Wave Life’s WVE-004 Shows Proof of Concept in Cell, Mouse Models

Marisa Wexler, MS avatar

by Marisa Wexler, MS |

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WVE-004, Wave Life Sciences‘ experimental therapy for people with amyotrophic lateral sclerosis (ALS) associated with mutations in the C9ORF72 gene, has demonstrated proof-of-concept efficacy in cell and animal models, a new study shows.

The nucleic acid-based therapy was able to “potently” reduce the toxic RNA molecules and small proteins associated with C9ORF72 mutations in a mouse model of ALS after only two doses of the treatment, according to researchers.

“These in vivo [in the lab] effects were durable, persisting for at least 6 months,” the team wrote.

The proof-of-concept study, “Preclinical evaluation of WVE-004, an investigational stereopure antisense oligonucleotide for the treatment of C9orf72-associated ALS or FTD,” was funded by Wave Life Sciences and published in Molecular Therapy Nucleic Acids.

Mutations in C9ORF72 are the most common genetic cause of ALS, found in up to half of familial cases and in up to one in 10 sporadic cases. Mutations in C9ORF72 also are associated with the related condition frontotemporal dementia (FTD).

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Trial of WVE-004 in Patients With C9orf72 Mutations Begins Dosing

The most common specific mutation is a hexanucleotide repeat, in which six nucleotides — specifically GGGGCC, the “letters” of the genetic code — are repeated an excessive number of times. These repeats ultimately result in the production of C9ORF72 protein with irregular structures called dipeptide protein repeats (DPRs).

When the gene is “read” to make protein, an intermediary molecule called messenger RNA (mRNA) is first produced, and then used as the template for protein production. Depending on how it is “read,” the C9ORF72 gene can produce one of three mRNA sequences, or transcripts, dubbed V1, V2, and V3.

When the C9ORF72 gene has a hexanucleotide repeat mutation, only V1 and V3 result in the production of proteins with DPRs — the mutation may alter the expression of V2, but does not actually change the sequence of the code or the protein that is produced.

Antisense oligonucleotides, or ASOs, are small nucleic acid chains that are able to bind to mRNA molecules with specific sequences, ultimately degrading the mRNA and reducing the production of protein. Researchers at Wave Life Sciences created an ASO called WVE-004, which aims to target only the disease-associated transcripts of C9ORF72.

“WVE-004 was designed to selectively deplete V1 and V3 transcripts, while sparing V2 transcripts and preserving C9orf72 protein,” the team wrote.

The researchers first conducted a series of tests in human nerve cells derived from a patient carrying the C9ORF72 hexanucleotide repeat mutation. Results showed that WVE-004 could significantly reduce levels of the V3 transcript, by 98.1%. Cell experiments also indicated that WVE-004 was neither pro-inflammatory nor cytotoxic, meaning toxic to the cells.

Experiments then were conducted in mice harboring the mutation. The researchers demonstrated that the therapy spread throughout the central nervous system (CNS), comprised of the brain and spinal cord, after an injection into the brain.

“These data show that WVE-004 reaches tissues in [C9ORF72 mutated] mice that are most profoundly affected in [C9ORF72 mutated]-ALS/FTD,” the researchers wrote.

Further analysis showed that the investigational ASO significantly reduced levels of the V3 transcript in the mice’s spinal cords and brains. Consistently, levels of poly-GP, one of the DPR proteins that are produced from the mutated gene, also were reduced. The response was dose-dependent, with the most profound effect seen with the highest tested dose of 100 micrograms.

“These data indicate that a 100 [microgram] total dose of WVE-004 selectively decreases repeat-containing transcripts and the biomarkers poly-GP, while preserving the expression of C9orf72 protein in both the spinal cord and cortex of [C9ORF72 mutated] mice,” the scientists wrote.

Additional tests showed that the effects of a 100 microgram dosage of WVE-004 lasted for at least six months in the mouse model.

“WVE-004 produced substantial reductions in V3 expression and poly-GP that are sustained for at least 6 months, without disrupting total C9orf72 protein expression,” the researchers wrote. “Even at later time points, when tissue concentrations of WVE-004 were markedly decreased, knockdown of repeat-containing transcripts and reduction of poly-GP persisted.”

Wave is currently running a Phase 1b/2a clinical trial called FOCUS-C9 (NCT04931862) to evaluate the safety and pharmacological properties of WVE-004 in people with ALS and/or FTD. Early trial data have indicated that the medication is reducing levels of poly-GP as intended.

FOCUS-C9 is recruiting adults, ages 18–80, at locations in Ireland, the Netherlands, the U.K., Canada, and Australia. More information is available on the clinical trials website.

“On the heels of the first clinical data from FOCUS-C9, we are excited to be publishing our preclinical data for WVE-004,” Michael Panzara, MD, chief medical officer and head of therapeutics discovery and development at Wave Life Sciences, said in a press release announcing the proof-of-concept findings for this ALS study.

“These preclinical data demonstrate that WVE-004 distributes widely throughout the CNS in mice, potently and durably lowering the toxic transcripts and poly(GP) driven by a C9orf72 expansion mutation,” Panzara said.