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Methods and compositions for the treatment of fabry disease

A genome and viral vector technology, applied in the field of gene therapy to prevent and/or treat Fabry disease, can solve problems such as α-GalA level fluctuations

Pending Publication Date: 2021-09-21
SANGAMO BIOSCIENCES INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it is expected that these will still require chronic administration, with associated risks of infusion-related reactions and / or inactivity due to neutralizing antibodies, and that α-Gal A levels will still fluctuate significantly over time

Method used

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  • Methods and compositions for the treatment of fabry disease
  • Methods and compositions for the treatment of fabry disease
  • Methods and compositions for the treatment of fabry disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0275] High plasma α-Gal A activity persists for 3 months in GLAKO mice treated with variant #4 expression construct

[0276] will be like Figure 1A Samples of the indicated variant #4 expression constructs were administered to male GLAKO mice to evaluate pharmacodynamic activity and biodistribution following a single intravenous (IV) dose.

[0277] GLAKO male mice were 8-12 weeks old at the start of the study. Animals (n=10-20 males / group) received formulation buffer containing phosphate buffered saline (PBS) containing CaCl2, MgCl2, NaCl, sucrose and Kolliphor (poloxa) on day 1. (M)P 188) (control mice)) or variant #4 expression vector receiving one of three dose levels (2.0E+12, 5.0E+12 or 5.0E+13 vg / kg, respectively; n=10 mice per group) as a single 200 μl tail vein administration. Mice were monitored for 3 months. figure 2 The results of the pharmacokinetic evaluation (plasma α-Gal A activity) in individual mice are presented in and image 3 Group means (mean + SD) ...

Embodiment 2

[0281] High levels of α-Gal A activity lead to a corresponding reduction in Fabry substrates

[0282] Variant #4 construct formulations were administered intravenously to GLAKO mice at doses of 0 vg / kg, 2.0E+12 vg / kg, 5.0E+12 vg / kg, or 5.0E+13 vg / kg to evaluate mouse plasma and tissue Fabry substrate levels in . Tissues were harvested at necropsy on day 91 post-dose and levels of the α-Gal A substrate Gb3 (isoforms C22:0 and C24:0) and its deacylated form lyso-Gb3 were determined using LC-MS . Briefly, tissues were weighed and mechanically disrupted in tissue disruption fluid (5% MeOH, 95% water and 0.1% acetic acid) at a rate of 5 ml fluid / mg tissue. Then 10 μl of plasma or tissue slurry was added to 90 μl of precipitation solvent (MeOH with internal standard N-tricosylceramide trihexoside (C23:0, Matrya) spiked into solution) in a siliconized tube, vortexed and placed in Place on a shaking plate at room temperature for 30 minutes. Samples were then centrifuged and 10 μl ...

Embodiment 3

[0287] Variant #21 expression vector produces plasma α-Gal A activity in vitro and in vivo.

[0288] The level and activity of secreted human α-Gal A was assessed in various mouse, cynomolgus monkey, and human primary cells and cell lines following transduction with variant #4 or variant #21 expression vectors. Variant #4 or variant #21 expression vectors were produced in 1) HEK293 cells or 2) Sf9 insect cell line.

[0289] HepG2 cells and iPSC-derived hepatocytes (iCell hepatocytes) were transduced using standard techniques and as described in US Publication No. 20180117181. Briefly, cells were seeded at varying densities per well and transduced at a multiplicity of infection (MOI) ranging from 100,000 to 600,000 vg variant #21 expression construct or variant #4 expression construct per cell. Supernatant samples were collected on days 3 to 7 and α-Gal A enzyme activity was assessed by α-Gal A fluorescence activity assay and in cell pellets collected at the end of the study (...

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Abstract

The present disclosure provides expression constructs comprising a GLA transgene encoding the at least one alpha-Gal A protein for use in expressing alpha-Gal A proteins and preventing, inhibiting or treating Fabry disease or one or more symptoms associated with Fabry disease.

Description

[0001] Cross References to Related Applications [0002] This application claims the benefit of U.S. Provisional Application No. 62 / 788,439, filed January 4, 2019, the disclosure of which is incorporated by reference in its entirety. [0003] sequence listing [0004] This application contains a Sequence Listing, which has been filed electronically in ASCII format, and is hereby incorporated by reference in its entirety. Said ASCII copy, created on December 3, 2019, is named 8325018840SL.txt and is 10,636 bytes in size. technical field [0005] This disclosure is in the field of gene therapy for the prevention and / or treatment of Fabry disease. Background technique [0006] The α-galactosidase A (GLA) gene encodes a lysosomal hydrolase, α-galactosidase A (α-Gal A). α-Galactosidase is an enzyme that catalyzes the hydrolysis of the terminal α-galactosyl moieties of oligosaccharides and polysaccharides. [0007] Fabry disease is an X-linked lysosomal storage disease caused ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K38/46A61K38/47A61K38/48A61K48/00C12N15/11
CPCA61K38/47A61K31/573A61P3/00C12Y302/01022C12N2750/14143C12N2830/48C12N2830/008A01K2227/105A01K2217/075A01K2267/0362A61K48/005C12N15/86C12N2830/42C12N2830/50C12N2800/22A61K48/0058C12N15/67C12N9/2465
Inventor M·W·赫斯顿
Owner SANGAMO BIOSCIENCES INC
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