Engineering erythrocytes for treatment of lysosomal storage diseases

A technology for lysosomal storage diseases and red blood cells, applied in animal cells, gene therapy, vertebrate cells, etc., can solve the problems of short half-life, limited bioavailability, inactivation or disappearance of therapeutic enzymes, etc.

Pending Publication Date: 2022-07-22
WEST LAKE BIOMEDICAL TECH HANGZHOU CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Of note, PEG may adversely affect the activity of the conjugating enzyme, resulting in reduced efficacy of the treatment
Second, previous ERTs used in vitro expressed recombinant enzymes that often lacked proper glycosylation modifications critical for enzyme uptake and intracellular transport
Third, therapeutic enzymes may be inactivated or lost in vivo due to short half-life, limited bioavailability, and / or interactions with plasma proteins
Fourth, enzyme production and purification are often time-consuming, and thus treatment with ERT is very expensive
While neither disrupting membrane integrity nor shortening the life cycle of red blood cells, this method is preferably used with membrane proteins that contain a (G)n sequence within the N-terminus, so its application is limited to certain membrane proteins

Method used

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  • Engineering erythrocytes for treatment of lysosomal storage diseases
  • Engineering erythrocytes for treatment of lysosomal storage diseases
  • Engineering erythrocytes for treatment of lysosomal storage diseases

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0157] Example 1: Engineering hematopoietic stem and / or progenitor cells to express alpha-galactosidase A for the treatment of Fabry disease

[0158] 1.1. Fabry disease

[0159]Fabry disease (OMIM 301500) is an X-linked lysosomal storage disorder caused by mutations in the GLA gene encoding the lysosomal enzyme alpha-galactosidase A. Defects in this gene lead to loss or reduction of α-galactosidase activity in lysosomes and to accumulation of globotriaosylceramide (Gb3), which in turn leads to damage in various cell types, including capillary endothelium cells, kidney cells, cardiomyocytes and nerve cells. Patients with Fabry disease present with a variety of progressive clinical symptoms, many of which first appear in early childhood, including neuropathic pain and / or gastrointestinal (GI) problems. As patients age, they tend to develop end-stage organ failure or life-threatening cardiovascular or cerebrovascular disease. The life expectancy of a patient is generally aroun...

Embodiment 2

[0189] Example 2: Engineering hematopoietic stem and / or progenitor cells to express GRHPR for the treatment of type II primary hyperoxaluria

[0190] 2.1.Type II primary hyperoxaluria

[0191] Primary hyperoxaluria type II (PH2) (OMIM 260000, 604296) is an autosomal recessive disorder caused by pathogenic variants in the glyoxylate reductase / hydroxypyruvate reductase (GRHPR) gene. When the activity of GRHPR is reduced, glyoxylate cannot be efficiently converted to glycolate. The accumulation of glyoxylate in cells in turn stimulates its oxidation by lactate dehydrogenase (LDH) to oxalic acid, which can combine with calcium to form calcium oxalate, a hard compound that is responsible for kidney and bladder stones. main ingredient.

[0192] GRHPR is expressed in all tissues, with the highest levels in the liver. The disease is characterized by the accumulation of calcium oxalate in the kidneys and urinary tract, which often leads to the development of kidney stones and progre...

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Abstract

Methods of treating a subject having a lysosomal storage disease are provided, comprising engineering Lin-hematopoietic stem and / or progenitor cells to obtain engineered erythrocytes expressing a polypeptide, where the polypeptide may be alpha-GAL A or GRHPR. Also provided are methods of producing erythrocytes from Lin-hematopoietic stem and / or progenitor cells in vitro, erythrocytes produced by the methods, and compositions comprising the erythrocytes.

Description

[0001] Field of Invention [0002] The present disclosure relates to methods of producing red blood cells, comprising (i) engineering hematopoietic stem and / or progenitor cells to express polypeptides, such as enzymes involved in lysosomal storage diseases, and (ii) exposing the engineered hematopoietic stem cells in vitro and / or progenitor cells differentiate into mature red blood cells, wherein the mature red blood cells express the polypeptide. Aspects of the present disclosure also relate to compositions comprising these red blood cells and therapeutic uses of these red blood cells. In some embodiments, the use comprises treating a subject with a lysosomal storage disease (eg, Fabry disease or primary hyperoxaluria type II). [0003] Background of the Invention [0004] Lysosomal storage diseases (LSDs) are a group of rare metabolic diseases characterized by a lack of functional individual lysosomal enzymes. Most LSDs are inherited as autosomal recessive or X-linked trait...

Claims

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Application Information

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Patent Type & AuthorityApplications(China)
IPC IPC(8): A61K38/42A61K48/00A61K35/18A61K35/28C12N15/09C12N15/85C12N5/10C07K14/47A61P3/00
CPCA61K35/28A61K35/18A61P3/00C12Y302/01022C12N9/2465C12N9/0006C12Y101/01026C12Y101/01079C12Y101/01081C07K2319/60C07K14/70582C07K14/70596A61K48/005C12N15/86C12N2740/13043C12N2510/00C12N5/0641A61K38/00
Inventor高晓飞聂小千
OwnerWEST LAKE BIOMEDICAL TECH HANGZHOU CO LTD