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Fabry disease

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  1. Vitavita 19 november 2018 17:44
    Ziekte van Fabry

    De ziekte van Fabry is een erfelijke stofwisselingsziekte. De oorzaak is een verandering in het DNA (erfelijk materiaal).

    De ziekte van Fabry is een van de lysosomale stapelingsziekten. Bij lysosomale stapelingsziekten werken lysosomen niet goed. Lysosomen zijn onderdelen van onze lichaamscellen, die zorgen voor de afbraak en het hergebruik van veel stoffen. Dit wordt gedaan door enzymen in het lysosoom.

    Als een van deze enzymen er niet is of niet goed werkt, gaan (afval)stoffen zich opstapelen in het lysosoom.
    Bij de ziekte van Fabry werkt het enzym alfa-galactosidase A niet goed. Normaal helpt dit enzym bij de afbraak van de stof globotriaosylceramide (dat is een vetachtige stof). Maar bij de ziekte van Fabry gaat deze stof zich opstapelen. Op den duur beschadigt dit weefsels en organen.

    Iemand met de ziekte van Fabry kan op de huid kleine rood-paarse puntjes krijgen (angiokeratomen). Deze plekjes zitten vooral tussen de navel en knieën. Ook kunnen mensen pijn hebben in de handen en voeten. De pijn kan continu aanwezig zijn, maar ook in aanvallen optreden na inspanning of bij koorts.

    Verder kan iemand vaak niet goed zweten en komen er maag- darmklachten voor. Ook kunnen er gehoorproblemen zijn. Soms zijn er afwijkingen op het hoornvlies, maar deze geven meestal geen klachten.
    Op langere termijn kunnen er afwijkingen aan het hart, de nieren en de hersenen ontstaan.

    De klachten beginnen meestal op kinderleeftijd of rond de puberteit. Zowel mannen als vrouwen kunnen de ziekte van Fabry hebben, maar mannen hebben vaak ernstigere klachten.

  2. Vitavita 19 november 2018 17:45
    “Fabry disease affects an estimated 1 in 40,000 to 60,000 males.”

    Estimated males with classic Fabry disease: Half of 323,000,000 people equals 161,500,000 males. Therefore, males with FD equals 161,500,000/50,000 for a total of 3,230 males in the U.S.

    Naar schatting komt de ziekte van Fabry in Nederland bij ongeveer 1 op 40.000 pasgeborenen voor.

  3. flosz 21 november 2018 14:23
    $QURE new product candidate AMT-190, a differentiated gene therapy for the treatment of Fabry disease.

    Fabry disease is an inherited lysosomal storage disorder caused by a defect in a gene that encodes for a protein called a-galactosidase A (GLA). The GLA protein is an essential enzyme required to breakdown globotriaosylsphingosine (Gb3) and lyso-globotriaosylsphingosine (lyso-Gb3). In patients living with Fabry disease, Gb3 and lyso-Gb3 accumulate in various cells throughout the body causing progressive clinical signs and symptoms of the disease.  Current treatment options, which consist of bi-weekly intravenous enzyme replacement therapy, have no therapeutic benefit in patients with advanced renal or cardiac disease. Studies have also shown that a majority of male patients develop antibodies that inhibit the GLA protein and interfere with therapeutic efficacy.

    AMT-190 is a one-time, intravenously-administered, AAV5-based gene therapy designed to circumvent GLA antibodies that can inhibit efficacy in Fabry patients. AMT-190 incorporates a modified version of a-N-acetylgalactosaminidase (NAGA), a protein that is structurally similar to the GLA protein but is not recognized by GLA-neutralizing antibodies.  As such, AMT-190 has the potential to be a more effective, longer-term treatment of Fabry disease.

    In cultured cells and in a study in wild-type mice, AMT-190 resulted in clinically relevant GLA activity.

    In a preclinical proof-of-concept study, Fabry mice were injected with a single dose of AMT-190, resulting in modified NAGA expression with subsequent GLA-activity in plasma. At 2 and 4 weeks post-dosing, this GLA activity already translated to up to 50 percent reduction in lyso-Gb3 levels.

    These studies demonstrate proof-of-concept of AMT-190 as a gene therapy candidate for Fabry disease.  A one-time administration of AMT-190 could potentially lead to long-term expression of GLA in the liver, kidneys and heart, with no loss of expression due to inhibitors.
  4. flosz 26 april 2019 16:55
    $QURE #ASGCT19 APRIL29-MAY2,WASHINGTON,D.C. Development of an AAV5-Based Gene Therapy for Fabry Disease
    Fabry disease is an X-linked hereditary metabolic disorder that is caused by a mutation in the alpha-galactosidase A (GLA) gene (Brady et al., 1967; Kint, 1970; Sweeley and Klionsky, 1963). The GLA enzyme is involved in degradation of glycolipids, specifically globotriaosylceramide (Gb3). In Fabry patients there is a continuous accumulation of Gb3 and its deacylated derivative globotriaosylsphingosine (lysoGb3) in cells and plasma, resulting in cell abnormalities and organ dysfunction particularly affecting heart and kidney (Aerts et al., 2008). The current treatment for Fabry disease is enzyme replacement therapy (ERT) that successfully improves kidney and heart pathology and the patients’ quality of life. However, ERT also has disadvantages, including poor stability in blood, low incorporation efficiency into target organs, high costs and the production of anti-GLA antibodies by some patients. Moreover, it is estimated that 55-83% of the ERT-treated patients develop antibodies against GLA (Schiffmann et al., 2006; Wilcox et al., 2004). To prevent the adverse effect of the current ERT, the a-N-acetylgalactosaminidase (NAGA) protein showing high structural resemblance with GLA was modified. The NAGA substrate specificity was changed to exert GLA activity by introducing mutations in the active site (Tajima et al., 2009). This modified NAGA protein has been shown to cleave accumulated Gb3 in cultured fibroblasts from Fabry patients, as well as in Fabry diseased mice resulting in prevention of Gb3 storage in liver, kidney and heart (Tajima et al., 2009). We are currently developing a gene therapy for Fabry disease by expressing this modified NAGA from AAV5 vectors. Different strategies are being explored that either entail liver-targeted expression of the modified NAGA that upon expression in the liver will be secreted and taken up by the target cells into the lysosomes, or constitutive expression throughout multiple organs (depending on the tropism of the AAV5 vector together with the promoter for expression). Six AAV vectors expressing modified NAGA were developed with distinct design and two different promoters. In vitro all constructs were shown to result in GLA activity in transduced liver cells. Administration of the AAV vectors in C57Bl/6 mice resulted in 10 and 20-fold higher GLA activity in plasma and liver, respectively, compared to vehicle-treated mice. In addition, AAV5-modified NAGA administration to Fabry GLA knockout mice showed significant lowering of Gb3 and LysoGb3 in plasma already at 2 weeks post-injection. Overall, the use of AAV gene therapy expressing modified NAGA with GLA-activity warrants further investigation as an attractive approach to treat Fabry patients.
  5. Vitavita 2 mei 2019 13:17
    uniQure Announces New Preclinical Data in Hemophilia A and Fabry Disease in Oral Presentations at the 22nd ASGCT Annual Meeting

    LEXINGTON, Mass. and AMSTERDAM, the Netherlands, May 02, 2019 (GLOBE NEWSWIRE) -- uniQure N.V. (NASDAQ: QURE), a leading gene therapy company advancing transformative therapies for patients with severe medical needs, will present today new preclinical data on its gene therapy candidates AMT-180 for the treatment of hemophilia A and AMT-190 for the treatment of Fabry disease. These data will be featured today in back-to-back oral presentations at the 22nd American Society for Gene and Cell Therapy (ASGCT) Annual Meeting in Washington D.C.

    AMT-190 for Fabry Disease

    Fabry disease is an X-linked genetic disorder resulting from a deficiency of a-galactosidase A (a-gal or GLA). The current standard of care for Fabry disease is bi-weekly infusions of enzyme replacement therapy, a treatment that has shown not to be effective in many patients due to poor targeting of target organs such as the kidney and heart. In addition, a significant number of patients develop antibodies to the enzyme, a-gal or GLA.

    AMT-190 is a novel AAV5 gene therapy approach for Fabry disease that comprises a recombinant AAV5 vector incorporating a proprietary, exclusively licensed, modified NAGA (ModNAGA) variant. AMT-190 provides expression of ModNAGA, which shows a high structural resemblance to a-gal. This approach may have several advantages over a-gal therapies, including higher stability in blood, better biodistribution in the target organs, secondary toxic metabolite reduction and improved cross-correction of neighboring cells. ModNAGA is also effective in the presence of a-gal antibodies.

    Data from in vitro and in vivo studies show that AMT-190 has the potential to become a one-time treatment option that improves upon the enzyme replacement standard of care with more efficient uptake in the kidney and heart and an improved immunogenicity profile.

    AMT-190 Preclinical Data Findings

    Proof-of-concept for AMT-190 was established through multiple studies in wild-type and Fabry mice. The oral presentation at ASGCT features the following data:

    Preclinical in vitro studies demonstrated that the expression of ModNAGA results in GLA activity in cells and suggest that uptake of ModNAGA is mediated by the Mannose-6-phosephase (M6P) receptor.

    In vivo studies in wild-type mice show that a single intravenous administration of AMT-190 resulted in a ten- to twenty-fold higher GLA activity in the plasma compared to the control group, suggesting that AMT-190 has the potential to provide therapeutically relevant GLA activity in plasma and in target organs.

    These results were underscored by a study in GLA knock-out mice, demonstrating significantly increased GLA activity in plasma and significantly reduced Lyso-Gb3 in the target organs after a single dose of AMT-190. In silico and in vitro studies also show that the modifications introduced into NAGA pose a very low immunogenicity risk.

    “These data show that AMT-190 has the potential to be a differentiated, one-time treatment option that could be used by all Fabry patients,” added Dr. van Deventer. “We will continue to advance our preclinical research toward our goal of developing a best-in-class gene therapy for Fabry disease.”
  6. Vitavita 31 mei 2019 00:27
    May 30, 2019 04:05 PM

    4D Molecular Therapeutics announces presentation of preclinical data at the 6th International update on Fabry Disease and provides clinical update.

    - Novel vector, 4D-C102, demonstrates superior performance compared to commonly used AAV1, AAV8, and AAV9 -

    - Fabry product candidate, 4D-310, is on track for anticipated clinical trial initiation in 2020 -

    4D was eens "partnered" met uniQure....zie uniQure niet meer op de site van 4D als "partnered" staan. En ook in de annual report 2017 van uniQure lijkt afscheid genomen te zijn. In annual report 2018 wordt nog kort ingegaan op 4D.

    Mr. Schaffer, de oprichter van 4D is wel non-executive member in de Board of directors van uniQure.

    Kortom, de huidige relationship is onduidelijk.
  7. colt 5 juli 2019 11:22
    Terapia génica en investigación de uniQure
    La terapia génica de uniQure en investigación se muestra promisoria como tratamiento para la enfermedad de Fabry

    4 julio 2019

    AMT-190, la terapia génica en investigación de uniQure para el tratamiento de la enfermedad de Fabry, se muestra promisoria como una opción de terapia de una sola vez que algún día puede reemplazar la terapia de reemplazo de enzimas (ERT) en esta población de pacientes.

    Los hallazgos fueron discutidos en una presentación oral titulada “Desarrollo de una terapia génica basada en AAV5 para la enfermedad de Fabry”, en la 22ª Reunión Anual de la Sociedad Americana de Terapia Genética y Celular (ASGCT) esta primavera en Washington, D.C.

    La enfermedad de Fabry es un raro trastorno genético causado por mutaciones en el gen GLA, ubicado en el cromosoma X, que brinda instrucciones para la producción de una enzima llamada alfa-galactosidasa A (alfa-GAL A). Estas mutaciones afectan típicamente la actividad de alfa-GAL A, lo que lleva a la acumulación de un tipo de grasa llamada globotriaosilceramida (Gb3) en tejidos y órganos.

    Hoy en día, los ERT, tratamientos en los que una enzima defectuosa es reemplazada por una saludable para compensar su falta de actividad, se consideran el estándar de oro para los pacientes con enfermedad de Fabry.

    “Sin embargo, la ERT también tiene desventajas, que incluyen una pobre estabilidad en la sangre, una baja eficiencia de incorporación a los órganos diana, altos costos y la producción de anticuerpos anti-GLA, [que] se estima que [ocurrirá en] 55–83% de los tratados con ERT pacientes “, declararon los investigadores.

    AMT-190 es un nuevo tipo de terapia génica, en la cual una versión modificada de alfa-N-acetilgalactosaminidasa (NAGA) que es capaz de descomponer Gb3, imitando la actividad de alfa-GAL A, se entrega a las células usando un adeno vector viral asociado (AAV5). La NAGA es una enzima que es muy similar a la alfa-GAL-A, pero al mismo tiempo, es lo suficientemente diferente para evitar ser atacada por anticuerpos anti-GLA dañinos.

    AMT-190 está siendo probado en modelos celulares y animales. Los hallazgos preclínicos presentados en la reunión mostraron que el constructo de NAGA modificado aumentó significativamente la actividad de alfa-GAL A en las células hepáticas.

    Una sola infusión intravenosa de la construcción en ratones sanos incrementó la actividad de alfa-GAL A 10 veces en el plasma y 20 veces en el hígado, en comparación con los animales tratados con una solución de vehículo (controles). Además, una administración única del constructo NAGA en un modelo de ratón de la enfermedad de Fabry aumentó la actividad de alfa-GAL A en el plasma sanguíneo y redujo significativamente los niveles de Gb3 y LysoGb3 tanto en el plasma como en los órganos diana dos semanas después de la administración inicial.

    Es importante destacar que los investigadores encontraron que las modificaciones en la estructura de NAGA plantean un menor riesgo de inmunogenicidad (capacidad de desencadenar la respuesta de un sistema inmunológico) en comparación con la ERT convencional.

    “Estos datos muestran que AMT-190 tiene el potencial de ser una opción de tratamiento único y diferenciado que todos los pacientes de Fabry podrían usar. “Continuaremos avanzando en nuestra investigación preclínica hacia nuestro objetivo de desarrollar una terapia génica de la mejor en su clase para la enfermedad de Fabry”, dijo en un comunicado de prensa el Dr. Sander van Deventer, MD, PhD, director científico de uniQure.
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