In Vivo Base Editing Extends Lifespan in Humanized Mouse Model of Prion Disease
Prion disease, a fatal neurodegenerative disorder caused by the misfolding of prion protein (PrP), currently lacks a cure. In a Nature Medicine study, scientists have successfully extended the lifespan of a humanized mouse model of prion disease using in vivo base editing. This research offers a promising therapeutic approach by targeting the PRNP gene, which encodes PrP, to reduce its levels in the brain.
The Innovation
Using advanced cytosine and adenine base editing strategies, delivered via adeno-associated viruses (AAVs), the research team achieved permanent modifications of the PRNP locus. This resulted in significant knockdown of PrP expression in the brain. A dual-AAV system, encoding BE3.9max base editors and a single-guide RNA (sgRNA), introduced the R37X mutation to the PRNP gene, leading to:
- 37% average installation of the desired genetic edit.
- 50% reduction in PrP levels in the brain.
- 52% increase in lifespan for mice inoculated with human prion disease isolates.
This approach proved effective against both sporadic and genetic subtypes of prion disease, which are the most common forms in humans.
Enhancements in Base Editing
The researchers also developed optimized base editing systems to improve delivery efficiency and minimize off-target effects. These refinements achieved:
- 63% average reduction in PrP levels with a lower viral dose.
- No clinically significant off-target editing in human cells or mouse tissues.
Complementary Strategies and Future Directions
While this study focused on base editing, another recent approach, CHARM (coupled histone tail for autoinhibition release of methyltransferase), demonstrated potent PrP reduction via epigenetic silencing of the Prnp promoter. However, CHARM was tested in wild-type mice with mouse-specific agents, leaving questions about its application to human PRNP and long-term durability.
The base editing strategy described in this study has broad potential for clinical translation. The mouse-specific AAV capsid used here, PHP.eB, could be replaced with human-compatible serotypes, such as BI-hTFR1, which can cross the human blood-brain barrier and achieve central nervous system-wide distribution.
Path to Clinical Application
Future work will focus on:
- Evaluating biodistribution and immune responses to AAVs and base editor transgenes.
- Assessing therapeutic benefits when treatment is initiated at later disease stages.
- Expanding these findings to human trials, with the goal of developing a one-time treatment to ameliorate all forms of prion disease.
This innovative approach represents a major step forward in the fight against prion diseases, offering hope for a disease-modifying therapy that could save lives and improve outcomes for affected individuals.
Source: https://www.nature.com/articles/s41591-024-03466-w
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