Treatment Of Fabry Disease Research Articles

Engineering α-galactosidase A (GLA) to improve protein stability, efficacy and reduced immune response for the treatment of Fabry disease

Fabry disease is an X-linked lysosomal storage disease resulting from a mutation in the GLA gene that encodes α-galactosidase A. The p.N215S (c.644A > G [p.Asn215Ser]) genotype is the most common later-onset variant reported in individuals of European or North American descent. It is usually referred to as a cardiac variant, although manifestations in other organ systems have been observed. In this report, we describe a nephropathy presentation in two related Chinese Fabry disease patients with p.N215S.

Preclinical development of SIG-007 for treatment of Fabry disease

Preclinical development of SIG-007 for treatment of Fabry disease

Cell Transplantation Combined with Recombinant Collagen Peptides for the Treatment of Fabry Disease

Fabry disease is caused by a decrease in or loss of the activity of alpha-galactosidase, which causes its substrates globotriaosylceramide (Gb3) and globotriaosylsphingosine (lyso-Gb3) to accumulate in cells throughout the body. This accumulation results in progressive kidney injury due to glomerulosclerosis and in heart failure due to hypertrophy. Enzyme replacement therapy (ERT) has been used as the standard therapy for Fabry disease, but it causes a significant financial burden, and regular administration is inconvenient for patients. Because of the short half-life of alpha-galactosidase in vivo, therapeutic methods that can supplement or replace ERT are expected to involve continuous release of alpha-galactosidase, even at low doses. Cell transplantation therapy is one of these methods; however, its use has been hindered by the short-term survival of transplanted cells. CellSaic technology, which utilizes cell spheroids that form after cells are seeded simultaneously with a recombinant collagen peptide scaffold called a μ-piece, has been used to improve cell survival upon implantation. In this study, syngeneic murine embryonic fibroblasts were used to generate CellSaic that were transplanted into Fabry mice. These spheroids survived for 28 days in the renal subcapsular space with forming blood vessels. These results indicate CellSaic technology could be a platform to promote cellular graft survival and may facilitate the development of cell transplantation methods for lysosomal diseases.

Novel mRNA-Based Therapy Reduces Toxic Galactose Metabolites and Overcomes Galactose Sensitivity in a Mouse Model of Classic Galactosemia.

Classic galactosemia (CG) is a potentially lethal inborn error of galactose metabolism that results from deleterious mutations in the human galactose-1 phosphate uridylyltransferase (GALT) gene. Previously, we constructed a GalT-/- (GalT-deficient) mouse model that exhibits galactose sensitivity in the newborn mutant pups, reduced fertility in adult females, impaired motor functions, and growth restriction in both sexes. In this study, we tested whether restoration of hepatic GALT activity alone could decrease galactose-1 phosphate (gal-1P) and plasma galactose in the mouse model. The administration of different doses of mouse GalT (mGalT) mRNA resulted in a dose-dependent increase in mGalT protein expression and enzyme activity in the liver of GalT-deficient mice. Single intravenous (i.v.) dose of human GALT (hGALT) mRNA decreased gal-1P in mutant mouse liver and red blood cells (RBCs) within 24h with low levels maintained for over a week. Repeated i.v. injections increased hepatic GalT expression, nearly normalized gal-1P levels in liver, and decreased gal-1P levels in RBCs and peripheral tissues throughout all doses. Moreover, repeated dosing reduced plasma galactose by 60% or more throughout all four doses. Additionally, a single intraperitoneal dose of hGALT mRNA overcame the galactose sensitivity and promoted the growth in a GalT-/- newborn pup.

Скрининг, диагностика и лечение болезни Фабри

Скрининг, диагностика и лечение болезни Фабри

Symptoms and Quality of Life in Patients with Fabry Disease: Results from an International Patient Survey.

IntroductionFabry disease is an X-linked lysosomal storage disorder caused by a deficiency of α-galactosidase A. Symptoms include neuropathic pain and gastrointestinal problems, such as diarrhoea. To inform and support the design of a Phase III clinical trial for a new oral treatment for Fabry disease, this study evaluated patients’ experiences of Fabry disease symptoms, the impact of symptoms on their quality of life, and their views on participating in clinical trials.MethodsAn online survey questionnaire was distributed to patients with Fabry disease, through relevant patient organisations. The questionnaire consisted mainly of quantitative, closed questions with pre-defined response options. Fabry-specific pain intensity and its impact on quality of life were rated on a scale from 0 to 10.ResultsIn total, 367 patients completed the survey, of whom half reported frequent pain, moderate to severe pain, and pain in their hands and feet. Pain frequency, intensity and location were similar for males and females. There was no clear association between Fabry-specific pain and the use of enzyme replacement therapy (ERT), with moderate to severe pain reported by 80.4% of participants receiving ERT and by 75.0% of participants not receiving ERT. Of participants who were receiving ERT, 35.7% said they were willing to discontinue it to take part in a clinical trial testing a new oral drug for treating Fabry disease. Gastrointestinal symptoms were more heterogeneous in nature and frequency than Fabry-specific pain, but still affected a significant proportion of participants.ConclusionsBoth male and female patients with Fabry disease experience significant Fabry-specific pain, which affects their quality of life. Furthermore, frequent diarrhoea affects many patients. The symptoms occur independently of the use of ERT. This suggests the healthcare needs of patients with Fabry disease are not being fully met, and additional treatments are required to improve symptoms and quality of life.FundingThis study was sponsored by Actelion Pharmaceuticals Ltd. Study sponsorship was transferred to Idorsia Pharmaceuticals Ltd in July 2018.Electronic supplementary materialThe online version of this article (10.1007/s12325-019-01061-x) contains supplementary material, which is available to authorized users.

Consensus recommendations for diagnosis, management and treatment of Fabry disease in paediatric patients.

Fabry disease (FD), a rare X‐linked disease, can be treated with bi‐monthly infusion of enzyme replacement therapy (ERT) to replace deficient α‐galactosidase A (AGAL‐A). ERT reduces symptoms, improves quality of life (QoL), and improves clinical signs and biochemical markers. ERT initiation in childhood could slow or stop progressive organ damage. Preventative treatment of FD from childhood is thought to avoid organ damage in later life, prompting a French expert working group to collaborate and produce recommendations for treating and monitoring children with FD. Organ involvement should be assessed by age 5 for asymptomatic boys (age 12‐15 for asymptomatic girls), and immediately for children diagnosed via symptoms. The renal, cardiac, nervous and gastrointestinal systems should be assessed, as well as bone, skin, eyes, hearing, and QoL. The plasma biomarker globotriaosylsphingosine is also useful. ERT should be considered for symptomatic boys and girls with neuropathic pain, pathological albuminuria (≥3 mg/mmol creatinine), severe GI involvement and abdominal pain or cardiac involvement. ERT should be considered for asymptomatic boys from the age of 7. Organ involvement should be treated as needed. Early diagnosis and management of FD represents a promising strategy to reduce organ damage, morbidity and premature mortality in adulthood.

Orphan designation: 1-Deoxygalactonojirimycin hydrochloride, Treatment of Fabry disease

Orphan designation: 1-Deoxygalactonojirimycin hydrochloride, Treatment of Fabry disease

Orphan designation: Adeno-associated viral vector serotype 8 containing the human alpha-galactosidase A gene, Treatment of Fabry disease

Orphan designation: Adeno-associated viral vector serotype 8 containing the human alpha-galactosidase A gene, Treatment of Fabry disease

Systemic mRNA Therapy for the Treatment of Fabry Disease: Preclinical Studies in Wild-Type Mice, Fabry Mouse Model, and Wild-Type Non-human Primates

Fabry disease is an X-linked lysosomal storage disease caused by loss of alpha galactosidase A (α-Gal A) activity and is characterized by progressive accumulation of globotriaosylceramide and its analogs in all cells and tissues. Although enzyme replacement therapy (ERT) is considered standard of care, the long-term effects of ERT on renal and cardiac manifestations remain uncertain and thus novel therapies are desirable. We herein report preclinical studies evaluating systemic messenger RNA (mRNA) encoding human α-Gal A in wild-type (WT) mice, α-Gal A-deficient mice, and WT non-human primates (NHPs). The pharmacokinetics and distribution of h-α-Gal A mRNA encoded protein in WT mice demonstrated prolonged half-lives of α-Gal A in tissues and plasma. Single intravenous administration of h-α-Gal A mRNA to Gla-deficient mice showed dose-dependent protein activity and substrate reduction. Moreover, long duration (up to 6weeks) of substrate reductions in tissues and plasma were observed after a single injection. Furthermore, repeat i.v. administration of h-α-Gal A mRNA showed a sustained pharmacodynamic response and efficacy in Fabry mice model. Lastly, multiple administrations to non-human primates confirmed safety and translatability. Taken together, these studies across species demonstrate preclinical proof-of-concept of systemic mRNA therapy for the treatment of Fabry disease and this approach may be useful for other lysosomal storage disorders.

Diagnosis and treatment of Fabry disease

Diagnosis and treatment of Fabry disease

Fabry disease and general anesthesia: A case report and literature review

Fabry disease (FD) is an X-linked lysosomal storage disease. FD presents with a variety of symptoms such as corneal clouding, reduced sweating, abdominal pain, neuropathic pain, angiokeratoma, sleep-disordered breathing, renal failure, cardiovascular diseases, and stroke. Severe organ damage may occur, and its gravity differs between individuals, usually being more serious in males and elders. According to previous reports, possible complications include hypertension, hypotension, bronchospasm, and intubation difficulty. Therefore, identifying FD patients carefully and performing detailed preoperative assessments, such as for cardiovascular, pulmonary, and renal functions, are both critical to increasing the chances of a positive treatment outcome. Advanced hemodynamic monitoring was recommended to prevent severe cardiovascular and respiratory impairment during surgery of advanced FD patients. To the best of our knowledge, there are only four reports on FD treatment, none being from Taiwan. Here, we report on a case of FD treatment undergoing general anesthesia in Taiwan and provide a literature review.

Prevalence of Fabry Disease in Korean Men with Left Ventricular Hypertrophy.

BackgroundFabry disease is an X-linked recessive disorder caused by deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A). Previous studies identified many cases of Fabry disease among men with left ventricular hypertrophy (LVH). The purpose of this study was to define the frequency of Fabry disease among Korean men with LVH.MethodsIn this national prospective multicenter study, we screened Fabry disease in men with LVH on echocardiography. The criterion for LVH diagnosis was a maximum LV wall thickness 13 mm or greater. We screened 988 men with LVH for plasma α-Gal A activity. In patients with low α-Gal A activity (< 3 nmol/hr/mL), we searched for mutations in the α-galactosidase gene.ResultsIn seven men, α-Gal A activity was low. Three had previously identified mutations; Gly328Arg, Arg301Gln, and His46Arg. Two unrelated men had the E66Q variant associated with functional polymorphism. In two patients, we did not detect GLA mutations, although α-Gal A activity was low on repeated assessment.ConclusionWe identified three patients (0.3%) with Fabry disease among unselected Korean men with LVH. Although the prevalence of Fabry disease was low in our study, early treatment of Fabry disease can result in a good prognosis. Therefore, in men with unexplained LVH, differential diagnosis of Fabry disease should be considered.

Production of Therapeutic Enzymes by Lentivirus Transgenesis.

Since ERT for several LSDs treatment has emerged at the beginning of the 1980s with Orphan Drug approval, patients' expectancy and life quality have been improved. Most LSDs treatment are based on the replaced of mutated or deficient protein with the natural or recombinant protein.One of the main ERT drawback is the high drug prices. Therefore, different strategies trying to optimize the global ERT biotherapeutic production have been proposed. LVs, a gene delivery tool, can be proposed as an alternative method to generate stable cell lines in manufacturing of recombinant proteins. Since LVs have been used in human gene therapy, clinical trials, safety testing assays and procedures have been developed. Moreover, one of the main advantages of LVs strategy to obtain manufacturing cell line is the short period required as well as the high protein levels achieved.In this chapter, we will focus on LVs as a recombinant protein production platform and we will present a case study that employs LVs to express in a manufacturing cell line, alpha-Galactosidase A (rhαGAL), which is used as ERT for Fabry disease treatment.

Urinary excretion profile of microRNAs related to renal fibrosis in Fabry disease patients. A pilot study

Irreversible renal histological lesions, including glomerulosclerosis and tubulo-interstitial fibrosis, have been described in asymptomatic Fabry disease (FD) patients with normal estimated glomerular filtration rate (eGFR) and mild or absent proteinuria. However, it is currently recommended to start FD treatment in presence of clinical manifestations. During renal fibrosis miR-21, miR-192, and miR-433 that promote fibrosis are activated by TGF-β, and miR-29 and miR-200 that suppress fibrosis, are inhibited by TGF-β. The aim of this work is to compare the urinary excretion of microRNAs related to renal fibrosis in FD patients with healthy subjects. In addition, the microRNAs urinary excretion was related to study population clinical variables. Results: 24 FD patients and 10 healthy subjects of similar characteristics were compared. Asymptomatic FD women with normal α-galactosidase-A (α-gal-A) enzyme activity and symptomatic FD women with normal α-gal-A enzyme activity, who were receiving enzyme replacement therapy (ERT) presented a microRNAs urinary profile excretion similar to controls. Asymptomatic FD men or women patients with decreased α-gal-A enzyme activity presented significant differences in miR-29 (p = 0.0478) and miR-200 (p = 0.0426) compared with controls. Symptomatic FD men with decreased α-gal-A enzymatic activity, who were receiving ERT presented significant differences in miR-200 (p = 0.0238) compared with controls. Conclusion: In asymptomatic FD patients with decreased α-gal-A enzymatic activity a microRNA profile indicative of renal fibrosis was found. These patients, at present, are not treated because they do not present clinical criteria to start ERT. In this population, the microRNAs urinary profile excretion could be useful to detect renal fibrosis in early stages.

Efficacy Evaluation of Liver-Directed Gene Therapy in Fabry Mice

Introduction: Fabry disease (FD) is an X-linked lysosomal storage disorder resulting from mutations in the gene encoding α-galactosidase A (GLA). It is characterised by the abnormal accumulation of neutral glycosphingolipids (GSL), predominantly Globotriaosylceramide (Gb3), in the lysosomes of multiple cell types including vascular endothelial cells. It is associated with early-onset stroke, cardiomyopathy, and progression to end-stage renal failure. Current standard of care for FD is enzyme replacement therapy but alternatives including allogeneic stem cell transplantation have also been explored. Fabry disease is a good model for liver-targeted gene therapy, as relatively low levels of enzyme correction may suffice to reduce storage. Additionally, a broad therapeutic window exists, and mouse models of FD enabling preclinical proof-of-concept studies are readily available. Here we report the preclinical results of adeno-associated virus (AAV) mediated, liver-targeted gene transfer of a self-complementary (sc) vector encoding a codon-optimised GLA transgene under transcriptional control of a hepatocyte-specific promoter pseudotyped with AAV8 capsid (scAAV2/8-LP1-GLAco).Methods: In this study a single dose of scAAV2/8-LP1-GLAco vectors were administered into the tail vein of homozygote GLA knockout Fabry mice at either 1 month or 3 months of age. Two doses were tested for each age group; 2x1012 vg/kg and 2x1013 vg/kg, and an additional age-matched group left as untreated to serve as an experimental control for the effects of treatment. Mice were followed in the treatment for up to 11 months before sacrificing at 11 or 14 months of age.To assess the kinetics and durability of transgene expression, plasma GLA levels were measured at various time intervals post injection.Results: Long-term follow-up of Fabry mice injected with scAAV2/8-LP1-GLAco vector demonstrated sustained, durable levels of plasma GLA throughout the typical lifespan of a mouse. Plasma GLA activity levels at 10 or 11-months post vector administration to 1 and 3-month-old mice respectively, demonstrated a dose response from 2 x 1012 to 2 x 1013 vg/kg of >1 log increase in expression. These GLA activity levels represent supra-physiological expression (x 4000 of normal levels) which resulted in uptake of GLA from the bloodstream into kidney and cardiac tissues leading to dose-dependent clearance of lipid deposits in these tissues as analysed by electron microscopy.Most importantly, sustained expression of GLA resulted in complete normalisation of Gb3 and lyso-Gb3 levels in plasma and liver tissues as quantified by mass spectrometry. Interestingly, these preclinical studies in Fabry mice at the age of 1 and 3 months demonstrated not only prevention but also reversal of lysosomal storage deposits through liver-specific expression of GLA.Finally, in these in vivo mouse studies no adverse clinical signs were observed, despite the increased plasma exposure to GLA.Conclusions: 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 a single dose IV procedure will pose minimal burden to Fabry patients and will be a viable alternative to biweekly enzyme infusions, potentially reducing treatment-related morbidity whislt improving patient quality of life and potentially providing them with a functional long-term cure. DisclosuresKia:Freeline: Employment, Equity Ownership. McIntosh:Freeline: Consultancy. Hosseini:Freeline: Employment, Equity Ownership. Sheridan:Freeline: Employment, Equity Ownership. Corbau:Freeline: Employment, Equity Ownership. Nathwani:BioMarin: Consultancy, Patents & Royalties; UniQure: Patents & Royalties; Freeline: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

PSY18 - An Economic Evaluation of Migalastat Versus ERT for the Treatment of Fabry Disease in Japan

PSY18 - An Economic Evaluation of Migalastat Versus ERT for the Treatment of Fabry Disease in Japan

Non-clinical evaluation of JR-051 as a biosimilar to agalsidase beta for the treatment of Fabry disease

Fabry disease (FD) is an X-linked lysosomal storage disease. It is caused by deficiency of the enzyme α-galactosidase A (α-Gal A), which leads to excessive deposition of neutral glycosphingolipids, especially globotriaosylceramide (GL-3), in cells throughout the body. Progressive accumulation of GL-3 causes life-threatening complications in several tissues and organs, including the vasculature, heart, and kidney. Currently available enzyme replacement therapy for FD employs recombinant α-Gal A in two formulations, namely agalsidase alfa and agalsidase beta. Here, we evaluated JR-051 as a biosimilar to agalsidase beta in a non-clinical study. JR-051 was shown to have identical primary and similar higher-order structures to agalsidase beta. Mannose-6-phosphate content was higher in JR-051 than in agalsidase beta, which probably accounts for a slightly better uptake into fibroblasts in vitro. In spite of these differences in in vitro biological features, pharmacokinetic profiles of the two compounds in mice, rats, and monkeys were similar. The ability to reduce GL-3 accumulation in the kidney, heart, skin, liver, spleen, and plasma of Gla-knockout mice, a model of FD, was not different between JR-051 and agalsidase beta. Furthermore, we identified no safety concerns regarding JR-051 in a 13-week evaluation using cynomolgus monkeys. These findings indicate that JR-051 is similar to agalsidase beta in terms of physicochemical and biological properties.

Detection of blood Gb3 deposits as a new tool for diagnosis and therapy monitoring in patients with classic Fabry disease.

The X-linked Fabry disease (FD) is a multiorgan disorder due to alpha-galactosidase A (α-GAL) deficiency with consequent lysosomal accumulation of globotriaosylceramide (Gb3). We established the immunocytochemical detection of Gb3 in blood cells of FD patients as a new method for FD diagnostics, follow-up and treatment control. We enrolled 67 FD patients (37 men, 30 women) and 52 healthy controls (26 men, 26 women). PBMC were isolated from whole venous blood and 3x105 cells were immunoreacted with antibodies against CD77 as a marker for Gb3. Using fluorescence microscopy, the mean percentage of Gb3 positive PBMC was determined by an investigator blinded to subject allocation. As a second method, we qualitatively assessed Gb3 positive cells in blood smears. Gb3 deposits were unequivocally visible in PBMC and in blood smears. Men (P < 0.001) and women (P < 0.01) with classical FD had more Gb3-positive PBMC than healthy controls, whose samples only occasionally showed positive cells. The number of Gb3 positive PBMC was negatively correlated with α-GAL activity and positively correlated with plasma lyso-Gb3 levels. Only the PBMC Gb3 load but not plasma lyso-Gb3 reflected short- and long-term effects of enzyme replacement therapy (P < 0.01). Gb3 can be visualized in PBMC and blood smears and can be used as a novel marker for diagnostics, follow-up and treatment control in FD.

Migalastat for the treatment of Fabry disease

ABSTRACTIntroduction: Fabry disease, a rare X-linked disorder of α-galactosidase A deficiency, leads to progressive multiorgan damage.Areas covered: Enzyme replacement therapy (ERT) is the current standard of care for Fabry disease; however, many patients progress despite treatment and the intravenous infusions present several challenges. Migalastat, an orally administered, small molecule pharmacological chaperone, binds to and stabilizes specific mutant forms of α-galactosidase A. Migalastat is approved in several countries for Fabry disease in patients with amenable GLA mutations; amenable mutations are identified using a good laboratory practice-validated assay. Data from clinical trials demonstrated that migalastat effectively reduces disease substrate, stabilizes renal function, decreases cardiac mass and improves gastrointestinal signs and symptoms in patients with Fabry disease and amenable mutations. Across trials, migalastat was generally well tolerated; headache was the most frequently reported treatment-emergent adverse event. Long-term treatment with migalastat was associated with sustained reduction in left ventricular mass index and evidence of left ventricular hypertrophy regression; migalastat was generally well tolerated over 48 months of treatment. An ongoing Phase III extension study will provide further evidence of the long-term safety and efficacy of migalastat.Expert opinion: Given the convenience of the orally administered small molecule and the efficacy and safety demonstrated in pivotal Phase III trials, migalastat offers a viable alternative to ERT for patients with Fabry disease and migalastat-amenable mutations.