Gene-editing therapy restores more normal function in FA cell model

Treatment reverses cellular defects and increases frataxin in recent study

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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A gene-editing therapy designed to correct the FXN gene defect that’s associated with Friedreich’s ataxia (FA) reversed several cellular features of the disease in patient-derived nerve cells, according to recent research.

Scientists identified that dysfunction of a cellular compartment called the endoplasmic reticulum (ER) might play a key role in driving FA-associated nerve cell death, but the gene therapy was also able to restore more normal function of this organelle.

“Taken together, these results represent a novel finding for disease pathogenesis [development] showing dramatic ER structural damage in [FA], validate the efficacy profile of our FXN gene editing approach in a disease relevant model, and support our approach as an effective strategy for therapeutic intervention for Friedreich’s ataxia,” the researchers wrote.

The study, “Gene editing improves endoplasmic reticulum-mitochondrial contacts and unfolded protein response in Friedreich’s ataxia iPSC-derived neurons,” was published in Frontiers in Pharmacology.

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In FA, mutations in FXN lead to a lack of the frataxin protein that’s important for energy production in cellular compartments called mitochondria. The ensuing dysfunction of mitochondria and impaired energy production are thought to be key cellular processes that drive nerve cell damage in FA.

For the vast majority of cases, FA-causing mutations involve the excessive repetition of a trio of DNA building blocks — a guanine (G) and two adenines (AA) — at a certain place in both copies of FXN. These so-called trinucleotide GAA repeat expansions disrupt the gene’s activity, thereby inhibiting frataxin production.

Previously, the researchers developed a gene-editing therapy to correct this defect. Essentially, the approach aims to collect a person’s own hematopoietic stem cells — the precursors to all mature blood cell types in the body — and edit them in the lab to cut out the excess GAA repeats in FXN. That’s done using CRISPR/Cas9, a Nobel Prize-winning gene-editing technology.

The theory is that those corrected stem cells could then be returned to the patient, where they would repopulate the body with healthy frataxin-producing cells, thereby slowing FA symptom progression.

The study and its results

In the recent study, the researchers aimed to test the safety and efficiency of this therapeutic approach in a disease-relevant, preclinical model. They generated FA patient-derived nerve cells as well as nerve cells derived from healthy people, comparing them with gene-edited versions of the same cells.

As expected, frataxin protein levels were significantly decreased in the cells from FA patients relative to healthy cells. Patient-derived cells also exhibited several disease-related abnormalities, including nerve cell structural changes, increased markers of cell death, mitochondrial dysfunction, and oxidative stress — a type of cellular damage associated with mitochondrial impairments that is seen in FA.

These deficits were prevented in the gene-edited patient cells, with increases in frataxin production also observed.

Genetic analyses revealed many alterations in patient-derived cells relative to healthy ones. Several genes associated with critical functions of the endoplasmic reticulum, or ER, had lower activity in patient-derived cells, for instance, but that was largely normalized with the gene-editing therapy.

The ER is a cellular compartment mainly involved in producing proteins and folding them into the right structures. Its dysfunction can lead to the accumulation of faulty proteins that drastically disturb cell function.

It also has a close relationship with mitochondria; the two organelles form physical contacts that are involved in regulating several processes that support cellular balance, or homeostasis.

Additional experiments revealed notable ER functional defects in the patient cells, as well as reductions in the number of mitochondria-ER interaction sites, with “strikingly compromised ER structures,” the authors noted. These abnormalities were again reversed in the gene-edited, patient-derived cells.

Taking all the evidence together, the researchers believe that problems in the ER may lead to protein toxicity that contributes to nerve cell death in FA. By restoring more normal ER and mitochondrial dynamics, the gene-editing therapy may be able to help protect nerve cells.

“Altogether, the results of this study represent crucial efficacy profile of our CRISPR/Cas9 approach in a disease relevant model of [FA],” the researchers wrote, concluding that the study positions the gene-editing therapy “as an effective strategy for therapeutic intervention for Friedreich’s ataxia.”