Methods of treating and diagnosing epilepsy
Inventors
BORDEY, Angelique • Hsieh, Lawrence • ZHOU, Jianbing
Assignees
Publication Number
US-12274756-B2
Publication Date
2025-04-15
Expiration Date
2040-03-04
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Abstract
In various aspects and embodiments the invention provides a method of treating epilepsy in a subject in need thereof, the method comprising contacting a target cell of the subject with an effective amount of an HCN4 disrupting agent.
Core Innovation
The invention provides methods for treating and diagnosing epilepsy by targeting HCN4 channels in neurons associated with epileptic activity. Specifically, the method of treating epilepsy involves contacting a target cell—such as a focal cortical malformation (FCM) neuron—with an effective amount of an HCN4 disrupting agent. This agent disrupts or eliminates HCN4 expression or activity to prevent seizure activity in the subject.
HCN4 disrupting agents can include a viral vector encoding a non-functional HCN4 (HCN4NF), antisense RNA, antigomer RNA, siRNA, shRNA, or a CRISPR system designed to reduce or eliminate HCN4 activity. The patent also describes pharmaceutical compositions and delivery methods, such as adenoviral vectors and encapsulation in liposome-templated hydrogel nanoparticles (LHNPs), for effective delivery of these agents to specific neurons implicated in epilepsy.
In addition, the invention encompasses methods for diagnosing epilepsy using HCN4 detecting agents, such as labeled antibodies or PET tracers that bind HCN4, enabling localization and identification of diseased neurons or regions requiring surgical intervention. This approach addresses the identified need for improved treatment and diagnosis of epilepsy, especially forms associated with mTOR hyperactivity like focal cortical dysplasia type II (FCDII) and tuberous sclerosis complex (TSC).
Claims Coverage
The patent claims include one independent inventive feature focused on a specific method of treating epilepsy using a defined genetic approach.
Method of treating epilepsy using an adenoviral vector comprising polynucleotide encoding HCN4NF
This feature describes contacting a target cell of a subject with an effective amount of an HCN4 disrupting agent. The HCN4 disrupting agent is explicitly defined as an adenoviral vector that includes a polynucleotide encoding a non-functional HCN4 (HCN4NF) variant. The HCN4NF variant is characterized by the mutations G480A and G482A relative to the HCN4 amino acid sequence as set forth in SEQ ID NO: 1. This approach is specified for use in treating epilepsy in a subject in need thereof, with the activity of HCN4 being disrupted through the introduced genetic material.
The patent’s claim coverage centers on the use of an adenoviral vector encoding a specific mutant HCN4 (HCN4NF with G480A and G482A mutations) as the disrupting agent for treating epilepsy by targeting HCN4 activity in affected cells.
Stated Advantages
The targeted disruption of HCN4 prevents the onset and progression of seizures in subjects with epilepsy.
Blocking HCN4 activity provides a highly specific gene therapy target for epilepsy associated with FCDII and TSC, potentially reducing adverse events compared to systemic treatments like rapamycin.
Detecting ectopic HCN4 expression allows for improved diagnosis, delineation, and surgical planning for focal cortical malformations in epilepsy.
The approach is applicable to a broad range of epilepsies linked to mTORopathies and related genetic disorders.
Documented Applications
Treatment of epilepsy, including mTORopathies, by disrupting HCN4 activity in target cells such as FCM neurons.
Diagnosis of epilepsy and identification of diseased brain regions by administering HCN4 detecting agents (e.g., labeled antibodies or PET tracers).
Surgical resection planning by visualizing HCN4-positive neurons to delineate areas for removal.
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