Development of an investigational medicinal stem cell gene therapy product to attempt curing human immunodeficiency virus infection
TL;DR
This work proposes to test an alternative strategy, namely expression of a designer recombinase which specifically excises HIV provirus from the genome under a Tat-inducible promoter so that expression is restricted to infected cells.
Abstract
For most people living with Human immunodeficiency virus (HIV), virus control and sufficient immune function can be achieved with polypharmacotherapy. A minority is intolerant to thereto, and drug-resistant mutants are emerging. Additionally, people living with HIV (PLWH) have significantly higher risk of cardiovascular morbidity and malignant diseases. HIV is in principle immunogenic. If T-cell depletion could be avoided immunological HIV eradication should be achievable. The “Berlin patient” in whom allogeneic stem cell transplantation from a CCR5Δ32/Δ32 donor induced long-term remission without antiviral therapy raised the hope that stem cell gene therapy with CCR5-deleted autologous stem cells could provide a cure, but the strategy did not live up to expectations. We propose to test an alternative strategy, namely expression of a designer recombinase which specifically excises HIV provirus from the genome under a Tat-inducible promoter so that expression is restricted to infected cells. A cGMP-compliant manufacturing protocol and quality control strategy for this investigational medicinal product was developed, validated, and a manufacturing authorization obtained. A First-in-Human-clinical trial, testing engraftment, repopulation of peripheral specific immunity, and ability to control HIV infection without antiviral medication is in preparation. Protocols can be adapted to other stem cell gene therapies by transferring alternative lentviral cargo.