Gene therapy for Fabry disease

Last updated June 7, 2024, by Marisa Wexler, MS
Fact-checked by Ana de Barros, PhD

A few gene therapies are currently being explored as a potential treatment for Fabry disease, a genetic condition caused by mutations in the GLA gene. These experimental therapies all share the goal of modifying a person’s genetic material to correct the disease’s underlying cause.

In people with Fabry, mutations in the GLA gene result in a deficiency of the alpha-galactosidase A (alpha-Gal A) enzyme, which is needed to break down certain fatty molecules, particularly globotriaosylceramide (Gb3), inside cells.

When the alpha-Gal A enzyme is dysfunctional or absent entirely, however, these fatty molecules build up to toxic levels inside cells, ultimately causing organ damage that drives disease symptoms.

Because gene therapy approaches counteract the genetic defects that cause Fabry disease, they hold promise as a one-time Fabry disease treatment that enables patients to produce enough alpha-Gal A for the rest of their lives. 

In theory, this could potentially free patients from lifelong treatment with existing therapies, potentially offering a lasting cure for the disease.

What is gene therapy?

Gene therapy is a broad term used to describe any technique that modifies genes within a person’s cells to treat or prevent a given condition. It can involve replacing a disease-causing gene with a healthy copy of the gene, disrupting or silencing a disease-causing gene, or introducing a novel or modified gene into a patient’s cells to treat the disease.

While the term “gene therapy” is sometimes used as a catch-all for any treatment that alters the genetic makeup of cells, gene therapy is distinct from another similar approach called gene-editing therapy.

The key difference is that gene therapy normally aims to introduce a healthy copy of a gene into a patient’s cells, while gene editing seeks to precisely alter the DNA sequence to correct the specific genetic mutation.

For Fabry, gene therapy is designed to deliver a functional version of the GLA gene to cells in the body, allowing them to produce a working version of the alpha-Gal A enzyme. As the functional enzyme can break down the excess fatty molecules that drive the disease, the approach has the potential to slow or stop disease progression.

Although no gene therapy is currently approved for Fabry disease, regulatory authorities in the U.S. and other countries have approved gene therapies for genetic disorders such as spinal muscular atrophy, sickle cell disease, and hemophilia, with transformative effects for some patients.

How gene therapy works

To insert a therapeutic gene into cells, most gene therapies use a modified virus. During a viral infection, viruses inject their own DNA into cells, allowing them to make more viruses and spread. Researchers have found ways to modify viruses so they cannot cause disease, but can use the same basic molecular machinery to deliver a therapeutic gene into cells.

Many different viral vector types, or delivery vehicles, can be used in gene therapies. However, most experimental gene therapies for Fabry disease specifically use vectors developed from a type of virus called an adeno-associated virus, or AAV.

This is a popular choice for gene therapies because the virus is easy to work with in a laboratory, doesn’t typically cause disease in people, and has a low immunogenicity, which reduces the risk of an immune response against the vector itself. Another clear advantage of AAV vectors is that they generally do not incorporate their DNA into the cell’s genome, which could disrupt important genes and lead to serious side effects, such as cancer.

Other delivery vectors also exist, including genetically engineered circular DNA molecules called plasmids, genetically modified bacteria, and artificial vesicles called liposomes that carry the genetic material inside fatty layers.

Gene therapies can be classified into two groups, depending on whether the process of genetic modification is done inside or outside the body:

• In in vivo gene therapies, the gene is delivered directly into the body, usually via an infusion into the bloodstream (intravenous infusion). As some vectors can specifically target a tissue or organ of interest, this delivery method allows the vector to travel through the bloodstream to reach its intended target.
• In ex vivo gene therapies, a patient’s cells are first collected and treated with the gene therapy in the lab. The modified cells are then returned to the patient’s body, where they are expected to modify certain biological processes to prevent or treat disease.

Clinical trials of gene therapies for Fabry disease

Currently, a few gene therapies for Fabry disease are being developed, each in different stages of clinical development.

While all aim to introduce a healthy GLA gene inside cells to restore the defective alpha-Gal A enzyme, these therapies typically target organs most affected by the disease, such as the heart or liver, and may not be able to ease disease processes in all affected organs.

Notably, the liver has the capacity to produce enzymes and release them into the bloodstream. Therefore, some liver-targeting therapies may be able to turn the liver into a “manufacturing hub” to make enough alpha-Gal A enzyme that can be distributed throughout the body and ease symptoms in other organs.

ST-920

ST-920 (isaralgagene civaparvovec) is an investigational Fabry gene therapy being developed by Sangamo Therapeutics to be administered as a one-time intravenous infusion.

The therapy uses an AAV vector called rAAV2/6 to deliver a functional version of the GLA gene to cells in the liver. This enables liver cells to produce a functional alpha-Gal A on their own, which is expected to reduce the abnormal accumulation of Gb3 and slow or halt disease progression.

According to the company, ST-920 is not expected to trigger an immune response that could undermine its effectiveness, which eliminates the need for pretreatment with steroids or other immunosuppressive medications to prevent those immune responses.

ST-920 is being evaluated in the Phase 1/2 STAAR clinical trial (NCT04046224) in adults with Fabry disease. Interim data from the first 24 participants showed the gene therapy led to an increase in alpha-Gal A levels, which were sustained for up to three years after treatment.

Patients also reported less severe symptoms and improved life quality, and most who were on enzyme replacement therapy (ERT) before ST-920 were able to stop it, with their alpha-Gal A levels continuing within or above normal levels.

Sangamo Therapeutics is preparing a Phase 3 clinical study to further investigate ST-920 in people with Fabry disease. Positive results from this trial could provide sufficient evidence to support an application for regulatory approval.

AMT-191

AMT-191 is an investigational therapy designed to deliver a healthy version of the GLA gene to liver cells using an AAV5 vector. In early development by uniQure, it’s expected to be given as a one-time infusion.

Studies in a Fabry mouse model have suggested it can boost alpha-Gal A enzyme activity in the liver, as well as in the kidneys, heart, and brain, normalizing Gb3 levels in these main organs.

The medication is now being evaluated in an open-label Phase 1/2a clinical trial (NCT06270316), where about 12 adults with suboptimal response to ERT will receive one of two AMT-191 doses. The main goal is to evaluate safety after more than two years of dosing.

4D-310

4D-310 is a gene therapy that’s being developed by 4D Molecular Therapeutics to deliver a healthy version of the GLA gene to heart muscle cells. This is expected to ease or improve the cardiac problems that are the main cause of death in Fabry disease.

Administered as a single intravenous infusion, the therapy uses an AAV-based vector called C102 that was developed specifically to deliver therapeutic genes to the heart. Notably, animal studies have shown it can also increase alpha-Gal activity and reduce Gb3 accumulation in a dose-dependent manner in other target tissues, including the liver and kidneys. 

Two open-label Phase 1/2 trials — one taking place in the U.S. (NCT04519749) and the other in Taiwan and Australia (NCT05629559) — are investigating 4D-310 in people with Fabry disease. A total of 36 adult patients are expected to participate, all of whom will be treated with 4D-310 at varying doses. The main goal is to assess the therapy’s safety after one year, and secondary measures include changes in blood levels of alpha-Gal A activity and lyso-Gb3, a disease biomarker.

Early data suggest 4D-310 improved heart health, but half of the patients given the gene therapy developed atypical hemolytic uremic syndrome, a rare autoimmune blood disorder marked by red blood cell destruction.

While these safety issues prompted the FDA to put a hold on 4D-310’s clinical program in early 2023, that hold was lifted a few months later after the company demonstrated that a different immunosuppressive regimen could reduce the risk of these side effects.

Potential side effects or complications from gene therapy

Like any medical treatment, gene therapy has the potential to cause side effects and complications. For instance, when gene therapies use a modified virus as a vector, the body’s immune system may mistakenly identify it as a harmful virus. This can lead to unwanted immune responses that can render the therapy less effective and give rise to inflammatory complications.

Notably, some gene therapies are known to cause liver inflammation, which can be serious or life-threatening. To mitigate these immune responses, patients are often administered anti-inflammatory medications such as corticosteroids around the time of the infusion. The specific regimen used for these medications, however, depends on the particular gene therapy and delivery vector being used.

Because viruses have the potential to affect multiple cell types, gene therapies can also inadvertently target the wrong cells. The likelihood of causing damage to healthy cells depends on the gene therapy approach and its intended purpose.

Fabry disease gene therapies are still in the early stages of clinical development, so their specific risk profile is not entirely known. Side effects observed so far in early clinical trials include:

• fever
• muscle pain
• atypical hemolytic uremic syndrome.

Fabry Disease News is strictly a news and information website about the disease. It does not provide medical advice, diagnosis, or treatment. This content is not intended to be a substitute for professional medical advice, diagnosis, or treatment. Always seek the advice of your physician or other qualified health provider with any questions you may have regarding a medical condition. Never disregard professional medical advice or delay in seeking it because of something you have read on this website.