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Interneuron-specific therapeutics for normalizing neuronal cell excitability and treating dravet syndrome

An interneuron-specific technology, applied in gene therapy, neurological diseases, chemical instruments and methods, etc., can solve problems such as deficiency

Pending Publication Date: 2022-01-21
THE BROAD INST INC +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Furthermore, lack of proper cortical interneuron function is associated with neurodevelopment and neurological diseases and disorders

Method used

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  • Interneuron-specific therapeutics for normalizing neuronal cell excitability and treating dravet syndrome
  • Interneuron-specific therapeutics for normalizing neuronal cell excitability and treating dravet syndrome
  • Interneuron-specific therapeutics for normalizing neuronal cell excitability and treating dravet syndrome

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0368] Example 1: Identification of Cis-Regulatory Sequences Restricting Reporter and Effector Gene Expression to PV-Expressing Cortical Interneuron Cell Populations (PV Interneuron-Specific Enhancer Sequences)

[0369] SCN1A, the gene encoding the Nav1.1 sodium channel, is expressed in multiple distinct neuronal populations in the cerebral cortex, including three non-overlapping neuronal populations: parvalbumin-expressing fast spike-forming cortical interneurons (PV cIN), Disinhibited cortical interneurons (VIP cIN) and layer 5 pyramidal neurons expressing vasoactive intestinal peptide. In a specific embodiment, SCN1A is expressed in PV-expressing cortical interneurons. SCN1A has attracted much attention because its loss of function has been linked to Della Virt syndrome, a premature and intractable epileptic encephalopathy characterized by early-onset seizures. More specifically, SCN1A haploinsufficiency or pathogenic variants trigger Dravet syndrome.

[0370] A comprehen...

Embodiment 2

[0378] Example 2: Viral targeting of mouse PV cortical interneurons (PV cIn)

[0379] E2 regulatory elements display 90% specificity for PV cIN, and this specificity provides a means of targeting fast-spiking neurons (e.g., basket and chandelier cells), which collectively account for all cortical (GABAergic) neurons. ) of 40% of interneurons. These neurons have strong inhibitory effects on local networks, and their dysfunction has been directly linked to neurological and neuropsychiatric disorders, including Dravet syndrome, focal epilepsy, autism spectrum disorder (ASD), and schizophrenia disease. Therefore, controlling the activity of these neurons is particularly important for both basic research and clinical applications. Therefore, E2 regulatory elements are studied and characterized for the development of agents with broad utility, eg as viral tools or therapeutics.

[0380] After systemic injection of rAAV-E2-dTomato into adult mice, the expression of the viral repor...

Embodiment 3

[0385] Example 3: Viral monitoring and manipulation of PV cortical interneurons in mice

[0386] As described in Example 2, having demonstrated the precise expression of E2 against PVcIN using different injection modes and at various developmental stages, this vector was evaluated for studying connectivity (using a presynaptic reporter gene) and activity (using a presynaptic reporter gene). imaging technology, coupled with the availability of genetically encoded calcium reporters). When E2 is used to drive the synaptophysin-tdTomato fusion gene (see, e.g., Madisen, L. et al., 2012, Nat Neurosci, 15(5):793-802), expression of the reporter gene is restricted to the presynaptic PV cIN, the terminal body is located on the pyramidal neurons ( Figure 5A ). When this vector was used to drive GCaMP6f expression (Chen, T.W. et al., Nature, 499:295-300 (2013)), it was demonstrated that PV cIN was recruited upon whisker stimulation ( Figure 5B and Figure 9A ). Together these resu...

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Abstract

Provided are therapeutic virus vectors, particularly, recombinant adeno-associated virus (rAAV) vectors, designed to contain an enhancer sequence that specifically restricts expression of an effector gene (e.g., an SCN1A-encoding polynucleotide, Gq-DREADD-encoding polynucleotide, or PSAM-encoding polynucleotide) contained in the vector to PV-expressing GABAergic interneuron or to neuron cell populations in the brain. The rAAV vectors, compositions and methods thereof are useful for treating subjects afflicted with neuropathologies, seizures, pharmacologically-intractable forms of epilepsy including Dravet syndrome (DS), a form of infantile epilepsy associated with severe seizures, cognitive impairment and premature death, as the cause of DS involves loss of function of a sodium channel encoded by the SCN1A gene. The described vectors restore expression of effector genes to the appropriate interneuron or neuron cell populations with specificity and sensitivity, advantageously to address the root cause of the disease by restoring the excitation-inhibition balance by means of gene-therapy (with SCN1A) or pharmacogenetics.

Description

[0001] Cross References to Related Applications [0002] This application is a PCT International Application asserting U.S. Provisional Patent Application No. US 62 / 801,483 filed February 5, 2019, U.S. Provisional Patent Application No. US 62 / 823,281 filed March 25, 2019 and October 17, 2019 Priority and benefit to filed U.S. Provisional Patent Application No. US62 / 916,477. The entire contents of these Provisional Patent Applications are incorporated herein by reference. [0003] Federally Sponsored Research Statement [0004] This invention was made with support from the National Institutes of Health grant (grant number: MH111529). The government has certain rights in this invention. Background technique [0005] There is a delicate balance between excitation and inhibition. This balance must be carefully maintained for the proper functioning of brain circuits and the activity of the neuronal cells operating within these circuits. Altered, defective or disrupted balance ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N15/864C12N15/12A61K48/00A61K38/17A61P25/08A61P25/00
CPCC12N15/86C12N2750/14143C12N2830/008C12N2830/48A61K48/005A61K48/0058C07K14/705A61K38/00A61K35/30C07H21/04C07K14/47A61K48/00A61P25/08C12N2830/001C12N2750/14123
Inventor J·迪米施斯坦G·菲舍尔O·德温斯基
Owner THE BROAD INST INC
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