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AAV-mediated gene therapy for maple syrup urine disease (MSUD)

A kind of allelic, base pair technology, applied in the composition of promoting the expression of functional BCKDHA protein in the subject, the composition of promoting the expression of functional BCKDHB protein in the subject, treating the subject with MSUD It can solve the problems of imperfect efficacy, difficulty in implementation, long-term immunosuppression accompanied by surgery, etc.

Pending Publication Date: 2022-02-01
UNIV OF MASSACHUSETTS +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Dietary BCAA restriction is the mainstay of treatment but is difficult to implement, has imperfect efficacy, and does not provide protection against paroxysmal and life-threatening encephalopathy crises
Liver transplantation is an effective alternative to dietary therapy but comes with risks of surgery and long-term immunosuppression

Method used

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  • AAV-mediated gene therapy for maple syrup urine disease (MSUD)
  • AAV-mediated gene therapy for maple syrup urine disease (MSUD)
  • AAV-mediated gene therapy for maple syrup urine disease (MSUD)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0188] Example 1: Analysis of bckdha gene therapy

[0189] MSUD is a rare genetic disease that affects branched amino acids (BCAA; leucine, isoleucine and proline) and degradation of ketoconic derivatives. It is caused by the mutation of the double allele in one of the three genes encoding the branzone sour dehydrogenase complex subunit (BCKDHA, BCKDHB and DBT). Serious (classic) MSUD is fatal in the absence of treatment. Diet BCAA restrictions are the main methods of treatment, but it is difficult to implement, uninterexably efficacy, and cannot provide the protection of an encephalopathy crisis against paroxysmia. Liver transplant is an effective alternative to diet therapies, but accompanied by surgery and long-term immunosuppression.

[0190] The impact of MSUD in the world is about 1 case per 185,000 birth population and is screened in most states and most developed countries. Due to the common Bckdha starting variant of the 4.5% group-specific carry frequency (C.1312T> a; p...

Embodiment 2

[0192] Example 2: Gene therapy by maplexia (MSUD) caused by bckdha or bckdhb

[0193] It is an aim to develop a AAV-mediated gene replacement therapy for MSUD caused by bckdha or bckdhb double allele mutation. Firstly, the AAV vector (OPTI-BCKDHA; SEQ ID NO: 1) or BCKDHB gene (OPTI-BCKDHB; SEQ ID NO: 4), which gene encodes the BCKD complex E1- α and E1-β subunits. BCKDHA activity is not effectively recovered in the art of the functional BCKDC E1 component (Alpha2-Beta2 "and BCKDHA or BETA2") and BCKDHA or BETA2 "and BCKDHA or BCKDHB. And BCKDHB Dual Carrier (Dual-Vector) Figure 1B And Figure 2). The protein expression of these carriers was verified in the HEK 293T cell line ( Figure 3A . Based on BCKDC enzyme activity assay, it is found that these carriers are functional. Figure 3b . Active recovery is more effective when bckdha and bckdhb are circulated. Pack Opti-Bckdha, Opti-BckDHB and Dual -Opti-Bckdha / BckDHB box is packaged in AAV9, which effectively targeted liver and ske...

Embodiment approach 1

[0197] Embodiment 1. A method for promoting functional BCKDHA protein in the subject, the functional BCKDHA protein is an E1-alpha subunit of branched alpha-ketoacly (BCAA) dehydrogenase complex, said method A nucleic acid comprising an effective amount comprising a casing is administered to the subject comprising an engineered nucleic acid to express BCKDHA in the liver and / or skeletal muscle of the subject, wherein the subject comprises at least An endogenous Bckdha allele, the endogenous Bckdha allele having a functionally lost mutation associated with maplexuria (MSUD).

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Abstract

In some aspects, the disclosure provides compositions and methods for promoting expression of functional BCKDHA protein, which is the E1-alpha subunit of the branched-chain alpha-keto acid (BCAA) dehydrogenase complex, in a subject. In some aspects, the disclosure provides compositions and methods for promoting expression of functional BCKDHB protein, which is the E1-beta subunit of the branched-chain alpha-keto acid (BCAA) dehydrogenase complex, in a subject. In some aspects, the disclosure provides compositions and methods for promoting expression of functional BCKDHA and BCKDHB proteins, in a subject. In some embodiments, the disclosure provides methods of treating a subject having Maple Syrup Urine Disease (MSUD).

Description

[0001] Cross-reference related application [0002] This application claims the rights of US Provisional Patent Application Serial No. 62 / 930, 687, filed on November 5, 2019. The entire contents of the above reference applications are incorporated herein by reference. [0003] Inventory background [0004] Maple Syrup Urine Disease (MSUD) is a rare genetic disease that affects branched chain amino acids (BCAA; leucine, isoleucine and proline) and its keto acid derivative degradation. It is caused by the mutation of the double allele in one of the three genes encoding the branzone sour dehydrogenase complex subunit (BCKDHA, BCKDHB and DBT). Serious (ie classic) MSUD is fatal. Diet BCAA restrictions are the main methods of treatment, but it is difficult to implement, the efficacy is not perfect, and it is not possible to provide the protection of an encephalopathy crisis against parity and threat life. Liver transplant is an effective alternative to diet therapies, but accompanied by ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/86C12N15/52C12N9/00A61P3/00A61P43/00A61K48/00
CPCA61P3/00A61P43/00C12N15/86C12N9/0008C12Y102/04004C12N2750/14143C12N2800/22A61K48/005A61K48/0058
Inventor 高光平王丹王家明K·A·施特劳斯
Owner UNIV OF MASSACHUSETTS