Cellular localization of h–Gal A protein was performed and as expected was found to localize in liver tissue lysosomes of the Fabry mice determined by co-localization h–Gal A and lysosomal marker Lamp2A immunofluorescence (Figure?2B)
Cellular localization of h–Gal A protein was performed and as expected was found to localize in liver tissue lysosomes of the Fabry mice determined by co-localization h–Gal A and lysosomal marker Lamp2A immunofluorescence (Figure?2B). A-deficient mice, and WT non-human primates (NHPs). The pharmacokinetics and distribution of h–Gal A mRNA encoded protein in WT mice demonstrated prolonged half-lives of -Gal A in tissues and plasma. Single intravenous administration of h–Gal A mRNA to (MIM: 300644) which encodes the enzyme alpha galactosidase A (-Gal?A). Deficiency of -Gal A results in the accumulation of glycosphingolipids, particularly globotriaosylceramide (Gb3) and the deacylated Gb3 analog globotriaosylsphingosine (lyso-Gb3) in most cell types.1, 2 Recently, lyso-Gb3 has been reported to be a useful biomarker of Fabry disease.3, 4, 5, 6, 7 It is markedly elevated in both classic male and BQ-788 symptomatic female Fabry-affected individuals relative to the level of Gb3 in affected tissues. Over time, accumulation of glycosphingolipids triggers cellular dysfunction and progressive damage in affected tissues such as kidney, heart, and skin.8, 9, 10, 11 Individuals with Fabry disease present clinically with a spectrum of disease severity that directly correlates with the level of the residual enzyme activity. Individuals with the early-onset or classic phenotype during childhood or adolescence typically BQ-788 have less than 1% of residual -Gal?A activity and often present with BQ-788 symptoms such as?angiokeratoma, acroparesthesias, corneal and lenticular opacities, and hypohidrosis.10, 11 Fabry disease is the most common lysosomal storage disease with reported prevalence of 1 1:40,000 to 1 1:117,000.9, 12, 13 The cardiac variant of Fabry disease affects 1:50,000 individuals.8 However, newborn screening assessments have found that the screen positive rate for mutations in the ranges from 1:3,000 to 1 1:10,000, indicating that Fabry disease might be significantly underdiagnosed.14, 15, 16 Currently there are several commercially available treatments for Fabry disease including enzyme replacement therapies (ERTs) such as Fabrazyme (Genzyme Sanofi) and Replagal (Shire) as well as a small molecule chaperone therapy (CT) such as Galafold (Amicus Therapeutics). BQ-788 While availability of these treatments depends on geographical location, most individuals have access to?one or more of these therapies. Aside from currently available therapies there are several treatment modalities currently in preclinical or clinical development for Fabry disease including ERT, gene therapy (GT), substrate reduction therapy (SRT), and combinatory modalities such as CT or SRT with ERT therapy. The standard of care for Fabry disease is ERT. ERT has been shown to have clinical benefit in Fabry-affected individuals, alleviating clinical symptoms such as neuropathic pain and gastrointestinal symptoms as well as normalizing plasma Gb3 levels and improving renal and cardiac manifestations in some individuals.12, 17 However, long-term evaluation of Fabry-affected individuals receiving ERT treatment demonstrates that despite clinical improvement some individuals still lose renal function at greater than normal rates and develop cardiac manifestations and experience infusion-associated reactions, which can be severe in some patients; thus an unmet medical need still exists for these individuals.18, 19, 20, 21 Messenger RNA treatment is emerging as a treatment modality that can treat a variety of diseases. Intravenous administration of mRNA formulated in lipid nanoparticles (LNPs) can produce therapeutic proteins to replace mutated or missing proteins within target cells such as hepatocytes. Therapeutic proteins made from exogenously administered mRNA in the body may mimic the endogenous target protein more closely than recombinant proteins, such as ERTs, which are manufactured from CHO, human, or plant cell lines. mRNA treatment produces transient protein levels, while avoiding genomic integration and the off-target risks of gene therapy or gene editing therapy.22, 23 Multiple mRNA-based cancer immunotherapies and vaccines are currently in clinical trials.24 Preclinical studies have evaluated mRNA-based therapy for various rare diseases. Recently we have reported preclinical proof-of-concept studies of mRNA Rabbit Polyclonal to GPR113 therapy for liver diseases methylmalonic acidemia (MMA [MIM: 251000]) and acute intermittent porphyria (AIP [MIM: 176000]). These studies demonstrated restoration of functional human methylmalonyl-CoA mutase (hMUT) and human porphobilinogen deaminase (hPBGD) BQ-788 in the liver by systemic mRNA treatment with corresponding amelioration.