PNA Nanoparticles for Gene Editing of Rett Syndrome

Peter Glazer, MD, PhD & Mark Saltzman, PhD | Yale University

$275,000 AWARDED

The goal of this proposal is to edit MECP2 mutations at the gene level. However, unlike the other DNA and RNA editing projects we are funding, this approach does not require delivery to the cell via a vector. Glazer and Saltzman propose to use synthetic molecules called peptide nucleic acids (PNAs), as well as donor DNA, which carries the correct sequence, to edit the genetic defect. The PNAs and donor DNA is delivered to cells via non-viral microscopic nanoparticle. This novel technology was developed by Glazer/Saltzman and utilizes tiny particles, billionths of a meter in diameter, specifically designed to penetrate targeted cells.

The PNA is synthetic DNA that is uniquely designed to target and bind to a specific location on a gene. In our case the location of an MECP2 mutation. When the PNA binds it distorts the DNA, turning it from a double helix into a bulging triple helix. The cells’ own DNA repair systems recognizes that the bulging shouldn’t be there and cuts out the PNA (the third helix). The donor DNA then swoops in to repair the cut and the result is corrected DNA where a mutation used to be.

This repair system has evolved over time and is designed to keep our DNA safe. For example, when we get a sunburn due to ultraviolet damage our DNA gets damaged and the DNA repair system works to fix that damage. Glazer/Saltzman have figured out a way to highjack this same system using the PNA to trigger the cut and the donor DNA to repair it.

Because this approach uses nanoparticles rather than vectors there is a possibility to re-dose multiple times to achieve the correct level of editing without the worry of an immune response. The other advantage is that once the editing is done, these PNA molecules will be cleared by the body leaving nothing behind but the correct sequence of MECP2.

Current Projects