RNA-editing Gene Therapy as a Treatment for FUS-ALS

• Applicant: Professor Dr. Jared Sterneckert
• Subject Area: Molecular and Cellular Neurology and Neuropathology
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 563042818

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease characterized by the progressive loss of upper and lower motor neurons (MNs). A subset of cases, referred to as juvenile ALS, are particularly tragic and have an onset of younger than 25 years of age. FUS mutations are one of (probably THE) most common known genetic cause of juvenile ALS. In addition, FUS mutations account for a significant number of familial as well as sporadic ALS cases, and FUS pathology marks a significant subset of frontotemporal dementia cases. Therefore, therapeutics designed specifically against FUS would benefit a significant number of patients – particularly patients who are among the most tragically affected by ALS at a young age. Antisense oligonucleotides (ASOs) are the most actively investigated therapeutic strategies for ALS, including FUS-ALS, and recent evidence has provided compelling evidence suggesting that reducing FUS levels could be an effective therapeutic approach. However, ASOs need to be regularly administered by intrathecal injection every four weeks, which is very invasive. Also, ASOs and their repeated administration have been associated with toxicity. Therefore, it is not easily possible to administer ASOs to individuals with mutant FUS before they show symptoms, which is a considerable problem because this is when the most MNs could be protected. Moreover, the repeated administration (potentially over decades for a young patient) that ASOs require would greatly increase the chance of toxicity occurring. We suggest that a gene therapeutic inducing long-term reduction of FUS mRNA could be a good therapeutic strategy. Gene therapeutics using adeno-associated virus (AAV) have shown tremendous promise in pre-clinical and clinical testing for MN diseases. A single administration of AAV showed therapeutic effects over 250 days later in mice. Here, we propose developing an AAV therapeutic vector that reduces FUS mRNA transcripts over a long period of time and after only a single injection. We will develop this vector using human MNs differentiated from induced pluripotent stem cells. A mouse model will be used to evaluate efficacy of AAV-CasRx against FUS when administered before and after symptom onset. Since an AAV-based vector is now clinically approved for one MN disorder and multiple companies produce AAV vectors under GMP conditions, our new AAV vectors could be rapidly translated into clinical testing.

• DFG Programme: Research Grants
• International Connection: USA
• Co-Investigator: Professor Dr. Björn Falkenburger
• Cooperation Partner: Professor Steven Gray, Ph.D.