Rocanavio therapy shows promise for C9ORF72 ALS

RocanavioInvestigational treatment significantly reduced the accumulation of toxic RNA molecules in the body. amyotrophic lateral sclerosis Patient cell and mouse models related to (ALS) C9ORF72 Mutation, according to new data.

These RNA products (intermediate molecules produced from DNA as a template for protein production) are associated with the formation of toxic proteins that disrupt cellular function in patients with: C9ORF72 mutation.

Of note, CRISPR-based gene-editing therapy did not affect levels in healthy individuals. C9ORF72 RNA. Allows production of the C9orf72 protein, which may be important for neuronal function.

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The findings were presented in a poster titled “.Cas13d multitargeting efficiently targets sense and antisense HREs, including toxic RNAs and Poly-GP DPRs, in C9ALS patient cells and C9-BAC500 mouse modelwas presented at the 26th Annual Meeting of the American Society for Gene and Cell Therapy (ASGCT) held May 16-20 in Los Angeles, CA.

Locanabio also announced research results for its next potential treatment. muscular dystrophyCRISPR gene editing technology is also used.

“We have generated significant proof-of-concept data in both human cells and cells. [animal] It is a disease model that will support the further development of these product candidates,” said Locanabio CEO Jim Burns, PhD. press release.

mutation of C9ORF72 Gene is the most common Genetic causes of ALSfound in about 50% of people with the following symptoms: Familial ALS and 10% of them Sporadic ALS. Similar mutations are found in some people with a related neurodegenerative disorder, frontotemporal dementia (FTD).

These mutations are usually characterized by aberrant supernumerary repeats of the six DNA building blocks GGGGCC within the gene sequence. These mutations, called hexanucleotide repeat expansions, lead to the production of two aberrant types of RNA molecules called G4C2 and C4G2 in cells.

Toxic RNA products

These defective RNA molecules are thought to promote the formation of small proteins that are toxic to cells. Furthermore, toxic RNA products can also directly damage cells by forming specific structures that promote cellular stress.

Locanavio’s investigational treatment is designed to target and destroy these problematic RNA molecules without affecting the production of healthy cells. C9ORF72 RNA.

To do this, a CRISPR/Cas13d based system is used. In essence, specialized ‘guide’ RNA molecules are designed to recognize the G4C2 and C4G2 sequences and guide the Cas13d enzyme to them. Cas13d then degrades the toxic RNA.

All components of the therapy are packaged in a harmless viral vector called adeno-associated virus 9 (AAV9), whose contents are delivered to cells throughout the body.

CORRECTx platform

This treatment was designed using Locanavio technology. CORRECTx platformusing CRISPR technology to edit, destroy, or replace harmful RNA associated with disease.

that previously found Reduces both G4C2 and C4G2 levels in laboratory cultured cells.

Now, researchers report that dual-targeted therapy effectively reduced the levels of both types of toxic RNA in cells from ALS patients. C9ORF72 mutation. It also reduced the amount of toxic proteins produced from those RNA molecules.

Delivery of Cas13d protein to a mouse model of ALS by a single injection just below the membrane surrounding the spinal cord resulted in normal production of Cas13d protein within the spinal cord after 5 weeks without signs of toxicity.

Both types of toxic RNA were significantly reduced in spinal cords after treatment compared to placebo-fed mice, whereas no changes were observed in healthy mice. C9ORF72 RNA level.

When the drug was instead administered directly to the brain, the animals similarly showed no signs of weight loss, inflammation or neuronal death, indicating that the drug was well distributed. Both toxic RNA types and their toxic protein products were also found to decrease in the brain 6 weeks after injection.

Of note is the overall level of health C9ORF72 RNA was also unaffected by gene-editing therapy delivered to the brain.

The findings suggest that targeting RNAs containing these toxic repeat expansions “may be an effective therapeutic strategy for C9ALS and C9ORF72-associated FTD,” the researchers said. writes.