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Phase 2 gene therapy trial of an anti-HIV ribozyme in autologous CD34+ cells

Abstract

Gene transfer has potential as a once-only treatment that reduces viral load, preserves the immune system and avoids lifetime highly active antiretroviral therapy. This study, which is to our knowledge the first randomized, double-blind, placebo-controlled, phase 2 cell-delivered gene transfer clinical trial, was conducted in 74 HIV-1–infected adults who received a tat-vpr–specific anti-HIV ribozyme (OZ1) or placebo delivered in autologous CD34+ hematopoietic progenitor cells. There were no OZ1-related adverse events. There was no statistically significant difference in viral load between the OZ1 and placebo group at the primary end point (average at weeks 47 and 48), but time-weighted areas under the curve from weeks 40–48 and 40–100 were significantly lower in the OZ1 group. Throughout the 100 weeks, CD4+ lymphocyte counts were higher in the OZ1 group. This study indicates that cell-delivered gene transfer is safe and biologically active in individuals with HIV and can be developed as a conventional therapeutic product.

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Figure 1: Ribozyme target site within HIV-1 genome, schematic of gene-modified cell manufacture and protocol design.
Figure 2: Participant disposition.
Figure 3: HIV-1 viral load: ITT population.
Figure 4: T lymphocyte counts over time.

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Acknowledgements

The following clinicians, research nurses and coordinators contributed substantially to the trial: S. Agrawal, R. Amado, C. Anderson, P. Cain, R. Cordova, G. Dolan, C. Farthing, E. Glutzer, M. Gonzalez, M. Harbour, N. Hyland, A. Lebel, S. Lundy, K. Macrae, S. Miller, J. Norris, L. O'Donnell, L. Pearce, J. Perram, V. Rees, R. Richardson, J. Sarangapany, D. Slamowitz, R. Vale, G. Vasquez, B. Williams and A. Zolopa. We also acknowledge the contribution of the leukapheresis collection and cell processing staff, W. Quan for assistance with quality assurance and A. Miller of the Biologics Group for assistance with regulatory aspects. S. Margrie had a key role in the development of the statistical analysis plan and in the statistical analyses. C. Ang and A. King assisted with the preparation of the manuscript. We acknowledge W. Gerlach, D. Wade, J. Peacock, R. de Feyter and L. Farrell for their vital role during the early stages of the development of OZ1. We sincerely thank the participants who enrolled in this intensive study and the members of the Data Safety Monitoring Board. The University of California–Los Angeles Center for AIDS Research and University of California–Los Angeles General Clinical Research Center were supported by US National Institutes of Health grants AI28697 and M01-RR00865.

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Authors and Affiliations

Authors

Contributions

R.T.M., T.C.M., A.C. and D.A.C. were involved in the design and clinical investigator leadership of the trial; J.A.Z., M.A.W. and J.L.M. were laboratory directors of cell manufacturing at their respective clinical sites; R.T.M., T.C.M., A.C., D.A.C., C.W., M.B., J.L., S.B., L.T., B.A., H.K., R.F., R.M. and D.E.S. were clinical investigators involved in the planning and conduct of the study, R.G., D.M. and J.M.M. provided advice about the design and ongoing conduct of the study; M.L. designed and reviewed the statistical analysis; C.v.K. set up, supervised and advised on the integration analysis; J.A.E. and S.M. Patino were the global clinical trial managers; A.E.K. was the project manager and lead clinical research associate; P.W. was head of quality assurance cell manufacturing and esoteric tests; A.V.T., M.H. and C.F. managed the central laboratory testing for esoteric tests; J.L.M., global product scientist, was responsible for the design and conduct of the cell and gene manufacturing protocols; G.P.S., global product leader, provided the interface between the manufacturing and sponsor clinical trial teams and overall strategic direction; L.A.E., global medical leader, provided oversight of the protocol, safety monitoring, regulatory reporting, data analysis and the sponsor clinical trial team; S.M. Pond, the global trial director, had oversight of the entire program; R.T.M., T.C.M., A.C., J.L.M., G.P.S., L.A.E., S.M. Pond and D.A.C. were the major contributors to writing of the manuscript; and all authors reviewed the raw data and the drafts and final manuscript.

Corresponding author

Correspondence to Ronald T Mitsuyasu.

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Competing interests

R.T.M. and T.C.M. are investigators who were contracted by Johnson & Johnson Research (JJR) to perform the clinical trial. This included payments for visits with subjects, equipment and salaries as part of the contracts with their institutions. D.A.C., C.W., M.B., J.L., S.B., L.T., B.A., H.K., R.F., R.M. and D.E.S. are investigators who were contracted by JJR to perform the clinical trial. A.C., J.A.Z. and M.A.W. are employees of the institutions where the clinical trial was conducted and acted as advisers during the conduct of the clinical trial. R.G., D.M., M.L. and J.M. are advisers who were contracted by JJR for their expertise during the conduct of the study. C.v.K. was responsible for one of the contract laboratories that was contracted by JJR during the conduct of the study. J.A.E., S.M. Patino, A.E.K., P.W., M.H., C.F. and L.A.E. are or were employees of JJR. J.L.M., G.P.S., S.M. Pond and A.V.T. are employees of JJR who hold shares in Johnson & Johnson in excess of $10,000.

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Mitsuyasu, R., Merigan, T., Carr, A. et al. Phase 2 gene therapy trial of an anti-HIV ribozyme in autologous CD34+ cells. Nat Med 15, 285–292 (2009). https://doi.org/10.1038/nm.1932

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