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Understanding the Technologies Involved in Gene Therapy
Published in Yashwant V. Pathak, Gene Delivery Systems, 2022
Manish P. Patel, Jayvadan K. Patel, Mukesh Patel, Govind Vyas
The HIV virus requires the expression of co-receptors C-C chemokine receptor type 5 (CCR5) for adhesion onto T cells. Thus, CCR5 is a promising target for the control of HIV entry into the host cell. Humans who are homozygous for a particular variation in the CCR5 gene are naturally resistant to HIV infection by blocking entry of the virus. Additionally, in clinical use the transplantation of ex vivo expanded CCR5 (-/-) primary human CD4+ T cells to HIV patients was found to be beneficial. In light of this evidence, ZFNs were also tested as a potential option for the treatment of HIV infection. The primary aim of this was to disrupt CCR5 in both primary CD4+ human T cells and human hematopoietic stem cells. Reconstitution of the patients’ immune systems using stem cells with an engineered “CCR5-negative genome” may render their T cells immune to HIV infection (Akçay et al. 2014).
Novel RNA Interference (RNAi)-Based Nanomedicines for Treating Viral Infections
Published in Dan Peer, Handbook of Harnessing Biomaterials in Nanomedicine, 2021
Nyree Maes, Skye Zeller, Priti Kumar
The natural resistance of CCR5A32 homozygous individuals to HIV [27, 58] has made CCR5 a promising target for both small molecule inhibitors, such as the FDA-approved maraviroc, and RNAi based interventions. Clinical proof-of-principle was provided by transplantation of stem cells from a CCR5A32 homozygous donor into a HIV+ leukemic patient [59]. Following transplant, HIV levels have remained undetectable even after discontinuing HAART. As only ~1% of Caucasians are homozygous for the CCR5A32 mutation and there is currently no infrastructure to track these individuals, RNAi targeting CCR5 is being explored as an alternative to homozygous donor stem cell transplantation. In a preclinical experiment with non-human primates Rhesus macaque CD34+ HSC transduced ex vivo with a lentiviral vector encoding a H1 driven shRNA targeting the macaque CCR5 was stably maintained for up to 14 months after transplantation into autologous recipients with no toxicity [2]. Surface levels of CCR5 decreased 3-10-fold and CCR5 mRNA levels decreased 5-10-fold. Lymphocytes isolated from these animals demonstrated a higher resistance to in vitro challenge with SIVmac239.
Genome Editing and Gene Therapies: Complex and Expensive Drugs
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2020
Deng et al. (1996) described CCR5, a seven-transmembrane chemokine receptor, as the major co-receptor for HIV-1 entry used by most of the HIV in vivo strains, and since then CCR5 has been investigated as a target for HIV therapy. Twelve years later, Perez et al. (2008) reported that they succeeded in ZFNs-mediated permanent disruption of the CCR5 gene in primary human CD4+ T lymphocytes. In a mouse model (see Watanabe et al., 2007) primary CD4+ T cells were transduced using Ad5/35 vectors expressing the CCR5 ZFNs which conferred protection against HIV infection in vivo and in vitro as proven by CCR5 reconstitution experiments. Finally, in 2014, Tebas and colleagues reported about a successful clinical trial with 12 HIV patients treated with infusion of autologous CD4 T cells modified at CCR5 by a ZFN; the nonhomologous end joining repair of the induced DSBs rendered the CCR5 gene permanently dysfunctional. As a consequence of the partial induced genetic HIV resistance the CD4 T-cell counts increased significantly in these patients that in addition showed decreased levels of HIV DNA. One important conclusion drawn from this study was that CCR5-modified autologous CD4 T-cell infusions are safe.
Ethical Challenges Associated with Pathogen and Host Genetics in Infectious Disease
Published in The New Bioethics, 2023
Richard Milne, Christine Patch
Numerous examples of the potential importance of host genetics have been identified (Tian et al.2017). Studies of Covid-19 host genetics have suggested variants that predispose individuals to severe consequences of infection and provide insights into potentially ‘druggable’ mechanisms (Kousathanas et al.2022). Other host genetic characteristics may provide protection against infection, such as HBB, which can reduce susceptibility to infection by the malaria parasite or FUT2, which confers some protection against norovirus infection. In the case of HIV/AIDS, it has been known since the mid-1990s that individuals who are homozygous for an allele of the CCR5 gene called Δ32 (carried by around 1% of Northern European ancestry individuals) have substantial resistance to infection with the dominant R5 strain of HIV (Samson et al.1996, Greely 2021). CCR5 is involved in virus entry and cell-to-cell spread and has been a key target for the development of drugs to protect those exposed to infection, commercial stem cell and gene therapy trials (Kirksey 2021). Notoriously, CCR5 also formed the focus of the first known case of human germline gene editing in 2018, reportedly in an attempt to protect against potential future HIV infection and the associated stigma and discrimination (Greely 2021). As in the case of genomic surveillance, this emphasizes how applications of pathogen genomics are shaped both by individual and community experiences of infectious disease in social, cultural and historical context – in which the attribution of vulnerability often exacerbates persisting injustices (Ganguli-Mitra et al.2020).