Gene Therapy Breakthroughs Offer New Hope for Prion Disease Treatment

American Society of Gene & Cell Therapy (ASGCT) 2025 Meeting Highlights Emerging Gene and Epigenetic Therapies

A series of groundbreaking studies presented at the 2025 American Society of Gene & Cell Therapy (ASGC) meeting highlighted major advances in developing one-time, brain-wide treatments for prion disease-a universally fatal and currently untreatable neurodegenerative disorder caused by misfolding of the prion protein (PrP).

One-Time Gene Therapy Shows Promise for Treating Fatal Prion Disease

Researchers from Sangamo Therapeutics (Richmond, CA; Brisbane, CA; San Mateo, CA), the Broad Institute of MIT and Harvard (Boston and Cambridge, MA), and Evotec SE (Hamburg, Germany) reported that a single intravenous dose of an adeno-associated virus (AAV) delivering a zinc finger repressor (ZFR) achieved long-lasting repression of the PRNP gene in mice and nonhuman primates (NHPs).

In C57BL/6 mice, neuron-specific ZFR expression led to a dose-dependent reduction of up to 50% in Prnp mRNA and 45% in PrP protein levels, with effects maintained for 17 months. In a disease model using Rocky Mountain Laboratory (RML) prion-inoculated mice, AAV-ZFR treatment significantly extended survival even when administered after symptom onset.

Parallel studies in cynomolgus monkeys using a novel blood-brain barrier-crossing capsid (STAC-BBB) demonstrated ZFR delivery to 35 brain regions, achieving up to 95% PRNP repression in neurons in key prion-relevant areas such as the hippocampus, thalamus, and putamen.

Further supporting the zinc finger strategy, Sangamo Therapeutics, in collaboration with the Broad Institute, SRI International (Menlo Park, CA), and Neuroscience Associates (Knoxville, TN), presented additional preclinical data. In RML-inoculated mice, a single IV dose of AAV-ZFR extended survival from a median of 170 days in controls to up to 494 days at the highest dose. The therapy also improved body weight and nesting behavior, while post-mortem analyses revealed dose-dependent reductions in brain PrP and cerebrospinal fluid PrP levels (50–80%).

The treatment was well tolerated in both prion-infected and healthy mice. Safety was also confirmed in nonhuman primates, supporting the continued development of the STAC-BBB ZFR platform as a potential therapeutic for prion disease.

Epigenetic Editing and siRNA Approaches Advance Toward Clinical Trials

A team from the Broad Institute, Massachusetts Institute of Technology, University of Massachusetts Chan Medical School, and University of California, San Francisco is pursuing two distinct therapeutic strategies to lower PrP levels: a divalent siRNA (di-siRNA) and an epigenetic editing platform known as CHARM (Coupled Histone tail for Autoinhibition Release of Methyltransferase).

The di-siRNA approach, consisting of linked siRNA duplexes targeting Prnp, reduced PrP by up to 70% in the mouse brain one month after a single cerebrospinal fluid injection and maintained target engagement for six months. CHARM, delivered via AAV to cross the blood-brain barrier, recruited endogenous DNMT3A to the Prnp promoter and achieved up to 80% PrP reduction, with stable effects also lasting at least six months.

Both methods showed significant disease-modifying effects in prion-infected mice and are being prepared for first-in-human studies.

Base Editing Achieves PrP Knockdown and Lifespan Extension

A separate study led by researchers from Harvard University, the Broad Institute, Prime Medicine, and Case Western Reserve University, in collaboration with David R. Liu’s laboratory, introduced an AAV-based in vivo base editing strategy. Using a dual-AAV system encoding a cytosine base editor (BE3.9max) and guide RNA targeting PRNP, researchers achieved a 37% edit frequency, a 50% reduction in PrP levels, and a 52% increase in survival in transgenic mice expressing human PRNP and inoculated with pathogenic prions.

Optimized versions of the base editing platform further enhanced potency while minimizing off-target effects. The improved system reduced PrP levels by 63% at a significantly lower viral dose, highlighting its potential as a precise and permanent genetic intervention.

Conclusion

Together, these studies represent a major leap forward in the pursuit of a durable, one-time therapy for prion disease. From zinc finger repressors and siRNA to base editing and epigenetic engineering, multiple platforms are now converging on the shared goal of reducing prion protein levels in the brain-a strategy increasingly validated across species and models.

As these programs advance toward human trials, they hold promise not only for treating symptomatic patients but also for preventive intervention in individuals carrying high-risk PRNP mutations.

Source: ASGCT 2025 Meeting Abstracts 

 

About Marin Biologic Laboratories

Our Recent Publication/Meeting Presentation on Gene Therapy

1.  Development of a Pharmacokinetic (PK) Mouse Serum GLP ELISA for an Anti–CD19–AntiCD3 Diabody
bioRxiv 2025.03.19.644217; doi: https://doi.org/10.1101/2025.03.19.644217
2. Cell-Based Potency Assay for Anti-CD3-Anti-CD19 Diabody. bioRxiv 2025.04.15.648836v1 https://www.biorxiv.org/content/10.1101/2025.04.15.648836v1
3.  American Society of Hematology (ASH) Annual Meeting 2024.
Abstract link: Using Gene Therapy to Solve Challenges with CAR-T Cell Immunotherapy: Lead Selection and Preclinical Development of an Adeno-Associated Virus with Reduced Immunogenicity  Exhibiting Efficient and Long-Term Expression of an Anti-CD19 T-Cell Engager.

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