First-in-human study of a liver-directed AAV gene therapy (FLT190) in Fabry disease

Hughes, Derralynn; Patel, Niten; Kinch, Russell; Dronfield, Leanne; Short, Gerard; Sheridan, Rose; Kia, Azadeh; Jeyakumar, Jey; Corbau, Romuald; Nathwani, Amit C.

doi:10.1016/j.ymgme.2019.11.188

Cited by 8 publications

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“…Two further clinical studies (NCT04046224, NCT04040049) [ 58 , 59 ] are based on adeno-associated viral (AAV) in vivo transduction of hepatocytes, using these cells as an AGAL-secreting platform instead of hematopoietic stem cell-derived cells (Fig. 3 e).…”

Section: Future Treatmentmentioning

confidence: 99%

“…FLT190 consists of a codon-optimized GLA transgene under the control of a liver-specific promoter. The construct, covered by a synthetic capsid, shows improved transduction of human hepatocytes compared to wild-type AAV serotypes [ 59 ]. A third clinical study on AAV-based gene therapy is also in the recruitment phase and uses an attenuated AAV (4D-310; 4D Molecular Therapeutics).…”

Section: Future Treatmentmentioning

confidence: 99%

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Fabry Disease: The Current Treatment Landscape

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Fabry disease (FD) is a rare X-linked lysosomal storage disease based on a deficiency of α-galactosidase A (AGAL) caused by mutations in the α-galactosidase A gene (GLA). The lysosomal accumulation of glycosphingolipids, especially globotriaosylceramide (Gb 3) and globotriaosylsphingosine (lyso-Gb 3 , deacylated form), leads to a multisystemic disease with progressive renal failure, cardiomyopathy with potentially malignant cardiac arrhythmias, and strokes, which considerably limits the life expectancy of affected patients. Diagnostic confirmation in male patients is based on the detection of AGAL deficiency in blood leukocytes, whereas in women, due to the potentially high residual enzymatic activity, molecular genetic detection of a causal mutation is required. Current treatment options for FD include recombinant enzyme replacement therapy (ERT) with intravenous agalsidase-alfa (0.2 mg/kg body weight) or agalsidase-beta (1 mg/kg body weight) every 2 weeks and oral chaperone therapy with migalastat (123 mg every other day), which selectively and reversibly binds to the active site of AGAL, thereby correcting the misfolding of the enzyme and allowing it to traffic to the lysosome. These therapies enable cellular Gb 3 clearance and improve the burden of disease. However, in about 40% of all ERT-treated men, ERT can lead to infusion-associated reactions and the formation of neutralizing antidrug antibodies, which reduces the efficacy of therapy. In chaperone therapy, there are carriers of amenable mutations that show limited clinical success. This article provides a brief overview of the clinical picture in FD patients, diagnostic confirmation, and interdisciplinary clinical management of FD. The focus is on current and future therapeutic options. Key Points Diagnosis of Fabry disease in males includes the detection of decreased α-galactosidase A activity and in females the determination of a disease-causing mutation. Current treatment options of enzyme replacement therapy and chaperone therapy can improve disease burden and quality of life. New therapy options include modified enzyme replacement therapy, substrate reduction therapy, and gene therapy.

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Section: Future Treatmentmentioning

confidence: 99%

Section: Future Treatmentmentioning

confidence: 99%

Fabry Disease: The Current Treatment Landscape

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2021

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“…In Gla −/− mice, FLT190 administration induced hepatic GLA expression and durable levels of plasma GLA activity, which resulted in the uptake of GLA in the heart and kidney, clearance of inclusion bodies, a reduction in renal Gb3, and reduction in Gb3 and lyso-Gb3 levels in the plasma and other tissues. In the NCT 04040049 study, FLT190 was Frontiers in Genetics frontiersin.org administered to 15 adult males, both treated and treatment-naive patients, with classic FD (Hughes et al, 2020). The long-term safety and durability of GLA in patients intravenously administered FLT190 were investigated (NCT 04455230) (Table 1).…”

Section: Fabry Diseasementioning

confidence: 99%

Gene therapy for lysosomal storage diseases: Current clinical trial prospects

2023

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Lysosomal storage diseases (LSDs) are a group of metabolic inborn errors caused by defective enzymes in the lysosome, resulting in the accumulation of undegraded substrates. LSDs are progressive diseases that exhibit variable rates of progression depending on the disease and the patient. The availability of effective treatment options, including substrate reduction therapy, pharmacological chaperone therapy, enzyme replacement therapy, and bone marrow transplantation, has increased survival time and improved the quality of life in many patients with LSDs. However, these therapies are not sufficiently effective, especially against central nerve system abnormalities and corresponding neurological and psychiatric symptoms because of the blood-brain barrier that prevents the entry of drugs into the brain or limiting features of specific treatments. Gene therapy is a promising tool for the treatment of neurological pathologies associated with LSDs. Here, we review the current state of gene therapy for several LSDs for which clinical trials have been conducted or are planned. Several clinical trials using gene therapy for LSDs are underway as phase 1/2 studies; no adverse events have not been reported in most of these studies. The administration of viral vectors has achieved good therapeutic outcomes in animal models of LSDs, and subsequent human clinical trials are expected to promote the practical application of gene therapy for LSDs.

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“…FLT190 is an AAV8 based vector driving α-Galactosidase A expression to the liver, which is currently being tested (NCT04040049, phase I/II) for the treatment of FD. The trial aims to evaluate safety and efficacy in 12 enrolled patients [ 68 , 69 ].…”

Section: Gene Therapy In Lsdsmentioning

confidence: 99%

Therapeutic Approaches in Lysosomal Storage Diseases

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Lysosomal Storage Diseases are multisystemic disorders determined by genetic variants, which affect the proteins involved in lysosomal function and cellular metabolism. Different therapeutic approaches, which are based on the physiologic mechanisms that regulate lysosomal function, have been proposed for these diseases. Currently, enzyme replacement therapy, gene therapy, or small molecules have been approved or are under clinical development to treat lysosomal storage disorders. The present article reviews the main therapeutic strategies that have been proposed so far, highlighting possible limitations and future perspectives.

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First-in-human study of a liver-directed AAV gene therapy (FLT190) in Fabry disease

Cited by 8 publications

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Fabry Disease: The Current Treatment Landscape

Fabry Disease: The Current Treatment Landscape

Gene therapy for lysosomal storage diseases: Current clinical trial prospects

Therapeutic Approaches in Lysosomal Storage Diseases

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