Project description
Engineered B cells for the functional elimination of HIV infection
Current chronic antiretroviral therapy does not eliminate HIV infection. Previous studies demonstrated that B cells engineered to express anti-HIV broadly neutralising antibodies (bNAb) using CRISPR/Cas9 technology produce high neutralising antibody titers. However, the CRISPR/Cas9 cleavage is associated with potential on-target and off-target mutagenesis and chromosomal aberrations. The EU-funded SwitchTargeting project aims to enhance the safety and efficacy of the approach by engineering the B cells without using CRISPR/Cas9 and by targeting the bNAb genes via adeno-associated viral vectors. The project will introduce the preliminary supporting results and present the research plan to establish B cell engineering based on activation-induced cytidine deaminase (‘switch targeting’) as the direct functional cure of HIV.
Objective
Chronic antiretroviral therapy (ART) does not eradicate HIV infection. As a potentially single-shot alternative, B cells engineered by CRISPR/Cas9 to express anti-HIV broadly neutralizing antibodies (bNAbs) were shown capable of secreting high and neutralizing antibody titers. In particular, we previously demonstrated that, upon immunization of mice, adoptively transferred B cells, that were engineered at the immunoglobulin heavy (IgH) locus by CRISPR/Cas9, differentiate into memory and plasma cells while undergoing class switch recombination (CSR) and somatic hyper mutation (SHM) followed by selection. B cells may thus be engineered as a living and evolving drug.
In the current application we plan to greatly enhance the safety, efficacy and the scalability of our approach by engineering the B cells without CRISPR/Cas9. CRISPR/Cas9 cleavage is associated with both on-target and off-target mutagenesis as well as with gross chromosomal aberrations. Importantly, the activation of B cells is associated also with double strand breaks initiated by activation-induced-cytidine-deaminase (AID). Therefore, applying CRISPR/Cas9 to activated B cells may bear a combined risk for potentially oncogenic translocations. To avoid these risks, we reasoned that bNAb genes could be targeted to AID induced breaks at the IgH locus using adeno associated viral vectors (AAV) without CRISPR/Cas9. Here, we present preliminary supporting results and outline the research plan for establishing AID-induced B cell engineering (“Switch targeting”) as a single-shot functional cure of HIV. Switch Targeting includes unique safety features. It addresses viral variability between patients and counteracts viral escape. We have a previous track record in spinning out gene therapy start-up companies to build public, clinical stage companies (Nasdaq: LOGC). Here, we plan to use this experience to translate Switch Targeting from bench to bedside, affect the lives of millions and disrupt a $25B market.
Fields of science
- engineering and technologycivil engineeringstructural engineeringstructural health monitoring
- medical and health sciencesmedical biotechnologygenetic engineeringgene therapy
- medical and health sciencesbasic medicineimmunologyimmunisation
- medical and health scienceshealth sciencesinfectious diseasesRNA virusesHIV
- natural sciencesbiological sciencesgeneticsmutation
Programme(s)
Funding Scheme
ERC-POC - Proof of Concept GrantHost institution
69978 Tel Aviv
Israel