RNA intervention as a therapeutic approach for HIV infection has been under evaluation
for a number of years. The initial approach utilized standard anti-sense (mirror
image) RNA (RNAi) molecules that associate with the HIV RNA in infected cells
and prevent virus components from being synthesized. The utility of RNAi was limited
in practice due to complicated chemistry, lack of stability in vivo, induction
of interferon in treated cells that resulted in toxicity, and inefficient delivery.
In addition, limitations in specificity and accessibility to target sequences
on the HIV RNA reduced the efficacy of the RNAi. A second approach to RNA intervention
was based on the use of catalytic RNA molecules (ribozymes). Ribozymes have shown
efficacy in vitro and are currently in clinical testing.
In recent years advances in ribonucleotide chemistry and in the understanding
of the HIV life cycle allowed the development of modified, more effective RNA
Small interfering RNA: siRNA
Dr. John Rossi of the Beckman Research Institute at City of Hope (Duarte, CA)
has developed a new approach for inactivating HIV RNA in cells using small double
RNA molecules (siRNA) (Lee N.-S., et al. Nature Biotechnology 19,500-505, 2002).
This approach is based on the presence of response mechanisms in cells that degrade
and eliminate double-stranded RNA molecules.
siRNA can be either generated inside the cell following expression of specifically
designed hairpin RNA that is processed into 21-23 bp siRNA molecules, or by introducing
the designed siRNA molecules into the cell directly. In the cytoplasm, the siRNA
associates with a protein complex that modifies and unfolds the siRNA, allowing
the anti-sense strand to bind to the complementary target mRNA. This association
exposes the target mRNA to degradation by RNAses in the “silencing complex.”
This concept is represented schematically below.
ITI has entered into a collaborative research agreement with City of Hope to evaluate
and characterize the anti-HIV properties of the specifically designed siRNAs as
well as new candidate siRNAs. The HIV virus is composed of a number of proteins
each made from a separate mRNA. Thus, a variety of siRNA molecules can be designed
and used in the inhibition of virus production.
ITI and City of Hope will co-own the intellectual property resulting from the
collaboration; and ITI has the option to license the joint technology.