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Wave Life Sciences releases preclinical data for ADAR editing and C9orf72 program

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CAMBRIDGE, Mass.—While genomic editing and CRISPR are all the rage in the industry of late, Wave Life Sciences is focusing its efforts on the RNA side of things, and the company’s efforts are being rewarded with encouraging preclinical data.
Wave’s novel RNA-editing platform uses endogenous ADAR (adenosine deaminases acting on RNA) enzymes via free uptake of A-to-I base editing oligonucleotides, also known as ADAR editing. Unlike with DNA editing, the effects of RNA editing are reversible, which avoids the potential damage of permanent off-target DNA editing. The free uptake of this platform means that the approach requires no viral vectors or nanoparticle delivery, simplifying the process.
In May, Wave reported the successful RNA editing of ACTB (Beta-actin) mRNA in non-human primates via endogenous ADARs through using stereopure Ga1NAc-conjugated oligonucleotides. In a proof-of-concept study, these oligonucleotides achieved up to 50 percent A-to-I (G) editing of ACTB mRNA in the livers of primates, and recent durability data showed significant editing even 45 days after the last dose—with the implication that the editing could last even longer.
“To date, in-vivo RNA editing data from other companies and researchers that we are aware of showed low levels of editing (at most, low single-digit percentages). The only other published scientific paper where endogenous ADAR was used showed fractions of percentages in editing,” Dr. Chandra Vargeese, chief technology officer for Wave, tells DDN. “In our non-human primate (NHP) proof-of-concept study, we saw up to 50 percent A to I (G) editing of ACTB mRNA in the liver of NHPs two-days after the last dose. So, we are excited that we are one of the leaders in this emerging field.”
“Wave is developing ADAR-mediated RNA editing as a platform capability, with potential application across multiple genetic diseases,” she adds. “ADAR editing may be used in multiple ways to restore protein function, to modify protein function, or to increase protein expression. Importantly, nearly half of known human pathogenic SNPs are G to A mutations. The unique capability of ADAR to potentially correct these mutations creates significant opportunities for us to hopefully treat a broad spectrum of human diseases, including diseases that currently have no treatments or only sub-optimal treatments.”
In addition, Wave has successfully conducted RNA editing in neurons within several tissue types in a humanized mouse model, including the cortex, hippocampus, striatum, brain stem, cerebellum and spinal cord.
At the late-stage end of the preclinical phase is Wave’s C9orf72 variant-selective silencing program in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The candidate in question, WVE-004, targets C9orf72 by selectively silencing the V1 and V3 transcripts and sparing healthy C9orf27 protein. Gene mutations in C9orf72 are the most common genetic cause of the familial forms of ALS and FTD, and these mutations also play a role in sporadic forms of each disease.
In a recent webcast, Wave relayed updated preclinical data for the C9orf72 program. In BAC transgenic mice, Wave saw sustained knockdown of up to six months of expanded C9orf72 repeat transcripts and dipeptide repeats in the spinal cord and cortex after two intracerebroventricular doses. The company is planning to submit a clinical trial application to explore WVE-004 in ALS and FTD in a proof-of-concept trial in the fourth quarter of this year.
“Wave’s planned proof-of-concept study of WVE-004 in ALS and FTD is designed to examine patients with documented C9orf72 expansion and confirmed ALS or FTD diagnosis,” says Vargeese. “We expect the study to explore single and multiple ascending doses, safety and tolerability of WVE-004, and pharmacodynamic effects on key biomarkers while on treatment, including PolyGP and NfL. The key exploratory clinical outcome measures are expected to include ALSFRS-R and CDR-FTLD.”
One of the tools in Wave’s arsenal is its PRISM platform, and its C9orf72 program leverages PN chemistry from this platform. PRISM allows for genetically defined diseases to be targeted with stereopure (containing only one stereoisomer) oligonucleotides for silencing, editing and splicing.
“Through our focus on stereochemical control, we are able to isolate single isomers rather than the stereorandom, mixture-based oligonucleotides being advanced by others. For this reason, we have the potential to fully characterize and investigate the structure activity relationship of all RNA therapeutics in our pipeline, as has become standard with small-molecule and antibody development. This will allow us to develop precise and rationally designed medicines that leverage the full potential of RNA therapeutics,” Vargeese remarks.

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