Broad Institute Scientists Nominate a Promising Drug Candidate for Prion Disease
SciFocus/Dec 11, 2024 — In a groundbreaking preclinical study led by Sonia Vallabh at the Broad Institute of MIT and Harvard, researchers have introduced a novel therapeutic approach for prion disease using divalent siRNA technology. The drug candidate, 2439-s4, offers unprecedented efficacy in lowering the expression of the prion protein (PrP), which is central to the progression of this devastating disease. This work, driven by Vallabh’s personal mission to find a treatment, represents a critical step toward addressing a currently untreatable condition.
Key Findings
- Efficacy in Preclinical Models:
- Tool compounds achieved ~50% PrP reduction, extending survival in prion-infected wild-type mice.
- New divalent siRNA drug candidate reduced PrP levels to as low as 17% in humanized transgenic mice, surpassing prior benchmarks.
- Innovative Drug Design:
- Utilizes a fixed tail and reduced phosphorothioate antisense strand with extended nucleic acid (exNA) linkages for enhanced potency and durability.
- Demonstrated sustained activity up to six months post-dosing and effectiveness with repeat dosing.
- Transgenic Models for Human Targeting:
- Development of humanized transgenic mouse models incorporating the full non-coding sequence of the human PrP gene to identify human-targeted siRNA sequences.
- Dose-Responsive PrP Lowering:
- Supports the hypothesis that deeper PrP reduction correlates with greater therapeutic benefit.
- Homozygous knockouts remain invulnerable to prions, emphasizing the potential of this approach.
“Prion disease remains a devastating diagnosis, but divalent siRNA 2439-s4 represents a beacon of hope. By pushing the boundaries of PrP-lowering technology, we are closer than ever to finding a treatment that could change lives.”
Challenges and Limitations
- In Vivo Validation:
- Efficacy of deeper PrP lowering in halting disease progression remains untested in humanized models due to safety concerns.
- Absence of cross-reactivity between the drug candidate and mouse PrP precludes certain rescue studies.
- Clinical Application:
- Translational hurdles, including long-term safety, scalability, and potential adverse effects, require further investigation.
This innovative research lays the groundwork for future breakthroughs in treating prion diseases, offering hope to patients and families affected by this rare but devastating condition. Sonia Vallabh’s relentless pursuit of a cure demonstrates the power of scientific determination and the profound impact of personal motivation in driving medical advancements.
Source: https://www.biorxiv.org/content/10.1101/2024.12.05.627039v1.full
