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Gene therapy for alzheimer's disease

A gene and disease technology, applied in the field of compositions for the treatment of Alzheimer's disease and other neurodegenerative diseases

Pending Publication Date: 2021-04-30
THE BRIGHAM & WOMEN S HOSPITAL INC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Currently, there is no treatment for Alzheimer's disease

Method used

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  • Gene therapy for alzheimer's disease
  • Gene therapy for alzheimer's disease
  • Gene therapy for alzheimer's disease

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0131] Example 1: Pyramidal neurons of patients with sporadic Alzheimer's disease (AD) exhibit reduced PSEN1 and PSEN2 mRNA levels

[0132] Presenilin (PS) protein is the catalytic subunit of γ-secretase, which is required for the production of Aβ peptides. Mutations in the presenilin-1 (PSEN1) and presenilin-2 (PSEN2) genes are associated with 90% of cases of familial Alzheimer's disease (FAD). PSEN mutations associated with FAD and temporofrontal dementia cause loss of presenilin expression and presenilin function, resulting in reduced γ-secretase activity (Xia et al., Neuron. 2015 Mar 4;85(5):967 -81; Watanabe et al., J Neurosci. 2012 Apr 11;32(15):5085-96; Brouwers et al., 2008 Ann Med 40(8):562–83).

[0133] Individual pyramidal neurons were collected using laser capture microdissection, and 300 neurons per human brain were pooled together for RNA preparation (PicoPure RNA Isolation Kit, Life Technologies KIT0204). qRT-PCR was performed using Platinum Taq DNA polymerase...

Embodiment 2

[0138] Example 2: Dose-Dependent Reduction of γ-Secretase Activity in MEFs Carrying Heterozygous and Homozygous PSEN1 Mutations

[0139] method

[0140] Generation of immortalized Psen mutant MEFs

[0141] Mouse embryonic fibroblasts (MEFs) carrying various Psen1 genotypes were maintained in medium supplemented with 10% FBS and 1% penicillin and streptomycin. In 6-well plates, 300,000 MEFs were immortalized by transfection with 1 μg of CMV-SV40. MEFs transfected with CMV-SV40 were compared to MEFs transfected with CMV-GFP (1 μg) that stopped dividing at about passage 7.

[0142] NdE and hPS1 transfection

[0143] To determine whether γ-secretase activity was impaired in various immortalized Psen mutant MEFs, CMV-NotchΔE (5 ng) was transiently transfected into 6-well plates using Lipofectamine LTX (ThermoFisher Scientific 15338030) following the manufacturer's instructions. MEF.

[0144] Approximately 24 hours after transfection, cells were lysed in RIPA buffer: 50 mM Tris...

Embodiment 3

[0145] Example 3: Dose-dependent rescue of γ-secretase activity in MEFs with various PS genotypes: PS1 + / + , PS1 L435F / + , PS1 + / - , PS1 L435F / L435F , PS1 - / - and PS1 - / - ; PS2 - / -

[0146] To determine whether the reduced γ-secretase activity associated with PSEN1 mutations could be corrected by introduction of wild-type (WT) hPS, primary MEFs derived from embryos carrying various PS genotypes: PS1 + / + , PS1 L435F / + , PS1 + / - , PS1 L435F / L435F , PS1 - / - and PS1 - / - ; PS2 - / - (DKO). Immortalized MEFs were transiently transfected with CMV-NdelE, and γ-secretase activity was assessed by measuring the levels of NICD and PS1 NTF / CTF. NICD levels decreased in a PS1 dose-sensitive manner and were undetectable in DKO cells ( Figure 3A ). NICD level at PS1 L435F / L435F MEF (“L435F KI / KI” MEF) and PS1 - / - Decreased but detectable in MEF ( Figure 3A ), however by using the L435F KI / KI and PS1 - / - In vitro γ-secretase assays of embryonic brains did not detect de novo...

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PUM

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Abstract

The present disclosure provides, among other things, methods for using presenilin based gene therapy to treat neurodegenerative dementia including, but not limited to Alzheimers disease, frontotemporal dementia, frontotemporal lobar degeneration, Picks disease, Lewy body dementia, memory loss, and cognitive impairment including mild cognitive impairment (MCI).

Description

[0001] priority statement [0002] This application claims the benefit of U.S. Provisional Patent Application Serial No. 62 / 675,003, filed May 22, 2018. The entire contents of the aforementioned documents are hereby incorporated by reference. [0003] Federally funded research or development [0004] This invention was made with US Government support under Grant Nos. NS041783 and NS075346 awarded by the National Institutes of Health. The US Government has certain rights in this invention. technical field [0005] Described herein are, inter alia, compositions and methods for using presenilin gene therapy constructs to treat Alzheimer's disease (AD) and other neurodegenerative diseases. Background technique [0006] Alzheimer's disease, also known as Alzheimer's disease, accounts for the majority of neurodegenerative dementias and is the fourth leading cause of death in the United States after heart disease, cancer and stroke. It is characterized by progressive loss of co...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61P25/28C07K14/47C12N15/86A61K9/127
CPCA61P25/28A61K9/5184A61K9/0085C07K14/4711A61K9/0019A61K9/5123A61K38/00A61K48/00C12N7/00C12N9/6478C12N15/86C12N2710/16132C12N2710/16143C12Y304/23045C12Y304/23046
Inventor 沈洁R·J·凯莱赫三世
Owner THE BRIGHAM & WOMEN S HOSPITAL INC
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