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

Abstract

SUMMARYGene 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, the first randomized, double-blind, placebo-controlled, phase II 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 statistical 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 provides the first indication that cell-delivered gene transfer is safe and biologically active in HIV patients and can be developed as a conventional therapeutic product.

In vitro and in vivo cleavage of HIV-1 RNA by new SOFA-HDV ribozymes and their potential to inhibit viral replication

“…In addition, the observed 90% decrease in RT suggests that the use of stronger promoters and additional combinations will further increase Rz concentration and overall efficacy against the virus. Together, the data presented here and the great potential of future delivery methods 13,41,49,50 suggest that SOFA-HDV Rzs constitute a very promising new avenue to control HIV replication.…”

“…Several molecules targeting the HIV RNA have been used to decrease HIV replication in cell culture, 12,36,37 in animal models 38 and some of them are in clinical trials for their use in gene therapy. 13,14,39 The experience with these compounds has provided several orientations and possible improvements including: (1) New compounds are always needed as leads 4 GApDh copies and normalized to a value of 100% for the hDV-Rzctl.…”

“…12 Hammerhead and hairpin Rzs are currently in clinical trials against HIV, expressed from murine retroviral or lentiviral vectors. [13][14][15] Therefore, Rzs appear to have a great potential for further development of a gene-inactivation system aiming to control HIV propagation.…”

Generation of human TRIM5α mutants with high HIV-1 restriction activity

“…For instance, after gene transfer of an anti-HIV ribozyme in hematopoietic stem cells, a fivefold reduction in expression of the ribozyme was observed within 6 months. 39 Rapid elimination of productively HIV-1-infected lymphocytes is well-known 40 and results from the action of cytotoxic T lymphocytes and also from virus-related killing. Therefore, it is likely that to succeed, a gene therapy approach for AIDS would need to disrupt viral replication either at entry or at immediate post-entry steps, before viral antigens are being synthesized.…”

Dix ans de thérapie génique Réflexions

“…Cela contribuerait à ce qu'un des goulots d'étranglement du développement clinique de la thérapie génique, la production à large échelle de lots de vecteurs cliniques, puisse être levé bien qu'il persiste aussi des obstacles techniques au développement de lignées stables de production de vecteurs. Il reste à anticiper un certain nombre de questions éthiques, comme l'accès des pays en voie de développement à cette thérapeutique bien plus simple que la greffe conventionnelle au moins dans le principe général du traitement, mais Anémie de Fanconi (n = 2) CSH ex vivo (CD34 + ) Non Non [14] CGD (n = 4) CSH ex vivo (CD34 + ) Oui : transitoire Oui : mutagenèse insertionnelle [3] ALD (n = 3) CSH ex vivo (CD34 + ) Oui : 3 ans Non [8] WAS (n = 2) CSH ex vivo (CD34 + ) Oui : 4 ans Non [5] Hémoglobinopathies (n = 2) CSH ex vivo (CD34 + ) Oui : 3 ans Non [4] VIH (n = 74) CSH ex vivo (CD34 + ) Difficile à évaluer Non [15] Reconstitution immunitaire après greffe de CSH (n = 85) Lymphocytes T ex vivo Oui Non [16] Épidermolyse bulleuse (n = 1) Kératinocytes ex vivo Oui : 4 ans Non [6] Rétinopathies congénitales (n = 15) Rétine in vivo Oui : 2 ans Non [7] Tableau I. Protocoles de thérapie génique. ADA : adénosine désaminase ; ALD : adrénoleucodystrophie ; CGD : granulomatose septique chronique ; CSH : cellules souches hématopoïétiques ; DICS-X1 : déficits immunitaires combinés sévères lié à l'X ; VIH : virus de l'immunodéficience humaine ; WAS : syndrome de Wiskott-Aldrich.…”