New Fabry gene therapy may work better than others in development
Treatment candidate gives extra boost to alpha-Gal A production in Fabry mice
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A new experimental gene therapy may boost the production of alpha-galactosidase A (alpha-Gal A) — the enzyme that’s missing or faulty in Fabry disease — beyond the levels of gene therapies now in development.
That’s according to laboratory data from a preclinical study that tested the new gene therapy in a juvenile mouse model of Fabry. The scientists noted that the one-time gene therapy, which delivers an optimized version of the GLA gene to liver cells, more effectively restored enzyme activity and reduced tissue involvement than a gene therapy that uses the unmodified, naturally occurring gene.
“This study provides a proof-of-concept showing that the tested liver-specific gene therapy vector is capable of preventing disease progression in juvenile Fabry mice at relatively low doses,” the researchers wrote.
Further, it “shows potential in treating both early- and late-onset [Fabry disease] in patients,” the team added.
The study, “Liver Gene Therapy in Fabry Disease Mice With Low Doses of rAAV2/8 Expressing a Codon-Optimized hGLA cDNA Results in Long-Term Disease Correction,” was published in the JIMD Journal of Inherited Metabolic Disease.
In Fabry, mutations in the GLA gene cause a deficiency of the enzyme alpha-Gal A. A lack of this enzyme activity results in the toxic buildup of fatty substances, mainly globotriaosylceramide (Gb3), leading to cellular dysfunction and multiorgan damage.
Gene therapy eyed as long-term treatment for Fabry disease
Enzyme replacement therapy (ERT) is the standard treatment for Fabry, providing patients with a lab-made version of alpha-Gal A to help clear Gb3 and its metabolite, lyso-Gb3, from cells.
However, despite its benefits, ERT has notable limitations, including the need for frequent infusions and the possibility of related reactions. Such treatments also can carry a high price tag, and patients can develop antibodies that can reduce the effectiveness of ERTs.
Given its typical one-time administration, gene therapy has emerged as a potential long-term treatment option for Fabry disease. These therapies are designed to deliver a healthy version of the GLA gene into cells using modified adeno-associated viruses (AAVs) to restore alpha-Gal A production.
In fact, several gene therapies for Fabry arenow undergoing clinical testing.
Similar to other gene therapies, the experimental Fabry disease treatment described in this study aims to deliver a healthy version of the GLA gene to liver cells. But in this case, the gene has been modified to boost alpha-Gal A production beyond what the naturally occurring, unmodified (wild-type) gene used in other gene therapies can achieve.
After testing several modified versions of the GLA gene, one, dubbed CO2, outperformed the wild-type gene at producing alpha-Gal A in liver cells and in the blood and liver of healthy mice, according to the scientists.
Fabry mice given new treatment saw greater benefits
The team then treated Fabry mice missing the Gla gene with an AAV8 vector carrying either the CO2 or wild-type GLA gene. A separate group of Fabry mice received ERT at five times the standard patient dose. Across all tested doses, blood alpha-Gal A enzyme activity in CO2-treated mice exceeded levels seen in both untreated healthy mice and ERT-treated mice, the data showed.
With the CO2 construct, blood lyso-Gb3 levels were reduced in a dose-dependent manner, the researchers noted. Further, lyso-Gb3 clearance was at least three times more pronounced with CO2 than with the wild-type gene.
In tissue analysis, ERT-treated animals showed elevated alpha-Gal A activity in the liver, kidney, and heart, resulting in reductions in lyso-Gb3 of 56% to 76% compared with untreated Fabry mice. CO2-treated animals also showed a dose-dependent increase in enzyme activity, consistently exceeding that of the wild-type gene. At all but the lowest dose, enzyme activity in CO2-treated mice equaled or exceeded that of untreated healthy controls. Even so, low-dose CO2 was significantly more effective than the wild-type gene at clearing lyso-Gb3 from the livers (95% vs. 68%), kidneys (87% vs. 40%), and hearts (84% vs. 34%) of Fabry mice.
A separate group of Fabry mice was then treated and monitored for one year to assess the gene therapy’s long-term effectiveness. Over time, enzyme activity remained stable and completely cleared lyso-Gb3 from all target tissues. Samples from the liver and kidney confirmed these findings: Gb3 deposits visible in untreated Fabry mice were absent in CO2-treated animals.
To assess neurological function, researchers used the hot plate test, which measures sensitivity to heat. Fabry mice show reduced heat sensitivity, with a response delay two to three times longer than that of normal mice. CO2 treatment restored heat sensitivity to near normal levels in these mice, the data show.
“Our work demonstrates that the AAV8-GLA-CO2 vector represents a promising novel therapy for treating juvenile and adult patients with [Fabry disease],” the team concluded. The scientists noted the new therapy candidate likely could be used for people “with the classical form [of Fabry disease] who are diagnosed late or currently receiving enzyme replacement therapy.”
