Wave Life ALS Therapy Shows Proof of Concept in Cellular and Mouse Models
WVE-004, Wave Life Sciences’ investigational therapy for people with amyotrophic lateral sclerosis (ALS) associated with mutations in the C9ORF72 gene, has demonstrated proof-of-concept efficacy in cellular and animal models, according to a new study.
Nucleic acid therapy was able to “potently” reduce toxic RNA molecules and small proteins associated with C9ORF72 mutations in a mouse model of ALS after just two doses of the treatment, according to the researchers.
“These live [in the lab] the effects were long-lasting, 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 ALS or FTD Associated with C9orf72was 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 up to one in 10 sporadic cases. Mutations in C9ORF72 are also associated with the related condition of frontotemporal dementia (FTD).
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 the C9ORF72 protein with irregular structures called dipeptide protein repeats (DPRs).
When the gene is “read” to make a protein, an intermediate molecule called messenger RNA (mRNA) is first produced and then used as a template for protein production. Depending on how it is “read”, the C9ORF72 The gene can produce one of three mRNA sequences, or transcripts, called V1, V2, and V3.
When the C9ORF72 The gene has a hexanucleotide repeat mutation, only V1 and V3 result in the production of proteins with DPR – the mutation can alter the expression of V2, but does not actually change the code sequence or the protein that is produced.
Antisense oligonucleotides, or ASOs, are small nucleic acid chains capable of binding to mRNA molecules with specific sequences, ultimately degrading mRNA and reducing protein production. Wave Life Sciences researchers have created an ASO called WVE-004, which aims to target only transcripts associated with the disease of C9ORF72.
“WVE-004 was designed to selectively deplete V1 and V3 transcripts, while sparing V2 transcripts and preserving the C9orf72 protein,” the team wrote.
The researchers first conducted a series of tests on human nerve cells from a patient with the C9ORF72 hexanucleotide repeat mutation. The results showed that WVE-004 could significantly reduce levels of the V3 transcript by 98.1%. Cellular experiments also indicated that WVE-004 was neither pro-inflammatory nor cytotoxic, i.e. toxic to cells.
Experiments were then carried out on mice carrying the mutation. The researchers demonstrated that the therapy spread throughout the central nervous system (CNS), made up 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 deeply affected in [C9ORF72 mutated]-ALS/FTD,” the researchers wrote.
Further analysis showed that experimental ASO significantly reduced V3 transcript levels in the spinal cord and brain of mice. Consistently, levels of poly-GP, one of the DPR proteins produced from the mutated gene, were also reduced. The response was dose-dependent, with the most profound effect observed with the highest tested dose of 100 micrograms.
“These data indicate that a 100 [microgram] full dose of WVE-004 selectively decreases repeat-containing transcripts and poly-GP biomarkers, while preserving C9orf72 protein expression in spinal cord and cortex of [C9ORF72 mutated] mice,” the scientists wrote.
Further testing showed that the effects of a 100 microgram dose of WVE-004 lasted for at least six months in the mouse model.
“WVE-004 produced substantial reductions in V3 and poly-GP expression that were sustained for at least 6 months, without disrupting total C9orf72 protein expression,” the researchers wrote. “Even at later time points, when tissue levels of WVE-004 were markedly reduced, inactivation of repeat-containing transcripts and reduction in poly-GP persisted.”
Wave is currently conducting 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 indicated that the drug reduced poly-GP levels as expected.
FOCUS-C9 recruits adults aged 18-80 from sites in Ireland, the Netherlands, the UK, Canada and Australia. More information is available on the Clinical Trials website.
“On the heels of the first clinical data for FOCUS-C9, we are excited to release our preclinical data for WVE-004,” said Michael Panzara, MD, Chief Medical Officer and Head of Therapeutic Discovery and Development at Wave Life Sciences. . in a press release announcing the proof-of-concept results of this ALS study.
“These preclinical data demonstrate that WVE-004 distributes widely throughout the CNS in mice, potently and sustainably reducing toxic transcripts and poly(GP) driven by a C9orf72 expansion mutation,” Panzara said.