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.

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Genetically Modified Cell Transplantation Through Macroencapsulated Spheroids with Scaffolds to Treat Fabry Disease

Cell Transplantation ◽

10.1177/09636897211060269 ◽

2021 ◽

Vol 30 ◽

pp. 096368972110602

Author(s):

Daisuke Kami ◽

Yosuke Suzuki ◽

Masashi Yamanami ◽

Takahiro Tsukimura ◽

Tadayasu Togawa ◽

...

Keyword(s):

Fabry Disease ◽

Cell Transplantation ◽

Fluorescent Protein ◽

Ex Vivo ◽

Disease Model ◽

Host Immune System ◽

Ethylene Vinyl Alcohol ◽

Enzyme Replacement ◽

Lysosomal Diseases ◽

Alpha Galactosidase

Cell transplantation is expected to be another strategy to treat lysosomal diseases, having several advantages compared to enzyme replacement therapy, such as continuous enzyme secretion and one-time treatment to cure diseases. However, cell transplantation for lysosomal diseases holds issues to be resolved for the clinical field. In this study, we developed a new ex vivo gene therapy platform using a transplant pack, which consists of a porous membrane made of ethylene-vinyl alcohol in the pack-type and spheroids with scaffolds. These membranes have countless pores of less than 0.1 µm2 capable of secreting proteins, including alpha-galactosidase enzyme, and segregating the contents from the host immune system. When the packs were subcutaneously transplanted into the backs of green fluorescent protein (GFP) mice, no GFP-positive cells migrated to the transplanted pack in either autogenic or allogenic mice. The transplanted cells in the pack survived for 28 days after transplantation. When cells overexpressing alpha-galactosidase were used as donor cells for the packs and implanted into Fabry disease model mice, the accumulation of the alpha-galactosidase enzyme was also observed in the livers. In this study, we reported a new ex vivo therapeutic strategy combining macroencapsulation and cellular spheroids with scaffolds. This pack, macroencapsulated spheroids with scaffolds, can also be applied to other types of lysosomal diseases by modifying genes of interest.

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Treatment of Anderson-Fabry Disease

Current Pharmaceutical Design ◽

10.2174/1381612826666200317142412 ◽

2020 ◽

Vol 26 (40) ◽

pp. 5089-5099 ◽

Cited By ~ 1

Author(s):

Irene Simonetta ◽

Antonino Tuttolomondo ◽

Mario Daidone ◽

Salvatore Miceli ◽

Antonio Pinto

Keyword(s):

Fabry Disease ◽

Treatment Strategies ◽

Signs And Symptoms ◽

Current Treatment ◽

Viral Gene ◽

Pharmacological Chaperone ◽

Enzyme Replacement ◽

Cell Based Therapy ◽

Organ Manifestations ◽

Alpha Galactosidase

: Fabry disease is an X-linked disorder of glycosphingolipid metabolism that results in progressive accumulation of neutral glycosphingolipids, predominantly globotriaosylsphingosine (Gb3) in lysosomes, as well as other cellular compartments of several tissues, causing multi-organ manifestations (acroparesthesias, hypohidrosis, angiokeratomas, signs and symptoms of cardiac, renal, cerebrovascular involvement). Pathogenic mutations lead to a deficiency of the lysosomal enzyme alpha-galactosidase A (GLA). In the presence of high clinical suspicion, a careful physical examination and specific laboratory tests are required. Finally, the diagnosis of Fabry’s disease is confirmed by the demonstration of the absence of or reduced alpha-galactosidase A enzyme activity in hemizygous men and gene typing in heterozygous females. Measurement of the biomarkers Gb3 and Lyso Gb3 in biological specimens may facilitate diagnosis. The current treatment of Anderson-Fabry disease is represented by enzyme replacement therapy (ERT) and oral pharmacological chaperone. Future treatments are based on new strategic approaches such as stem cell-based therapy, pharmacological approaches chaperones, mRNA therapy, and viral gene therapy. : This review outlines the current therapeutic approaches and emerging treatment strategies for Anderson-Fabry disease.

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Fabry Cardiomyopathy: Current Practice and Future Directions

Cells ◽

10.3390/cells10061532 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1532

Author(s):

Jeffrey Yim ◽

Olivia Yau ◽

Darwin F. Yeung ◽

Teresa S. M. Tsang

Keyword(s):

Fabry Disease ◽

Early Stage ◽

Point Of Care ◽

Left Ventricular ◽

The Body ◽

Cardiac Biomarkers ◽

Dried Blood Spot ◽

Point Of Care Ultrasound ◽

Enzyme Replacement ◽

Blood Spot

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by mutations in the galactosidase A (GLA) gene that result in deficient galactosidase A enzyme and subsequent accumulation of glycosphingolipids throughout the body. The result is a multi-system disorder characterized by cutaneous, corneal, cardiac, renal, and neurological manifestations. Increased left ventricular wall thickness represents the predominant cardiac manifestation of FD. As the disease progresses, patients may develop arrhythmias, advanced conduction abnormalities, and heart failure. Cardiac biomarkers, point-of-care dried blood spot testing, and advanced imaging modalities including echocardiography with strain imaging and magnetic resonance imaging (MRI) with T1 mapping now allow us to detect Fabry cardiomyopathy much more effectively than in the past. While enzyme replacement therapy (ERT) has been the mainstay of treatment, several promising therapies are now in development, making early diagnosis of FD even more crucial. Ongoing initiatives involving artificial intelligence (AI)-empowered interpretation of echocardiographic images, point-of-care dried blood spot testing in the echocardiography laboratory, and widespread dissemination of point-of-care ultrasound devices to community practices to promote screening may lead to more timely diagnosis of FD. Fabry disease should no longer be considered a rare, untreatable disease, but one that can be effectively identified and treated at an early stage before the development of irreversible end-organ damage.

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Circulating microRNAs in Fabry Disease

Scientific Reports ◽

10.1038/s41598-019-51805-6 ◽

2019 ◽

Vol 9 (1) ◽

Cited By ~ 5

Author(s):

Ke Xiao ◽

Dongchao Lu ◽

Jeannine Hoepfner ◽

Laura Santer ◽

Shashi Gupta ◽

...

Keyword(s):

Fabry Disease ◽

Premature Death ◽

Circulating Mirnas ◽

Serum Samples ◽

Significant Differential Expression ◽

Enzyme Replacement ◽

Beneficial Effects ◽

Mirna Sequencing ◽

Continuous Progress ◽

Alpha Galactosidase

Abstract Fabry disease is an X-linked deficiency of the lysosomal hydrolase alpha-galactosidase A (alpha-Gal). This results in an accumulation of globotriaosylceramide (GL-3/Gb3) in a variety of cells with subsequent functional impairment. The continuous progress of FD often leads to decreased quality of life and premature death caused by multi-organic complications. The overall aim of our study was to determine the amount of circulating miRNAs in Fabry patients and to test whether ERT would alter the level of individual circulating miRNAs. We used miRNA sequencing by the HTG EdgeSeq System to identify the circulating miRNA pool from Fabry patients with and without enzyme replacement therapy (n = 6). In total, 296 miRNAs in serum of patients were identified. Among them 9 miRNAs were further evaluated in extra serum samples (n = 31) using real-time qPCR and 6 of them showed significant differential expression. The resulting miRNA pattern may help to better understand mechanisms involved in the beneficial effects of ERT and these new miRNA markers could help to estimate the efficacy of ERT or to identify Fabry patients with specific need for ERT.

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Tracer Technique to Measure in Vivo Chemical Transport Rates within an Implantable Cell Transplantation Device

Cell Transplantation ◽

10.1177/096368979500400205 ◽

1995 ◽

Vol 4 (2) ◽

pp. 201-217 ◽

Cited By ~ 1

Author(s):

Jeffrey G. Sarver ◽

Ronald L. Fournier ◽

Peter J. Goldblatt ◽

Tamara L. Phares ◽

Sara E. Mertz ◽

...

Keyword(s):

Cell Transplantation ◽

Circulatory System ◽

Quantitative Measure ◽

Chemical Transport ◽

Porous Matrix ◽

The Body ◽

Model Parameters ◽

Tracer Technique ◽

Capillary Growth

An in vivo tracer technique that uses radiolabeled inulin as the tracer molecule has been developed to assess the rate of chemical transport between the cell transplantation chamber of an implantable bioartificial device and the host's circulatory system. The device considered here employs site-directed neovascularization of a porous matrix to induce capillary growth adjacent to an immunoisolated cell implantation chamber. This device design is being investigated as a vehicle for therapeutic cell transplantation, with the advantages that it allows the cells to perform their therapeutic function without the danger of immune rejection and it avoids damaging contact of blood flow with artificial surfaces. A pharmacokinetic model of the mass transport between the implantation chamber, the vascularized matrix, and the body has been devised to allow proper analysis and understanding of the experimental tracer results. Experiments performed in this study have been principally directed at evaluation of the tracer model parameters, but results also provide a quantitative measure of the progression of capillary growth into a porous matrix. Measured plasma tracer levels demonstrate that chemical transport rates within the implanted device increase with the progression of matrix vascular ingrowth. Agreement between the fitted model curves and the corresponding measured concentrations at different levels of capillary ingrowth demonstrate that the model provides a realistic representation of the actual capillary-mediated transport phenomena occurring within the device.

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Conjunctival lymphangiectasia associated with classic Fabry disease

British Journal of Ophthalmology ◽

10.1136/bjophthalmol-2016-310088 ◽

2017 ◽

Vol 102 (1) ◽

pp. 54-58 ◽

Cited By ~ 7

Author(s):

Melanie D Sivley ◽

Eric L Wallace ◽

David G Warnock ◽

William J Benjamin

Keyword(s):

Fabry Disease ◽

Dry Eye ◽

Imaging System ◽

University Of Alabama ◽

Multisystem Disease ◽

Enzyme Replacement ◽

Clinical Presentations ◽

Alpha Galactosidase ◽

The University

BackgroundFabry disease (FD) is a treatable multisystem disease caused by a defect in the alpha-galactosidase gene. Ocular signs of FD, including corneal verticillata, are among the earliest diagnostic findings. Conjunctival lymphangiectasia (CL) has not previously been associated with FD.MethodsWe examined the eyes of a cohort of 13 adult patients, eight men and five women, with documented classic FD, all treated with enzyme replacement therapy (ERT) at the University of Alabama at Birmingham between February 2014 and April 2015. The average age was 48 years with a range of 35–55 years for men and 21–71 years for women. The mean duration of ERT was 8.4 years (men 8.9 years, women 7.6 years) with a range of 4–14 years. Classical Fabry mutations included Q283X, R227X, W236X and W277X. A high resolution Haag-Streit BQ-900 slit lamp with EyeCap imaging system was used to record conjunctival images.ResultsCL was observed in 11 of the 13 patients (85%) despite long-term ERT. Clinical presentations included single cysts, beaded dilatations and areas of conjunctival oedema. Lesions were located within 6 mm of the corneal limbus. Ten of the 13 subjects (77%) had Fabry-related cataracts and all 13 demonstrated bilateral corneal verticillata. Twelve of the 13 patients had evidence of dry eye, 9 of whom were symptomatic, and 10 had peripheral lymphoedema.ConclusionCL represents a common but under-recognised ocular manifestation of FD, which persists despite ERT, and is often accompanied by peripheral lymphoedema and dry eye syndrome.

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ANDERSON-FABRY DISEASE: MANIFESTATION AND PROGNOSIS

Ukrainian Journal of Nephrology and Dialysis ◽

10.31450/ukrjnd.3(39).2013.07 ◽

2017 ◽

pp. 46-50

Author(s):

N. O. Pichkur

Keyword(s):

Fabry Disease ◽

Activity Level ◽

Social Adaptation ◽

Disease Manifestation ◽

Enzyme Replacement ◽

Renal Manifestation ◽

Patient State ◽

Alpha Galactosidase ◽

Stage Renal Disease ◽

End Stage

The aim of the study was to describe diagnostic and treatment experience of Fabry disease in Ukraine, rare inherited multisystem metaboliс disorder with chronic kidney insufficiency as one of signs. The diagnosis was found in nine years old boy with acroparestesia and multiply angiokeratomas after enzymodiagnostic test (determination of lysosomal enzyme alpha-galactosidase A activity level in peripheral blood leucocytes). The parents gave consent to examine of the other child in family, 19 years old boy with myeloradiculonevritis and inferior paraparesis, and glomerulonephritis presented by proteinuria. Fabry disease was confirmed in proband by special enzymodiagnostic test. Clinical-genealogical analysis was exposed by the "phenomenon of grandfather": grandfather exitus from End Stage Renal Disease, probably due renal manifestation of Fabry disease. Enzyme replacement therapy was stabilized patient state, decreased the proteinuria level and saved the renal function. Early and classic signs of Fabry disease which allows to suspect a genetic anomaly were presented in article. Information about Fabry disease physician followed by in-time diagnosis and onset of specific therapy those provide favorable disease course, social adaptation and rehabilitation of patient, effective medical-genetic consultation in gen-compromised families.

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First two years of reimbursed enzyme replacement therapy in the treatment of Fabry disease in Poland

F1000Research ◽

10.12688/f1000research.55313.1 ◽

2021 ◽

Vol 10 ◽

pp. 841

Author(s):

Michał Nowicki ◽

Monika Komar ◽

Mariusz Kusztal ◽

Katarzyna Mizia-Stec ◽

Tomasz Liberek ◽

...

Keyword(s):

Enzyme Replacement Therapy ◽

Fabry Disease ◽

Replacement Therapy ◽

Clinical Symptoms ◽

Final Diagnosis ◽

The Body ◽

Lysosomal Storage ◽

Enzyme Replacement ◽

Number Of Patients ◽

Mean Time

Fabry disease (FD) is an ultra-rare genetic lysosomal storage disease caused by pathologic gene variants resulting in insufficient expression of α-galactosidase A. This enzyme deficiency leads to accumulation of globotriaosylceramide and globotriaosylsphingosine in plasma and in different cells throughout the body, causing major cardiovascular, renal, and nervous system complications. Until 2018, reimbursed enzyme replacement therapy (ERT) for FD was available in all European Union countries except Poland. We present the preliminary results of the first two years of reimbursed ERT in Poland. We obtained data from the seven largest academic centers in Katowice, Kraków, Wrocław, Poznań, Gdańsk, Warszawa, and Łódź. The questionnaire included the following data: number of patients treated, number of patients qualified for ERT, and patient characteristics. All centers returned completed questionnaires that included data for a total of 71 patients (28 men and 43 women) as of June 2021. Thirty-five patients with the diagnosis of FD confirmed by genetic testing (22 men and 13 women) had already qualified for reimbursed ERT. Mean (SD) age at the commencement of the ERT program was 39.6 (15.5) years (range 18-79 years). Mean time from the first clinical symptoms reported by the patients to the FD diagnosis was 21.1 (8.9) years, and the mean time from the final diagnosis of FD to the beginning of ERT was 4.7 (4.6) years. FD is still underdiagnosed in Poland. To identify undiagnosed FD patients and to ensure that patients in Poland benefit fully from ERT, implementation of an effective nationwide screening strategy and close cooperation with a network of rare disease centers is advised.

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Synuclein alpha accumulation mediates podocyte injury in Fabry nephropathy

10.1101/2021.12.17.473164 ◽

2021 ◽

Author(s):

Ahmed Abed ◽

Fabian Braun ◽

Dominik Sellung ◽

Mathias Woidy ◽

Oystein Solberg Eikrem ◽

...

Keyword(s):

Cell Injury ◽

Kidney Injury ◽

Human Kidney ◽

Organ Damage ◽

Alpha Synuclein ◽

Podocyte Injury ◽

Enzyme Replacement ◽

Alpha Galactosidase ◽

Fabry Nephropathy ◽

And Function

Current therapies for Fabry disease are based on reversing intra-cellular accumulation of globotriaosylceramide (Gb3) by enzyme replacement therapy (ERT) or chaperone-mediated stabilization of the defective enzyme, thereby alleviating lysosome dysfunction. However, their effect in the reversal of end-organ damage, like kidney injury and chronic kidney disease remains unclear. First, ultrastructural analysis of serial human kidney biopsies showed that long-term use of ERT reduced Gb3 accumulation in podocytes but did not reverse podocyte injury. Then, a CRISPR/CAS9-mediated alpha-Galactosidase knockout podocyte cell line confirmed ERT-mediated reversal of Gb3 accumulation without resolution of lysosomal dysfunction. Transcriptome-based connectivity mapping and SILAC-based quantitative proteomics identified alpha-synuclein (SNCA) accumulation as a key event mediating podocyte injury. Genetic and pharmacological inhibition of SNCA improved lysosomal structure and function in Fabry podocytes, exceeding the benefits of ERT. Together, this work reconceptualizes Fabry-associated cell injury beyond Gb3 accumulation, and introduces SNCA modulation as a potential intervention, especially for patients with Fabry nephropathy.

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