Gene-editing therapy for Fabry disease

Last updated May 29, 2024, by Marisa Wexler, MS
Fact-checked by Ana de Barros, PhD

Gene-editing therapy, which involves making precise modifications to specific segments of DNA to treat or prevent a certain disease, is a strategy that may hold promise as a potential Fabry disease treatment.

Fabry is a rare genetic disorder caused by mutations in the GLA gene, which provides the instructions to make the alpha-galactosidase A enzyme (alpha-Gal A). The enzyme is necessary for breaking down fatty molecules, mainly globotriaosylceramide (Gb3), into building blocks that cells can use.

Alpha-galactosidase A deficiency leads to the harmful accumulation of Gb3 inside cells, which ultimately results in organ damage and leads to Fabry disease symptoms.

By targeting the disease’s underlying genetic defects, gene-editing therapy seeks to ease symptoms and prevent the complications associated with Fabry disease.

Gene-editing therapy for Fabry disease is still in the early stages of development, however. Extensive research, including preclinical studies and clinical trials, will be necessary to optimize this approach and determine whether it is a viable treatment option for people with the disease.

What is gene-editing therapy?

Gene-editing therapy is a type of treatment that involves the introduction, alteration, or deletion of specific segments within a person’s genetic code. This lets researchers correct certain genetic defects that may be causing disease, offering a potential curative option for a wide range of inherited genetic diseases and conditions.

Gene-editing therapy and gene therapy are two different approaches that alter the genetic makeup of cells to address the cause of a specific disease. The main difference is that, in comparison with gene therapy, which seeks to introduce a functional gene into cells, gene editing typically aims to correct the specific mutation.

The approach can be designed to target disease-causing mutations in a person’s DNA, which has durable effects but carries certain risks. In particular, gene-editing systems can sometimes have off-target effects, altering unintended genes, which could lead to serious side effects and complications like cancer.

Recently, researchers have been working on gene-editing therapies that correct the genetic defect in an intermediate molecule called messenger RNA. This molecule is produced when the gene is read and is used as a template for protein synthesis.

By correcting the mRNA molecule, these gene-editing approaches can result in a functional protein being produced while reducing the risk of off-target effects. However, mRNA editing therapies must be administered repeatedly for a sustained effect to be observed.

Gene-editing therapies hold potential for numerous diseases, including inherited disorders, blood disorders, cancer, and viral infections. In the context of Fabry, they mostly aim to “correct” disease-causing mutations in the GLA gene to enable a functional alpha-Gal A enzyme to be produced.

Approaches in gene editing that prevent Gb3 from being made have also been tested in animal models of the disease and targeting other genes involved in disease mechanisms may also prove beneficial in Fabry.

How gene-editing therapy works

A number of technologies have been developed for gene-editing therapies. The most famous one is the CRISPR/Cas9 system, which was adapted from a set of molecular tools that bacteria use to fight off infecting viruses.

The system uses short pieces of RNA, referred to as guide RNAs, that are designed to target a specific region of a gene. When the guide RNA binds to the target gene, it triggers an enzyme — usually Cas9, though other enzymes may be used — to make a cut in the DNA at the targeted location.

By harnessing the natural defense mechanism of bacteria, scientists can program the CRISPR/Cas9 system to modify specific genetic sequences within a patient’s genome.

The process of gene-editing therapy involves several steps. First, scientists design the guide RNAs to target a specific sequence within a patient’s DNA. Then, the CRISPR/Cas9 complex is introduced into a patient’s cells, where the Cas9 protein will cut the DNA at the targeted site to allow the removal, replacement, or repair of the defective gene.

After the DNA has been cut, the cells’ natural DNA repair mechanisms take over to mend the break. With the corrected gene sequence in place, the cell can produce functional proteins, restoring the normal cellular function and alleviating disease symptoms.

Along with the CRISPR/Cas9 system, other gene-editing tools, such as transcription activator-like effector nucleases (TALENs) and zinc finger nucleases (ZFNs), also exist.

These tools also work by recognizing specific DNA sequences and cutting the DNA at those regions, allowing scientists to edit genes by either letting the cell repair the DNA naturally or by providing a piece of DNA that can be used as a template during the repair process.

Regardless of the technique used, gene-editing therapies can generally be classified in two groups, so-called in vivo and ex vivo gene-editing therapies, depending where the genetic modification takes place.

While ex vivo therapies involve collecting and modifying the cells outside the body and reintroducing them into a patient via an infusion, in vivo therapies are designed to edit the genome in cells inside a patient’s body.

Gene-editing therapy for Fabry disease

A number of gene-editing approaches have been tested in preclinical studies as a potential Fabry disease treatment.

In animal models, gene-editing systems have been shown to reduce the toxic buildup of fatty molecules that marks the disease, and studies using human cells have shown it’s possible to “correct” the mutated GLA gene using gene editing, at least in lab conditions.

In theory, this could lead to potential benefits, such as easing symptoms and slowing or even stopping disease progression.

In one study, a research team in Taiwan explored the potential of using CRISPR/Cas9 technology to correct GLA mutations in patient-derived cells. They focused on a specific mutation that’s common in Taiwanese patients with cardiac Fabry disease.

Removing the mutation with CRISPR/Cas9 resulted in a significant increase in alpha-Gal A enzyme activity, which cleared the accumulation of Gb3 in cells. These findings supported CRISPR/Cas9 as a promising approach for Fabry patients with this specific mutation.

Another study investigated whether suppressing  the A4GALT gene with the CRISPR/Cas9 system could revert kidney issues associated with Fabry disease. The gene codes for a protein involved in producing Gb3, so suppressing it could reduce the amount of Gb3 accumulation inside cells.

To test this, a team in Korea collected blood cells from a Fabry patient and created stem cells, which were used to generate kidney organoids, that is, miniature versions of a kidney developed in a laboratory and designed to mimic how cells are organized in the organ itself. Suppressing A4GALT in the organoids could reverse the damage observed in kidney structures, data showed, suggesting it as a potential therapeutic approach.

Still, gene editing hasn’t been tested in people with Fabry disease and a number of challenges and limitations will need to be overcome before the approach can be tried in Fabry patients.

In addition to side effects and the risk of complications caused by off-target gene editing, another problem is that it’s very challenging for a gene-editing system to alter the DNA of every single cell in a patient’s body.

It’s also not clear how many cells need to be edited to achieve a therapeutic effect or which types of cells are most suitable for targeting.

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