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(https://directorsblog.nih.gov/2024/07/25/epigenetic-editor-silences-toxic-proteins-in-the-mouse-brain-offering-promising-path-to-treat-deadly-prion-diseases/) Epigenetic Editor Silences Toxic Proteins in the Mouse Brain, Offering Promising Path to Treat Deadly Prion Diseases
Jul 25th 2024, 09:00

Credit: Donny Bliss/NIH

(https://www.niaid.nih.gov/diseases-conditions/prion-diseases) Prion diseases are fatal neurodegenerative disorders caused by a malfunction of the prion protein in the brain. Exposure to a misfolded version of the protein triggers normal proteins of the same type in the brain to misfold, forming clumps that produce infectious disease and fatal brain damage over time. There are currently no treatments, preventive vaccines, or cures for prion diseases, which can be acquired, like mad cow disease, or inherited, like fatal familial insomnia. But an encouraging new study in mice suggests a potentially promising path for developing a treatment for people with these deadly conditions.

Findings from an NIH-supported study reported in (https://pubmed.ncbi.nlm.nih.gov/38935715/) Science show that the key to this approach is a molecular tool capable of silencing prion protein throughout the brain using epigenetic editing.1 Unlike gene editing approaches, which change the sequence of genes, epigenetic editing can turn gene expression off with the addition of a chemical tag that prevents genes from being translated into proteins. Such a strategy may be able to deliver modifying tools to the brain or other parts of the body to silence specific toxic or disease-causing genes, including the one encoding the prion protein, without the risks associated with altering DNA sequences.

Earlier findings in mouse studies have shown that reducing prion protein levels can halt disease progression. However, attempting this with gene editing approaches has been a challenge. In the new study, researchers led by (https://wi.mit.edu/people/member/weissman) Jonathan Weissman at the Whitehead Institute and (https://www.broadinstitute.org/bios/sonia-vallabh) Sonia Vallabh at the Broad Institute, both in Cambridge, MA, pursued an epigenetic approach to this problem as a potentially more feasible and safer option than gene editing. To do it, they first had to develop an epigenetic silencer that was compact enough for delivery into cells using an adeno-associated virus (AAV) vector, which is the preferred way to get therapeutic payloads into the central nervous system, including the brain.

They call their programmable epigenetic silencer “CHARM,” short for Coupled Histone tail for Autoinhibition Release of Methyltransferase. To target a gene with the needed specificity, CHARM uses a guide protein to direct the tool to a target site in DNA. The tool also recruits enzymes that are naturally present in cells to deliver a silencing methyl group. The researchers engineered their tool to include parts that successfully switch the methyltransferase enzyme on to do its work of silencing the prion gene in just the right spot.

To get the molecular tools into the brain, the researchers built on a previous NIH-supported advance made by a team including study co-author (https://www.broadinstitute.org/bios/ben-deverman) Benjamin Deverman, also at the Broad Institute, that improves the delivery of therapeutic molecular tools such as CHARM into the brain. As reported in (https://pubmed.ncbi.nlm.nih.gov/38753766/) Science, the researchers showed they could shuttle an AAV across the blood-brain barrier using a receptor that normally brings iron into the brain.2

The latest study shows that, when delivered to the mouse brain using this new AAV, CHARM efficiently silences the prion gene in most neurons without altering the underlying DNA sequence. As a result, prion protein levels dropped by more than 80%. That’s important given that earlier studies have shown that reducing prion protein by as little as 20% can improve symptoms. The researchers also engineered their CHARM editors such that they turn themselves off after silencing the target gene to limit the possibility of unwanted effects.

This study was supported in part by the NIH Common Fund as part of the (https://commonfund.nih.gov/editing) NIH Somatic Cell Genome Editing (SCGE) Program. The researchers report they are now fine-tuning their tool to make it more effective, safer, and easier to manufacture in quantities that are necessary for future testing in clinical trials enrolling people with degenerative and otherwise fatal prion diseases. It’s likely to be a long road, but if all goes well, this impressive work could one day enable effective treatments for people with prion diseases. This approach may also hold promise for treating other neurodegenerative conditions that involve the accumulation of toxic protein aggregates in the brain.

References:

[1] Neumann EN, et al. (https://pubmed.ncbi.nlm.nih.gov/38935715/) Brainwide silencing of prion protein by AAV-mediated delivery of an engineered compact epigenetic editor. Science. DOI: 10.1126/science.ado7082 (2024).

[2] Huang Q, et al. (https://pubmed.ncbi.nlm.nih.gov/38753766/) An AAV capsid reprogrammed to bind human transferrin receptor mediates brain-wide gene delivery. Science. DOI: 10.1126/science.adm8386 (2024).

NIH Support: Common Fund Somatic Cell Genome Editing Program, National Institute of Neurological Disorders and Stroke, National Human Genome Research Institute, National Institute of Biomedical Imaging and Bioengineering

Forwarded by:
Michael Reeder LCPC
Baltimore, MD

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