Liver-directed gene therapy corrects Fabry disease in mice

Jeyakumar, Jey; Kia, Azadeh; McIntosh, Jenny; Verhoef, Daniël; Kalcheva, Petya; Hosseini, Paniz; Sheridan, Rose; Corbau, Romuald; Nathwani, Amit C.

doi:10.1016/j.ymgme.2018.12.196

Cited by 8 publications

(8 citation statements)

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“…Studies on α-galactosidase A knockout (GLAko) mouse model demonstrated that this approach was able to induce the production of α-galactosidase by the liver in a dose-dependent manner. 48 A comparable method utilizing another vector was able to strongly increase α-galactosidase levels after single-stranded AAV8 vector administration and lyso-Gb3 and Gb-3 levels decreased comparable to wild-type animals. 49 In the ex vivo method, hematopoietic stem cells from the patient are harvested, underwent gene editing and subsequently are engrafted back to the patient after myeloablative therapy.…”

Section: Gene-based Therapymentioning

confidence: 90%

Current and experimental therapeutics for Fabry disease

et al. 2021

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Fabry (or Anderson‐Fabry) is a rare pan‐ethnic disease affecting males and females. Fabry is an X‐linked lysosomal storage disease, affecting glycosphingolipid metabolism, that is caused by mutations of the GLA gene that codes for α‐galactosidase A. Fabry disease (FD) can be classified into a severe, classical phenotype, most often seen in men with no residual enzyme activity, that usually appear before 18 years and a usually milder, nonclassical (later‐onset) phenotype that usually appear above 18 years. Affected patients show multifactorial complications, including renal failure, cardiovascular problems, and neuropathy. In this review, we briefly report the clinical trials so far performed with the available therapies, and then we focus on the in vitro and the in vivo experimental models of the disease, to highlight the relevance in improving the existing therapeutics and understand the mechanism of this rare disorder. Current available in vivo and in vitro models can assist in better comprehension of the pathogenesis and underlying mechanisms of FD, thus the existing therapeutic approaches can be optimized, and new options can be developed.

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Section: Gene-based Therapymentioning

confidence: 90%

Current and experimental therapeutics for Fabry disease

et al. 2021

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“… 40 Nevertheless, in one of the newest studies for Fabry disease, a tissue-specific promoter that targets the liver was used with the AAV vector, not the lentiviral one, resulting in the supraphysiological enzyme level in plasma up to 1,061-fold of WT level and correction of lysosomal storage pathology in visceral organs, such as the liver, kidney, heart, and spleen. 73 …”

Section: Promotersmentioning

confidence: 99%

Promoter considerations in the design of lentiviral vectors for use in treating lysosomal storage diseases

Rintz

Higuchi

Kobayashi

et al. 2022

Molecular Therapy - Methods & Clinical Development

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More than 50 lysosomal storage diseases (LSDs) are associated with lysosomal dysfunctions with the frequency of 1:5,000 live births. As a result of missing enzyme activity, the lysosome dysfunction accumulates undegraded or partially degraded molecules, affecting the entire body. Most of them are life-threatening diseases where patients could die within the first or second decade of life. Approximately 20 LSDs have the approved treatments, which do not provide the cure for the disorder. Therefore, the delivery of missing genes through gene therapy is a promising approach for LSDs. Over the years, ex vivo lentiviral-mediated gene therapy for LSDs has been approached using different strategies. Several clinical trials for LSDs are under investigation. Ex vivo lentiviral-mediated gene therapy needs optimization in dose, time of delivery, and promoter-driven expression. Choosing suitable promoters seems to be one of the important factors for the effective expression of the dysfunctional enzyme. This review summarizes the research on therapy for LSDs that has used different lentiviral vectors, emphasizing gene promoters.

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“…26 Using a similar approach with a different vector (Freeline Therapeutics, Stevenage, UK) have described marked increases of a-GAL levels after administration of a single-stranded AAV8 vector that was liver targeted (FLT190), with GB-3 and lyso-GB-3 levels reduced close to those of wild-type mice. 27 As FD is a multisystemic disease, nontargeted gene therapies that raise the plasma concentrations of a-GAL may be reasonable strategies, and indeed measurements of plasma and/or leukocyte a-GAL may provide important long-term assessments of efficacy, as well as shorter-term endpoints for pivotal clinical trials. Kidney transplantation and liver transplantation for patients with FD have not been successful at alleviating the effects of the disease, probably because the endogenous a-GAL is not optimized for export from the transplanted wild-type engrafted cells.…”

Section: Ex Vivo Gene Therapymentioning

confidence: 99%

Current and Investigational Therapeutics for Fabry Disease

Felis

Whitlow

Kraus

et al. 2020

Kidney International Reports

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Fabry disease (FD) is an X-linked lysosomal storage disease caused by a deficiency in the lysosomal enzyme a-galactosidase (a-GAL). This in turn leads to the buildup of globotriaosylceramide, resulting classically in progressive kidney disease, peripheral neuropathy, early-onset cerebrovascular disease, gastrointestinal symptoms, hypertrophic cardiomyopathy, arrhythmias, corneal whorls, and angiokeratomas. The diagnosis of FD relies on identification of a low a-GAL enzyme activity, identification of a genetic mutation, or histologic evidence of disease. With more than 900 mutations identified, there is phenotypic variability deriving from both mutational effects as well as the effect of skewed X-inactivation in females. Treatment of this disease has relied on intravenous replacement of the deficient enzyme with agalsidase a or agalsidase b. However, treatment options for some patients with FD have recently expanded, with the approval of migalastat, an oral molecular chaperone. In addition to chaperone-based therapies, there are several additional therapies under development that could substantially reshape treatment options for patients with FD. Four approaches to gene therapy, through both ex vivo and in vivo methods, are under development. Another approach is through the administration of a-GAL mRNA to help stimulate production of a-GAL, which is another unique form of therapy. Finally, substrate reduction therapies act as inhibitors of glucosylceramide synthase, thus inhibiting the production of GB-3, promise another oral option to treat FD. This article will review the literature around current therapies as well as these newer therapeutics agents in the pipeline for FD.

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Liver-directed gene therapy corrects Fabry disease in mice

Cited by 8 publications

References 0 publications

Current and experimental therapeutics for Fabry disease

Current and experimental therapeutics for Fabry disease

Promoter considerations in the design of lentiviral vectors for use in treating lysosomal storage diseases

Current and Investigational Therapeutics for Fabry Disease

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