Targeted Antisense Oligonucleotide Approach To Amyotrophic Lateral Sclerosis (ALS) And Frontotemporal Dementia (FTD)

SUMMARY

Antisense oligonucleotide (ASO) therapeutic with a precise, targeted approach to the genetic underpinnings of C9ORF72-linked ALS and FTD

The Unmet Need: Front-line disease modifying therapies for ALS and FTD

• The prevalence of ALS is increasing at a steady rate in line with population growth and despite the availability of several marketed drugs, all of them lack efficacy and only succeed in prolonging life by a moderate margin. Glutamate antagonists (riluzole) are used as the front-line backbone therapy but only provide a six-month improvement in prolonging a patient's life. Free radical scavengers are used typically as an add-on therapy and have only marginal additional survival impact. Therefore, there is need for other drug classes with better symptom control and life prolonging benefits.

• There is a significant unmet need for treatment options that are disease modifying, targeting the underlying cause of ALS to halt/reverse or cure the disease rather than focusing on symptomatic improvement. In the current treatment algorithm, there is only one approved disease modifying therapy, Biogen’s Qalsody, an ASO proposing a curative approach.

• Seen as the first complex biologic to enter the ALS market, Qalsody (tofersen sodium) in early 2023 became the first ASO to receive FDA approval to treat adults with SOD1 mediated ALS. However, ALS patients with SOD1 protein mutation only make up only 3% of total ALS patients.

The Proposed Solution: Targeted and precise ASO approach to treating ALS and FTD that reduces the toxic gain of function caused by the repeat expansion mutation in the C9ORF72 gene

• The faculty inventor developed a novel ASO to target the antisense transcripts containing repeating CCCCGG sequences in the C9ORF72 gene, which is the most common monogenic cause of inherited ALS and FTD. This mutation is predicted to cause ALS/FTD via three non-mutually exclusive mechanisms: (1) a loss-of-function mechanism due to reduced C9ORF72 protein expression, (2) a gain-of-function mechanism due to toxicity from repeat-containing sense (GGGGCC) and antisense (CCCCGG) RNA, and (3) toxicity from dipeptide repeat (DPR) proteins produced from these transcripts.

• This ASO strategy provides a novel mechanism to reduce the toxic gain of function caused by the repeat expansion mutation in the C9ORF72 gene. By intervening at the mRNA level, it has the potential to slow disease progression and improve patient outcomes significantly.

ADVANTAGES

ADVANTAGES

• Targeted intervention: specifically targets the genetic mutation responsible for ALS and FTD
• Potential to slow or halt disease progression by reducing the production of toxic proteins
• High-precision treatment operating at the molecular level
• Potentially applicable to other genetic disorders with similar mechanisms
• Cost-effective scalability
• Controlled release

APPLICATIONS

• Amyotrophic lateral sclerosis
• Frontotemporal dementia
• Gene therapy

January 10, 2025

Proof of concept

Patent Pending

Licensing,Co-development

Paschalis Kratsios