Idera Presents New Data on 3rd Generation Antisense Platform, Possible Treatment for FSHD

Idera Pharmaceuticals recently presented preclinical data regarding the gene-silencing mechanisms of its third generation antisense (3GA) technology platform, a potential therapeutic for diseases that include, but are not limited to, facioscapulohumeral muscular dystrophy (FSHD). The presentations took place at the recent 12th Annual Meeting of the Oligonucleotide Therapeutics Society in Montreal, Canada.

The presentations of new data on the platform’s mechanism of action support selective targeting of single-point mutations. In addition, Idera presented results on 3GA targeting the NLRP3 gene for the treatment of inflammatory disorders.

Diseases like FSHD are caused by impairments or mutations in certain genes. Correcting these mutations and the mechanisms of action involved are mostly still in development stages.

Antisense technology is a type of treatment for genetic disorders like FSHD. As the genetic sequence of certain genes that cause these diseases is known, scientists can synthezise a strand of nucleic acids, such as DNA or RNA, that can turn off or inactivate defective genes.

Idera’s 3GA technology specifically silences disease-causing genes using small molecules called oligonucleotides, which offer an improvement over a similar technique called inhibitory RNA (RNAi).

In the presentation, “Selective Targeting of Point Mutations by Third Generation Antisense Oligonucleotides,” Reina Improgo, PhD, a research scientist on Idera’s Discovery Team, provided an overview of the novel mechanism of action of 3GA technology. The data showed that 3GA exerts potent gene silencing activity in cell-based assays as well as in vivo. In addition, gene silencing activity observed with 3GA was sustained in vivo without tissue build up. 3GA alsogenerates excision sites in the target RNA in a similar region as that observed with siRNA, the researchers found.

“The understanding we have gained of the mechanism of action of 3GA is providing insights into the increased potency and specificity of its gene silencing.  This data has illustrated to us a way in which 3GA could be used to target point mutations,” Sudhir Agrawal, president of Research at Idera Pharmaceuticals said in a press release.  “We are continuing to employ 3GA technology to target multiple genes, including NLPR3, with a goal of prioritizing a candidate for clinical development.”

NLRP3 inflammasome is a gene implicated in multiple inflammatory disorders, and serves as a potential therapeutic target. In this context, in the presentation “Third generation antisense (3GA) targeting NLRP3 for the treatment of inflammatory disorders,” Fugang Zhu, PhD, and Wayne Jiang, MD, PhD, scientists with Idera’s Discovery Team, showed that targeting NLRP3 by 3GA allows inhibition of downstream induction of proinflammatory cytokines IL-1b and IL-18 . Treatment with 3GA-targeting NLRP3 also showed promising therapeutic activity in models of interstitial cystitis and uveitis.

The company announced that it is investigating recently identified potential gene targets NLRP3 (NOD-like receptor family, pyrin domain containing protein 3) and DUX4 (Double Homeobox 4) for FSHD and other diseases, including  lupus nephritis, uveitis, and interstitial cystitis, with the intent of starting clinical studies in 2017.  Idera said it also produced 3GA agents for a series of additional gene targets earlier this year.