Recombinant adeno-associated virus for treatment of grn-associated adult-onset neurodegeneration

A technology of viruses and uses, applied to nervous system diseases, single-stranded DNA viruses, viruses, etc.

Pending Publication Date: 2021-11-26
THE TRUSTEES OF THE UNIV OF PENNSYLVANIA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] There are currently no disease-modifying therapies for adult-onset neurodegeneration caused by GRN haplotype insufficiency

Method used

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  • Recombinant adeno-associated virus for treatment of grn-associated adult-onset neurodegeneration
  • Recombinant adeno-associated virus for treatment of grn-associated adult-onset neurodegeneration
  • Recombinant adeno-associated virus for treatment of grn-associated adult-onset neurodegeneration

Examples

Experimental program
Comparison scheme
Effect test

example

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example 1

[0145] Example 1: Materials and methods

[0146] carrier

[0147] Cloning of the engineered human PGRN cDNA into an expression construct containing the chicken β-actin promoter with the cytomegalovirus early enhancer, chimeric intron, and rabbit β-globin polyadenylation sequence ( figure 1 ). The second engineered human PGRN cDNA was cloned into an expression construct containing the human ubiquitin C promoter. The expression construct was flanked by AAV2 inverted terminal repeats. Adeno-associated virus serotypes 1, 5 and human 68 (AAVhu68) were generated from this construct by triple transfection of HEK293 cells and purification with iodixanol as previously described (Lock M et al., Human Gene Therapy 2010; 21(10):1259-71).

[0148] animal procedure

[0149] All animal protocols were approved by the Institutional Animal Care and Use Committee of the University of Pennsylvania. A breeding pair of GRN knockout mice (stock no. 013175) was purchased from The Jackson labo...

example 2

[0161] Example 2: AAV-mediated delivery of human GRN transgenes in murine disease models

[0162] Recombinant AAV vectors with expression under the control of the CB7 promoter and chimeric intron (CB7.CI.hPGRN.rBG) were produced using the published triple transfection technique as described, for example, in WO 2018 / 160582 AAVhu68 capsid of human PGRN (SEQ ID NO:3).

[0163] Evaluation of AAV-mediated delivery of the human GRN transgene in a GRN knockout mouse model. Mice heterozygous for the GRN mutation (GRN + / - ) did not exhibit the pathological features of GRN-associated neurodegenerative diseases, possibly because the mouse lifespan did not allow for the sequelae of GRN haplotype insufficiency that were first manifested in humans decades later. In contrast, GRN - / - Intact PGRN deficiency in mice recapitulates several early features of human GRN haplotype deficiency, such as impaired lysosomal function, accumulation of autofluorescent lysosomal storage material (lipofusc...

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Abstract

A recombinant AAV (rAAV) suitable for use in treating adult onset neurodegeneration caused by granulin (GRN) haploinsufficiency, such as progranulin (PGRN) - related frontotemporal dementia (FTD), is provided. The rAAV comprises (a) an adeno-associated virus 1 capsid, and (b) a vector genome packaged in the AAV capsid, said vector genome comprising AAV inverted terminal repeats, a coding sequence for human progranulin, and regulatory sequences which direct expression of the progranulin. Also provided are a method for treating a human patient with PGRN -FTD and other adult onset neurodegeneration caused by granulin (GRN) haploinsufficiencies, comprising delivering to the central nervous system (CNS) a recombinant adeno-associated virus (rAAV) having an adeno-associated virus 1 (AAV1) capsid, said rAAV further comprising a vector genome packaged in the AAV capsid, said vector genome comprising AAV inverted terminal repeats, a coding sequence for human progranulin, and regulatory sequences which direct expression of the progranulin.

Description

[0001] Cross References to Related Applications [0002] This application claims U.S. Provisional Application No. 62 / 809,329, filed February 22, 2019, U.S. Provisional Application No. 62 / 923,812, filed October 21, 2019, and U.S. Provisional Application No. 62 / 923,812, filed February 2, 2020 The benefit and priority of Application No. 62 / 969,108, which is incorporated herein by reference in its entirety for all purposes. Background technique [0003] Frontotemporal dementia (FTD) is a fatal neurodegenerative disease presenting deficits in executive function, behaviour, speech or language comprehension, usually in the sixth or seventh decade of life. These symptoms are associated with a characteristic pattern of brain atrophy affecting the frontal and temporal cortices. Patients generally show a progressive course with a mean 8-year survival from symptom onset (Coyle-Gilchrist IT et al., Neurology, 2016;86(18):1736-43). [0004] FTD is highly heritable, with approximately 40%...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K48/00C12N15/861
CPCA61K48/005C12N15/86C12N2750/14143C12N2750/14171C07K14/47A61P25/28A61K9/0085A61K38/00C12N7/00
Inventor C·欣德勒N·米勒J·M·威尔逊
Owner THE TRUSTEES OF THE UNIV OF PENNSYLVANIA
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