Methods and compositions for enhancing functional myelin production

Inactive Publication Date: 2020-02-06
CASE WESTERN RESERVE UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0041]In certain embodiments, the method restores the lifespan of the subject to at least 30%, 40%, 50%, 60%, 70%, 80%, 90%, or about 100% of a control subject withou

Problems solved by technology

Myelin-related disorders impact millions of people, levying a heavy burden of morbidity and mortality on affected individuals and their families.
These disorders lack disease-modifying therapies and inevitably resu

Method used

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  • Methods and compositions for enhancing functional myelin production
  • Methods and compositions for enhancing functional myelin production
  • Methods and compositions for enhancing functional myelin production

Examples

Experimental program
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Effect test

example 1

Nuclease Mediated PLP1 Inactivation to Treat Genetic Myelin Disorders

Introduction

[0328]Abnormal myelination results in aberrant neuronal-signaling and neurological dysfunction. Restoration of the myelinating-capacity in these patients by correction of the genetic abnormalities within their endogenous, myelinating cells represents a promising curative avenue, however the feasibility of this therapeutic approach has yet to be demonstrated. Therefore, we chose to validate this paradigm by focusing on a severe, archetypal leukodystrophy called Pelizaeus-Merzbacher Disease (PMD).

[0329]PMD is a severe X-linked genetic disorder of myelin caused by mutations in the proteolipid protein 1 (PLP1). PMD patients typically experience severe neurological disease, including profound cognitive and motor disability, which invariably culminates in early mortality during childhood or adolescence. Therefore, we looked to determine if severe PMD patients could be treated through introduction of nuclease ...

example 2

Post-Natal Inactivation of PLP1 Using AAV Delivery of CRISPR / Cas9

[0352]This example demonstrates that post-natal inactivation of PLP1 can be used to effectively treat PMD, or reduce the severity of PMD.

[0353]To facilitate the delivery of the CRISPR / Cas9 system with sgRNA targeting the PLP1 locus in a patient, several CNS-targeted AAV serotypes, including PHP.B, were generated, and AAV tropism for OPCs were validated. The AAV constructs (AAV9 or AAV-PHP.B) contain a SaCRISPR-Cas9 nuclease (CMV-SaCas9, SaCas9 coding sequence under the control of a CMV promotor) with a site directed guide RNA (sgRNA) against PLP1 (U6-sgRNA, the sgRNA is under the control of the U6 promotor), which is designed to generate indels in the PLP1 gene and thus prevent expression of the defective PLP1 protein.

[0354]Mice were maintained in accordance with approved protocols reviewed by Case Western Reserve University's Institutional Animal Care and Use Committee. Mice were housed in a temperature and humidity c...

example 3

Post-Natal Knockdown of PLP1 Using Antisense Oligonucleotides (ASO)

[0362]This example demonstrates that post-natal down-regulation or knockdown of PLP1 gene activity using ASO can be used to effectively treat PMD, or reduce the severity of PMD.

[0363]Mice are maintained in accordance with approved protocols reviewed by Case Western Reserve University's Institutional Animal Care and Use Committee. Mice are housed in a temperature and humidity controlled housing unit under a 12 hour day / light cycle and are allowed ad libitum access to food.

[0364]Male postnatal day 0 pups are obtained from jimpy (a severe mouse model of Pelizaeus Merzbacher Disease) breeding pairs and rapidly anesthetized using cryoanesthesia. A 10 μL Hamilton syringe with a 32 gauge needle is loaded with antisense oligonucleotides targeting PLP1. The needle is lowered through the skull to a depth of about 2 mm at a position 2 / 5 from the intersection of the saggital suture and lambdoid to the eye. 2 μL of ASO solution i...

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Abstract

A method of generating a cell that enhances functional myelin production is provided, the method including genetically modifying the cell such that: (i) an endogenous PLP1 gene is modified to decrease its ability to inhibit myelin production; (ii) an endogenous PLP1 genetic regulatory element is modified to decrease its ability to promote PLP1 expression; (iii) an endogenous PLP1 genetic regulatory element is modified to increase its ability to inhibit PLP1 expression; or (iv) an endogenous PLP1 gene product or a PLP1 regulatory element gene product that promotes PLP1 expression is modified to decrease the PLP1 expression level, wherein the cell produces functional myelin.

Description

REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of the filing dates of U.S. Provisional Patent Application No. 62 / 431,787, filed on Dec. 8, 2016, and U.S. Provisional Patent Application No. 62 / 542,660, filed on Aug. 8, 2017, the entire contents of each of which are incorporated herein by reference.BACKGROUND OF THE INVENTION[0002]Myelin-related disorders impact millions of people, levying a heavy burden of morbidity and mortality on affected individuals and their families. Leukodystrophies are genetic myelin-related disorders that collectively impact 1 in 7,500 newborns in the United States. These disorders lack disease-modifying therapies and inevitably result in severe morbidity and mortality during childhood and adolescence. Several common leukodystrophies have known genetic mutations that result in improper myelination (myelin wrapping) of neuronal axons by oligodendrocytes in the central nervous system (CNS).[0003]Pelizaeus Merzbacher Disease (PMD) is...

Claims

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Application Information

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IPC IPC(8): C12N15/63C12N15/10C07K14/47
CPCC07K14/4713C12N15/102C12N15/63C12N2750/14143C12N2310/20A61P21/02A61P25/00A61P25/04A61P25/14A61P25/16A61P25/28A61P27/02A61P3/00A61P7/00
Inventor TESAR, PAULELITT, MATTHEW
Owner CASE WESTERN RESERVE UNIV
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