KR-102961646-B1 - GENE DELIVERY VEHICLE COMPRISING IL-17A EXPRESSION SEQUENCE AND PHAMACEUTICAL COMPOSITION FOR TREATING NEURODEVELOPMENTAL DISORDER COMPRISING THE SAME

Abstract

The present invention relates to a recombinant gene delivery vehicle that specifically overexpresses IL-17a in brain neurons and a pharmaceutical composition for treating neurodevelopmental disorders containing the same. The present invention provides an effect of improving symptoms of neurodevelopmental disorders through the expression or overexpression of IL-17a in specific neurons of the brain.

Inventors

• 이은이
• 이유경
• 권호근

Assignees

• 연세대학교 산학협력단

Dates

Publication Date

20260508

Application Date

20250627

Claims (8)

1. Double floxed inverted orientation (DIO) system; A nucleotide sequence encoding interleukin-17a (IL-17a); and A pharmaceutical composition for treating neurodevelopmental disorders comprising a gene delivery vehicle containing a neuron-specific promoter that regulates the expression of Cre recombinase, A pharmaceutical composition for treating neurodevelopmental disorders that overexpresses IL-17a in a Cre recombinase-dependent manner in target cells, including excitatory or inhibitory neurons located in the cerebral cortex and hippocampus .
2. In paragraph 1, A pharmaceutical composition in which the gene delivery vehicle is one or more selected from the group consisting of adeno-associated virus (AAV) vectors, lentivirus vectors, retrovirus vectors, adenovirus vectors, plasmids, vaccinia virus vectors, herpes simplex virus (HSV) vectors, and non-viral nanoparticle vectors.
3. In paragraph 2, Adeno-associated virus vectors contain AAV capsid proteins, and A pharmaceutical composition in which the AAV capsid protein is one selected from the group consisting of AAV1, AAV2, AAV4, AAV6, AAV9, AAVrh10, and AAV-PHP.Eb.
4. In paragraph 1, A pharmaceutical composition for a neurodevelopmental disorder, autism spectrum disorder, communication disorder, attention deficit hyperactivity disorder, tic disorder, dyslexia, Rett syndrome, intellectual disability, or behavioral disorder.
5. In paragraph 1, A pharmaceutical composition for the treatment of neurodevelopmental disorders that increases interaction, improves communication skills, reduces repetitive behaviors, improves self-regulation skills, improves motor and sensory functions, restores social functions, improves attention, or improves learning functions.
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Description

Gene delivery vehicle comprising IL-17a expression sequence and pharmaceutical composition for treating neurodevelopmental disorders comprising the same The present invention relates to a recombinant gene delivery vehicle that specifically overexpresses IL-17a in brain neurons and a pharmaceutical composition for treating neurodevelopmental disorders containing the same. Autism Spectrum Disorder (ASD) is a complex neurodevelopmental disorder characterized by deficits in social interaction and communication, as well as restricted and repetitive behavioral patterns. ASD typically manifests during infancy or childhood, and symptoms can persist throughout life. ASD exhibits highly variable phenotypes and shows significant individual differences in intelligence, language ability, sensory sensitivity, and behavioral patterns. Although the pathophysiology of ASD has not yet been clearly elucidated, it is known that genetic and environmental factors interact in a complex manner. In particular, numerous studies suggest that immune system abnormalities, such as maternal immune activation, infection and fever, and inflammatory bowel disease (IBD), can affect fetal brain development and contribute to autistic behavior. These findings support the close link between immune responses and neurodevelopment. Cytokines are a major group of proteins that regulate immune responses and have been found to be involved not only in mediating inflammatory reactions but also in the development and maintenance of central nervous system function. In particular, changes in the expression of specific cytokines can affect synapse formation, neuronal differentiation, and survival in the brain, which can ultimately lead to abnormalities in neural circuits and behavioral disorders. Accordingly, there is an increasing number of reports indicating that changes in cytokine concentrations are associated with the onset and symptoms of neurodevelopmental disorders, particularly autism spectrum disorders (see Saghazadeh A, Ataeinia B, Keynejad K, Abdolalizadeh A, Hirbod-Mobarakeh A, Rezaei N. Anti-inflammatory cytokines in autism spectrum disorders: A systematic review and meta-analysis. Cytokine. 2019 Nov; 123:154740. doi: 10.1016/j.cyto.2019.154740. Epub 2019 Jun 19.). Interleukin-17a (IL-17a) is a representative inflammatory cytokine secreted by Th17 cells that has primarily garnered attention for its role in infection defense and autoimmune diseases. However, there is now a possibility that IL-17a acts as a molecular link capable of influencing neurodevelopment and behavior, extending beyond its traditional immune-modulating functions. Consequently, the regulation of specific cytokines, including IL-17a, can serve as a crucial biological target for understanding the mechanisms of neurodevelopmental disorders—particularly autism spectrum disorder—and for developing new therapies. Figure 1a shows the results of analyzing cytokine concentrations and immune cell populations in the peripheral and central nervous systems of Shank2 WT (wild type) and KO (knockout) mice. Figure 1b shows the results of confirming cytokine concentrations in the brain parenchyma. Figure 2a shows the results of an in situ hybridization analysis to confirm IL-17a expression. Figure 2b shows a fluorescently tagged gene delivery vehicle for confirming IL-17a expression and the analysis results using it. Figure 2c shows the gene delivery vehicle and immunohistochemical staining results for confirming IL-17a expression. Figure 2d shows the results of confirming IL-17a expression in inhibitory neurons of the brain parenchyma. Figure 3a is a schematic diagram of a behavioral experiment of an IL-17a-expressing Shank 2 mouse using an AAV vector. Figure 3b shows the results of confirming IL-17a concentrations throughout the brain parenchyma using ELISA when the DIO-GFP virus was applied. Figure 3c shows the results of a direct interaction test during the behavioral analysis of mice. Figure 4a shows the results of confirming intrinsic excitability during the analysis of electrophysiological characteristics of a conditioned mouse identical to the behavioral analysis. Figure 4b shows the results of the spontaneous excitatory postsynaptic current (sEPSC) experiment during the analysis of electrophysiological characteristics of a conditioned mouse identical to the behavioral analysis. Figure 4c shows the results of the NMDA/AMAP ratio analysis during the analysis of electrophysiological characteristics of conditioned mice identical to the behavioral analysis. Figure 5a shows the results of a mouse behavioral experiment in which IL-17R was deleted in neurons. Figure 5b shows the results of the analysis of electrophysiological characteristics of mice when IL-17R is deleted. Figure 6 shows the results of a mouse behavioral experiment when IL-17a was administered via the intranasal method. Throughout this specification, when a part is described as “comprising” a certain component, it means th