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Treatment of spinal muscular atrophy

A technology for spinal muscular atrophy and treatment methods, applied in the field of recombinant adeno-associated virus vectors, which can solve the problems of exon 7 skipping and low protein efficiency

Pending Publication Date: 2020-04-24
GENETHON +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Nonetheless, SMN2 cannot fully compensate for the loss of SMN1 function because the SMN2 gene produces lower amounts of full-length RNA and is less efficient at producing protein, although it does produce small amounts of protein
More specifically, the SMN1 and SMN2 genes differ by 5 nucleotides; one of these differences, a translationally silent substitution from C to T in the exon splicing region, results in frequent skipping of exon 7 during SMN2 transcription

Method used

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  • Treatment of spinal muscular atrophy
  • Treatment of spinal muscular atrophy

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Experimental program
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Embodiment 1

[0256] It is demonstrated herein that survival of a mouse model of SMA is greatly improved beyond expectations following administration of an AAV vector carrying the human SMN1 gene in the single-stranded genome.

[0257] Materials and methods

[0258] Vector production

[0259] The AAV vector used was a single-chain recombinant AAV9 vector with human SMN1 under the control of the CAG promoter (hybrid CMV enhancer / chicken β-actin promoter and β-globin splice acceptor site) gene, and the polyA region from the HBB2 gene.

[0260] The ssAAV9 vector was produced by a triple transfection system using standard procedures (Xiao et al., J. Virol. 1998; 72:2224-2232). Pseudotyped recombinant rAAV2 / 9 (rAAV9) virus preparations were generated by packaging the AAV2-terminal inverted repeat (ITR) recombinant genome in an AAV9 capsid. Briefly, a cis-acting plasmid carrying the CAG-hSMN1 construct, a trans-complementing rep-cap9 plasmid encoding proteins essential for the replication an...

Embodiment 2

[0270] Additional experiments were performed to show the improvement obtained using the present invention.

[0271] The aim of this study was to evaluate the therapeutic efficacy of a single-chain (ss) AAV9 vector expressing human SMN1 in a mouse model of spinal muscular atrophy. We compared intraventricular (ICV) administration to Smn 2B / - Effects of three ssAAV9-hSMN1 vectors and one ssAAVrh10-hSMN1 vector in neonatal mice at 21 and 90 days post-injection.

[0272] We analyzed different parameters:

[0273] - lifetime,

[0274] -weight,

[0275] - exercise and muscle strength,

[0276] - vector biodistribution and transgene expression,

[0277] - human SMN protein expression in various tissues,

[0278] - Spinal motor neuron counts,

[0279] - skeletal muscle histology,

[0280] - Neuromuscular junction (NMJ) morphology.

[0281] Three ssAAV9-hSMN1 vectors (7209, 7210, and 7211) containing wild-type human SMN1 coding sequence (NCBI reference sequence: NM_000344.3) a...

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Abstract

The present invention relates to a recombinant adeno-associated virus (rAAV) vector comprising a serotype 9 or rh10 AAV capsid, for use in a method for the treatment of spinal muscular atrophy (SMA).

Description

technical field [0001] The present invention relates to recombinant adeno-associated virus (rAAV) vectors comprising serotype 9 or rh10 AAV capsids for use in methods of treatment of spinal muscular atrophy (SMA). Background technique [0002] Broadly, spinal muscular atrophy ("SMA") describes a spectrum of inherited and acquired central nervous system (CNS) disorders characterized by loss of motor neurons in the spinal cord, resulting in muscle weakness and atrophy. The most common form of SMA is caused by mutations in the Survival Motor Neuron ("SMN") gene and exhibits varying degrees of severity affecting infants through adults. SMA in infancy is one of the most severe forms of this neurodegenerative disorder. Onset is usually sudden and violent. Some symptoms include: muscle weakness, poor muscle tone, weakness in crying, weakness or tendency to fall over, difficulty sucking or swallowing, accumulation of secretions in the lungs or throat, difficulty eating, and increa...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/86
CPCA61K48/0075C12N15/86C12N2750/14143C12N2750/14171A61P25/00A61K38/1709A61K48/0066C07K14/47
Inventor 安娜·布吉贝洛玛蒂娜·马里诺萨米亚·马丁
Owner GENETHON
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