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Research Update
RESEARCH UPDATE
Sirna Reports Phase I Results for RNAi Therapeutic for AMD
S
irna Therapeutics, Inc., an RNAibased therapeutics company, reported the final results in August from its recently completed Phase 1 trial for Sirna-027, a therapeutic for age-related macular degeneration (AMD). Single ascending doses of Sirna-027 were safe and well tolerated, and all 26 patients (100%) showed visual acuity stabilization eight weeks after a single injection. In addition, at the same time point, five of 26 patients (19%) experienced clinically significant improvement in visual acuity, indicated by an increase of at least three lines on an eye chart. Three months after a single injection, 24 of 26 patients (92%) showed visual acuity stabilization, with four of 26 patients (15%) experiencing clinically significant improvement in visual acuity; only two of 26 patients (8%) experienced a reduction in visual acuity of three lines or more. Importantly, a decrease in foveal thickness was observed in some patient groups, which is an indication of biological activity of Sirna-027. "This is the first demonstration of biological activity of a chemically optimized siRNA in humans," said Sirna Chief Medical Officer Roberto Guerciolini, M.D. "These data represent an important milestone toward the demonstration of the potential therapeutic benefit of Sirna-027 and the clinical validation of RNAi as a therapeutic modality." The potential for a long-lasting effect on visual acuity after a single dose of Sirna-027 could be due to the unique catalytic mechanism of short interfering RNA (siRNA), and could make this compound amenable to a more favorable dosing regimen than other approved products. "Less frequent dosing in this dev-
MOLECULAR THERAPY Vol. 14, No. 5, November 2006 Copyright © The American Society of Gene Therapy
astating disease should greatly improve patient convenience, compliance, and quality of life," said Dr. Guerciolini. The Phase 1 study evaluated the safety, tolerability, and biological effect of single-ascending doses of Sirna-027 in patients with AMD. A total of 26 patients with active disease were enrolled to receive a single intravitreal injection of Sirna-027 ranging from 100-1,600 micrograms. In September 2005, Sirna and Allergan established a Strategic Alliance in eye diseases which includes Sirna-027 for AMD. Under the terms of the Agreement, Allergan assumed all developmental and commercialization costs for Sirna-027. Sirna and Allergan expect to initiate the Phase 2 trial during the second half of 2006. Source: Sirna Therapeutics, Inc.
p75 Found to Tether HIV Integrase to Chromosomes
A
group of virologists has discovered that a specific human protein is essential for HIV to integrate into the human genome. The protein, LEDGF/p75 (p75), forms a molecular tether between chromosomes and HIV integrase. The finding might lead to new approaches for HIV or safer methods of gene therapy. The details appear in the 7 September 2006 issue of Science. "How an incoming virus co-opts the cell's assistance as it proceeds to establish its permanently integrated state is a fascinating question," says Eric Poeschla, who led the research. "It's critical to understand this better because permanently integrated viruses in long-lived cells prevent elimination of HIV. In the future, it will be of interest to examine whether HIV's dependence on p75 can be exploited
therapeutically." The researchers found that p75 "tethers" HIV integrase to human chromosomes and thus protects it from the cell's protein-degrading machinery. The team then used RNA interference delivered by an HIVderived lentiviral vector to block p75 expression. Without its p75 partner, HIV was highly impaired. As a result, human T cells became resistant to HIV infection. Ectopic expression of p75 rendered the cells vulnerable again to infection. Finally, expression of a "dominant-negative" fragment from p75 further impaired the virus (over 500-fold). "It turns out that the virus needs surprisingly little p75 to integrate," says Dr. Poeschla. "Future studies will want to factor such potential potency into designs of screens for additional key cellular proteins that HIV either appropriates as partners, as in the case of p75, or schemes to evade. Quite a few more likely exist." Science, online edition, doi: 10.1126/science.1132319
Submit Your Article to Molecular Therapy Today! We Offer Rapid Turnaround: Time to First Decision: Three Weeks Response to Presubmission Enquiries: Forty-eight Hours Email Us at [email protected]
609
Sirna Reports Phase I Results for RNAi Therapeutic for AMD
S
irna Therapeutics, Inc., an RNAibased therapeutics company, reported the final results in August from its recently completed Phase 1 trial for Sirna-027, a therapeutic for age-related macular degeneration (AMD). Single ascending doses of Sirna-027 were safe and well tolerated, and all 26 patients (100%) showed visual acuity stabilization eight weeks after a single injection. In addition, at the same time point, five of 26 patients (19%) experienced clinically significant improvement in visual acuity, indicated by an increase of at least three lines on an eye chart. Three months after a single injection, 24 of 26 patients (92%) showed visual acuity stabilization, with four of 26 patients (15%) experiencing clinically significant improvement in visual acuity; only two of 26 patients (8%) experienced a reduction in visual acuity of three lines or more. Importantly, a decrease in foveal thickness was observed in some patient groups, which is an indication of biological activity of Sirna-027. "This is the first demonstration of biological activity of a chemically optimized siRNA in humans," said Sirna Chief Medical Officer Roberto Guerciolini, M.D. "These data represent an important milestone toward the demonstration of the potential therapeutic benefit of Sirna-027 and the clinical validation of RNAi as a therapeutic modality." The potential for a long-lasting effect on visual acuity after a single dose of Sirna-027 could be due to the unique catalytic mechanism of short interfering RNA (siRNA), and could make this compound amenable to a more favorable dosing regimen than other approved products. "Less frequent dosing in this dev-
MOLECULAR THERAPY Vol. 14, No. 5, November 2006 Copyright © The American Society of Gene Therapy
astating disease should greatly improve patient convenience, compliance, and quality of life," said Dr. Guerciolini. The Phase 1 study evaluated the safety, tolerability, and biological effect of single-ascending doses of Sirna-027 in patients with AMD. A total of 26 patients with active disease were enrolled to receive a single intravitreal injection of Sirna-027 ranging from 100-1,600 micrograms. In September 2005, Sirna and Allergan established a Strategic Alliance in eye diseases which includes Sirna-027 for AMD. Under the terms of the Agreement, Allergan assumed all developmental and commercialization costs for Sirna-027. Sirna and Allergan expect to initiate the Phase 2 trial during the second half of 2006. Source: Sirna Therapeutics, Inc.
p75 Found to Tether HIV Integrase to Chromosomes
A
group of virologists has discovered that a specific human protein is essential for HIV to integrate into the human genome. The protein, LEDGF/p75 (p75), forms a molecular tether between chromosomes and HIV integrase. The finding might lead to new approaches for HIV or safer methods of gene therapy. The details appear in the 7 September 2006 issue of Science. "How an incoming virus co-opts the cell's assistance as it proceeds to establish its permanently integrated state is a fascinating question," says Eric Poeschla, who led the research. "It's critical to understand this better because permanently integrated viruses in long-lived cells prevent elimination of HIV. In the future, it will be of interest to examine whether HIV's dependence on p75 can be exploited
therapeutically." The researchers found that p75 "tethers" HIV integrase to human chromosomes and thus protects it from the cell's protein-degrading machinery. The team then used RNA interference delivered by an HIVderived lentiviral vector to block p75 expression. Without its p75 partner, HIV was highly impaired. As a result, human T cells became resistant to HIV infection. Ectopic expression of p75 rendered the cells vulnerable again to infection. Finally, expression of a "dominant-negative" fragment from p75 further impaired the virus (over 500-fold). "It turns out that the virus needs surprisingly little p75 to integrate," says Dr. Poeschla. "Future studies will want to factor such potential potency into designs of screens for additional key cellular proteins that HIV either appropriates as partners, as in the case of p75, or schemes to evade. Quite a few more likely exist." Science, online edition, doi: 10.1126/science.1132319
Submit Your Article to Molecular Therapy Today! We Offer Rapid Turnaround: Time to First Decision: Three Weeks Response to Presubmission Enquiries: Forty-eight Hours Email Us at [email protected]
609