Early Data Support Gene-editing Platform’s Ability to Fix FA Deficits

Prime Medicine's platform found to correct genetic deficits in patient-derived cells

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Prime Medicine’s gene-editing technology — called Prime Editing — successfully corrected the genetic deficits associated with Friedreich’s ataxia (FA) and restored nerve cell projections in preclinical studies using patient cells, the company has announced.

The company also announced positive updates from a number of its 18 other developmental programs also using Prime Editing technology, including cystic fibrosis and Wilson disease.

“Today, we are pleased to announce accomplishments across our portfolio and platform, including new preclinical proof-of-concept data in Friedrich’s ataxia and cystic fibrosis showing restoration of genetic function,” Keith Gottesdiener, MD, president and CEO of Prime, said in a company press release.

“Together, these updates reinforce our belief in Prime Editing as an extremely powerful, differentiated technology, with the potential to deliver one-time, curative genetic therapies to address a wide spectrum of diseases,” Gottesdiener said.

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Friedreich’s ataxia is caused by FXN gene mutations

FA is caused by mutations in the FXN gene that provides instructions for making the frataxin protein, a protein critical for the function of cellular energy production centers called mitochondria. As a result, cells cannot make enough functional frataxin protein, leading to a disruption in energy production within cells and damage to multiple bodily systems. People with FA experience symptoms such as loss of coordination and muscle strength as the disease progresses.

The most common type of FA-causing mutation is called a GAA trinucleotide repeat expansion. The healthy FXN gene contains a region where a trio of nucleotides — the building blocks of DNA — is repeated several times. This trio, containing a guanine (G) and two adenines (A), is usually repeated about 5–33 times.

But in FA, the number of repeats is much higher, ranging from about 66 to more than 1,000 repeats in both copies of the gene.

It’s been reported that FA patients show signs of hypermethylation at their FXN gene. Methylation is a chemical or epigenetic modification that works to regulate a gene’s activity.

Together, these updates reinforce our belief in Prime Editing as an extremely powerful, differentiated technology, with the potential to deliver one-time, curative genetic therapies to address a wide spectrum of diseases

Prime Editing is designed to remove harmful GAA repeats in the FXN gene

Prime is using its technology to remove the harmful GAA repeats in the FXN gene, with the aim of preventing excess methylation and restoring more normal frataxin levels.

With an ability to edit, correct, insert or delete DNA, the technology acts like a “DNA word processor, with the power to search and replace genetic sequences,” the company states on its website.

Essentially, the program will search for the part of the DNA that houses GAA repeats in FA cells, and create nicks where its technology can help to delete the expansion sequences. The goal is to create a normal, or wild-type version of the DNA that restores nervous system function.

It’s designed to be precise, with minimal off-target changes that could compromise safety and tolerability. The editing is also intended to be permanent, meaning it will require only a single treatment. The corrected gene will pass along the correction to all of its daughter cells.

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Gene Editing Seen to Restore Frataxin Level in Cells From Patients

Data from in vitro, or in-the-lab, studies showed that by removing the GAA repeats, the hypermethylation at the FXN gene was corrected in cells from FA patients, restoring overall function of the gene to wild-type levels.

Moreover, the editing restored frataxin levels in patient cells and restored sensory nerve cell function.

In addition to showing promise as a treatment approach for FA, the Prime Editing technology could hold potential for other diseases marked by repeat expansions.

Other diseases in Prime’s pipeline include sickle cell disease, forms of muscular dystrophy, Huntington’s disease, fragile X syndrome, and amyotrophic lateral sclerosis.

“As we enter 2023, we look forward to progressing our most advanced programs toward the clinic, while continuing to optimize our technology and build the internal organization, culture and expertise necessary to meet our ambitious goals,” Gottesdiener added.

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