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RNAi s Therapeutic Potential Continues to Grow in HIV, Reaches into Periodontal Disease

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HIV has proven to be a popular target for experimental RNAi-based therapies, catching the interest of researchers from both industry and academia. Among them is Colorado State University’s Ramesh Akkina, who with some funding from the National Institute of Allergy and Infectious Diseases, is investigating the use of multiple siRNA constructs in fighting HIV.

Akkina has been awarded a five-year National Institute of Allergy and Infectious Diseases grant, worth up to roughly $1.1 million in direct costs, which began on April 1 and runs until the end of March 2009.

According to Akkina, while siRNAs have proven effective in inhibiting HIV-1 in vitro, RNAi will translate into a therapy against the virus only with “stable introduction of the siRNA genes into hematopoietic stem cells and derivation of viral-resistance T-cells and macrophages.”

Using in vitro assays and a novel SCID-hu mouse in vivo model that harbors transplanted human tissue, Akkina and colleagues “recently showed that CD34 hematopoietic progenitor cells transduced with anti-HIV siRNAs, ribozymes, and RNA decoys could be differentiated into virus-resistant T-cells and macrophages,” he said in the grant project’s abstract.

Building on this recent progress, the abstract states that the grant program is designed to examine the efficacy of novel combinatorial siRNA constructs “targeted to different stages of [the] HIV-1 life cycle in vitro, and analyze their mechanism of action.”

The project also aims to transduce siRNAs targeting HIV into CD34 hematopoietic progenitor cells using lentiviral vectors, with the goal of creating HIV-1 resistant macrophages.

A third aspect of the effort is to “determine the in vivo protective effects of various anti-HIV-1 siRNAs, either individually or in combination, in SCID-hu mice thy/liv grafts against HIV-challenge,” while also evaluating the “functional competence” of transgenic T-cells, Akkina wrote.

Finally, the grant program plans to “transduce siRNA constructs into … newly described CD34+/HDR+ primitive hematopoietic cells and derive macrophages in vitro and thymocytes in vivo and evaluate their HIV-1 resistance,” the abstract states.

As the number of scientists using RNAi to fight HIV grows, so too does the number of people using the gene-silencing technology in new ways. One of those people is Toshihisa Kawai, a Forsyth Institute researcher, who has been awarded a two-year grant from the National Institute of Dental and Craniofacial Research worth up to $100,000 in direct costs to examine RNAi as a treatment for periodontal disease.

Kawai’s primary interest is in the immunological basis of periodontal disease, which has two pathogenic outcomes, he told RNAi News. “One is soft tissue destruction — destruction of the [tissue’s] collagens. The other is … bone resorption,” he said.

“We are now focused on how to prevent bone resorption in periodontal disease,” Kawai added. “Recently we found some factors produced by … lymphocytes that cause bone resorption.” Specifically, he and his colleagues are looking at the osteoclast differentiation cytokine RANKL (receptor activator of NF-kappaB ligand).

In January, they published a paper in the Journal of Bone and Mineral Research that demonstrated that systemic administration of the potassium channel blocker kaliotoxin in a rat model of periodontal disease was able to decrease the bone resorption, as well as RANKL mRNA expression by T-cells in gingival tissue. The induction of RANKL-dependent osteoclastogenesis by activated T-cells was also reduced by kaliotoxin in vitro in the experiments.

“We were successful in inhibiting bone resorption,” Kawai said. “However, I’m a little skeptical to [take] an aggressive approach to inhibit lymphocyte activation” using, for example, kaliotoxin or immune suppressants such as cyclosporine. While these can be good options for combating bone resorption associated with serious diseases like rheumatoid arthritis, he noted, “they always have side effects,” such as increased susceptibility to bacterial infections.

As such, Kawai said he decided to take a different approach using RNAi, which would allow him to target osteoclast differentiation alone rather than suppressing the whole immune system.

To do so, Kawai and his colleagues will use siRNA targeting the TRAF6 (tumor necrosis factor receptor-associated factor 6) in a rat model of periodontal disease that causes T-cell-mediated bone resorption in a RANKL-dependent manner. According to Kawai, RANKL signaling activates TRAF6-mediated gene transcription events, which are required for osteoclast differentiation.

“Importantly, TRAF6 gene knockout mice exhibit severe osteopetrosis and are defective in osteoclast formation,” he told RNAi News in an e-mail. “Therefore, we believe that local administration of RNAi targeting the TRAF6 gene can inhibit the RANKL-mediated osteoclastogenesis.”

Kawai said that his lab plans on delivering the siRNA, which are to be purchased from Qiagen, in a liposomal formulation. He said he also will explore systemic delivery of the siRNAs, and that he plans on trying to create his own siRNAs using a kit sold by Invitrogen.

“If that doesn’t work, I’ll try hairpin siRNA,” he added.

Kawai’s grant project began on April 1 and runs until March 31, 2006.

—DM

 

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