A single injection with candidate gene therapy FLT190 showed positive results in a mouse model of Fabry disease by significantly increasing blood levels of GLA — the enzyme affected in this disease — and reducing Gb3 storage levels in the heart and kidney, the therapy’s developer, Freeline, announced.
A Phase 1/2 trial, called MARVEL1 (2018-002097-51), is now recruiting participants in Europe to test FLT190 in adult males with classic Fabry disease.
The preclinical results were presented in a poster titled “Liver-Directed Gene Therapy Corrects Fabry Disease in Mice” (GT-02) during the 6th Update on Fabry Disease, May 26–28, in Prague, Czech Republic.
Fabry disease is caused by mutations in the GLA gene that provides instructions for the production of an enzyme called alpha-galactosidase A (alpha-GAL A). These mutations typically affect the function of alpha-GAL A and lead to the accumulation of a type of fat called globotriaosylceramide (Gb3) in several tissues and organs such as the heart, kidney, or liver, which can result in organ damage.
FLT190 is a gene therapy that uses an adeno-associated virus (AAV8) — a harmless virus that does not cause disease or infection — as a vehicle to deliver a healthy copy of the GLA gene in the hopes that it will induce the production of normal alpha-GAL A.
Researchers used a mouse model of Fabry disease that was genetically engineered to lack the GLA gene. A single dose of FLT190 (2×10^12 vg/kg) was injected into the blood to deliver a human version of the GLA gene specifically to liver cells.
Four weeks after the treatment, the levels of the alpha-GAL A enzyme in the blood increased more than 1000-fold when compared with healthy mice after 14 weeks. These high levels were maintained throughout the duration of the study (14 weeks).
FLT190 treatment also resulted in marked and durable decreases in Gb3 storage levels by 64% in the kidney, 97% in the spleen, 99% in the liver, and 98% in the heart compared with age-matched untreated Fabry animals.
Moreover, the levels of LysoGb3, which have been suggested as a useful and accurate biomarker to diagnose and monitor Fabry disease, were also reduced by 98%, reaching similar levels to those observed in healthy animals.
No adverse clinical signs or toxicity associated with high levels of alpha-GAL A in the liver or blood were detected.
“Collectively, these data provide strong evidence that our liver-directed AAV-mediated gene therapy approach holds considerable therapeutic potential for the treatment of Fabry disease. We anticipate that AAV mediated gene transfer will be safe and efficacious in patient with Fabry’s,” the researchers wrote.
“Our preclinical data are very encouraging, demonstrating clear evidence of the therapeutic potential of FLT190 in treating Fabry Disease,” Anne Prener, CEO of Freeline, said in a press release.
In a second poster, titled “Investigation of a Novel Adeno-Associated Viral Vector Gene Therapy (FLT190) in Patients with Fabry Disease – Design of the Phase 1/2 Study,” (GT-03) Freeline presented the design of its upcoming Phase 1/2, MARVEL1 (2018-002097-51) study, an open-label trial that will test FLT190 in adult males with classic Fabry Disease.
The study, which will take place in multiple centers across Europe and the U.S., will test a single dose of FLT190 in both untreated patients and those previously treated with either pharmacological chaperone therapy or enzyme replacement therapy.
The study’s main objective is to assess FLT190’s safety. Secondary objectives include assessment of alpha-GAL A activity, clearance of Gb3 and LysoGb3, and levels of Gb3 in several organs, including the kidneys, skin, and heart. During the trial, all patients will be given preventive steroids.
The study is currently recruiting at two sites in Europe.
“This study aims to investigate the safety of FLT190, a new gene therapy, and its potential to treat the signs and symptoms of Fabry disease following a single administration of FLT190 with the potential to lead to continuous production of αGLA,” the researchers wrote.