;130(11):1327-1335