Both preclinical and clinical studies have demonstrated that blocking or mutating CCR5, an R5-tropic HIV-1 coreceptor — whether through small molecule inhibition, presence of a natural mutation, or therapeutic gene modification — can render cells resistant to HIV-1 infection.3-7 In one instance, a patient was ‘cured’ following transplant of allogeneic stem cells containing a bi-allelic CCR5 mutation (CCR5Δ32/Δ32) with no evidence of HIV for eight years despite the halting of ART.8,9 Allogeneic stem cell transplant as a routine HIV therapy is limited by the availability of HLA- matched CCR5Δ32/Δ32 donors and comes with a high risk of morbidity and mortality.10
Adoptive transfer of autologous CD4+ T cells following ZFN-mediated CCR5 disruption (SB-728-T) was shown to be clinically safe, with cells engrafting and persisting over time.2 The limitation of this approach, however, is that patient monocytes — a population of immune cells believed to be a key reservoir for HIV infection — maintain wild-type CCR5. In contract, CCR5 gene editing of autologous HPSCs has the potential to result in HIV-1- resistant immune cells of multiple lineages, including both CD4+ T-cells and monocytes, throughout the patient’s lifespan.
Disruption of CCR5 in adult mobilized CD34+ cells using ZFN in a clinical setting has been reported. Unfortunately, the cytotoxicity of the adenoviral vector used to deliver the ZFN machinery prevented its use in the intended clinical trial.5 It was determined that to move the clinical trial forward a non- viral, clinically-feasible, and regulatory-compliant technology was necessary to deliver the ZFN gene editing machinery to HSPC.