HIV-1 Gene Therapies Considered: RNAi Versus CRISPR-Cas
Though human immunodeficiency virus type 1 (HIV-1) can now be effectively treated to prevent disease progression through the use of potent antiviral drugs, decades after this disease’s discovery, there still is no cure for this precursor to acquired immune deficiency syndrome, also known as AIDS. In a recent article published in the journal Biochemical Society Transactions by Herrera-Carrillo and Berkhout from the Center for Infection and Immunity Amsterdam (CINIMA), new possible gene therapy approaches, including the use of RNAi and CRISPR-cas, are considered and discussed.
Though the end goal of each of these anti-HIV therapeutic options is the same – to stop the replication of HIV-1 – the two proposed mechanisms vary greatly in their biological origin: RNAi acts through suppressing mRNA and CRISPR targets the DNA. And although both RNAi and CRISPR-cas mechanisms both offer some significant hope for future clinical applications, neither is without risk and both may induce unwanted side effects at the cellular level. RNAi, for example, may cause “saturation or off-targeting of unrelated mRNAs” and CRISPR-cas can cause “permanent mutagenic effects” via cleavage of off-target DNA sequences, according to Herrera-Carrillo, et al.
The biggest problem with both RNAi and CRISPR-cas gene therapies is that one cannot reliably predict these adverse events, indicating that the safety and efficacy of each of these new gene therapies should be tested and verified in appropriate in vivo models. Herrera-Carrillo, et al tested the combinatorial RNAi therapy using a humanized immune system mouse model and a “single RNA-based anti-HIV gene therapy has moved into clinical trials” as a result. The CRISPR-cas system, however, still requires additional safety tests to more fully understand the “sustained expression of this foreign endonuclease in human cells, which may possibly lead to off-target cleavage events.”
The field of gene therapy has recently made great strides in the advancement of human applications. As additional in vivo testing in humanized rodent models continues, it is likely that researchers will develop increasingly efficient and safer therapeutic strategies designed to suppress the replication of HIV-1.
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