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.
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