Modulatory polynucleotides
Inventors
Hou, Jinzhao • Nonnenmacher, Mathieu E. • Zhou, Pengcheng
Assignees
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Publication Number
US-12071625-B2
Publication Date
2024-08-27
Expiration Date
Abstract
The invention relates to compositions and methods for the preparation, manufacture and therapeutic use of modulatory polynucleotides.
Core Innovation
The disclosure describes an adeno-associated virus (AAV) viral genome comprising a nucleotide sequence positioned between two inverted terminal repeats (ITRs), wherein the sequence encodes a modulatory polynucleotide. The modulatory polynucleotide is structured as an artificial pri-miRNA or pre-miRNA comprising guide and passenger strand payload regions, a 5′ flanking region, a loop region, and a 3′ flanking region selected from specified sequence options.
The constructs are directed to suppressing expression of the SOD1 gene, providing potent and specific gene modulation with reduced off-target effects. The disclosure reports SOD1 mRNA reduction by AAV-delivered modulatory polynucleotides in human motor neurons, U251MG cells, and human astrocytes, alongside reduced SOD1 protein in Tg(SOD1) mice. The background section and the problem addressed are not explicitly described in the patent.
Claims Coverage
The claim coverage includes two inventive features identified across the claims, covering an AAV viral genome encoding a modulatory polynucleotide with specified flanking and loop regions.
AAV viral genome encoding a modulatory polynucleotide
An AAV viral genome comprises a nucleotide sequence positioned between two inverted terminal repeats, wherein the nucleotide sequence encodes a modulatory polynucleotide.
Specified flanking and loop regions
The modulatory polynucleotide comprises a 5′ flanking region comprising any one of SEQ ID NOs: 1–4, a loop region comprising any one of SEQ ID NOs: 5–9, and a 3′ flanking region comprising any one of SEQ ID NOs: 10–14 or 810.
The independent claim covers the AAV genome configuration and the modulatory polynucleotide architecture with specified flanking and loop regions. Dependent claims further specify strand complementarity, inhibition of SOD1 gene expression, expression-cassette elements, capsid types, and a method of treating a central nervous system disease.
Stated Advantages
The design features are intended to provide potent and specific gene modulation with reduced off-target effects.
Documented Applications
The modulatory polynucleotide is described for inhibiting expression of the SOD1 gene.
A recombinant AAV particle is described for treating a disease of the central nervous system by administering an effective amount to a subject.
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