Compositions and methods to restore paternal UBE3A gene expression in human Angelman syndrome
Inventors
Chamberlain, Stormy • GERMAIN, Noelle
Assignees
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Publication Number
US-12221609-B2
Publication Date
2025-02-11
Expiration Date
Abstract
The present invention relates to compositions and methods for activating expression from the paternally-inherited allele of UBE3A in human Angelman's Syndrome neurons using viral vector delivery of short hairpin RNAs, ribozymes, and/or microRNAs.
Core Innovation
The invention relates to compositions and methods for treating human Angelman syndrome by restoring paternal UBE3A expression in neurons. UBE3A is described as being expressed only from the maternal allele, and paternal UBE3A is silenced by a long non-coding UBE3A antisense transcript (UBE3A-ATS). The described approach inhibits the silencing of the paternal UBE3A gene by inhibiting or reducing UBE3A-ATS.
The invention provides RNA therapeutics that target UBE3A-ATS, where the target is defined as UBE3A-ATS encoded by SEQ ID NO:1. The disclosed RNA therapeutic designs include short hairpin RNA (shRNA), ribozymes, and microRNAs (miRNA) configured to inhibit UBE3A-ATS through cutting, reducing, or terminating UBE3A-ATS such that paternal UBE3A expression is reactivated. The shRNA nucleotide sequence encoding SEQ ID NO:2 is described as inhibiting the silencing of paternal UBE3A.
The disclosed therapeutics are delivered using viral-vector delivery, including lentiviral vectors and adeno-associated virus (AAV) vectors. The compositions include expression vectors and pharmaceutical compositions configured for neuron/brain delivery, with examples including AAV9. The document describes using sequence-defined inhibitors of UBE3A-ATS to achieve reduction of UBE3A-ATS and activation of paternal UBE3A in the context of Angelman syndrome.
Claims Coverage
The independent claim coverage in the provided material consists of a single independent polynucleotide claim. The claim is directed to an shRNA-encoding polynucleotide with a specified sequence (SEQ ID NO:2) that inhibits silencing of the paternal UBE3A gene.
shRNA polynucleotide inhibiting paternal UBE3A silencing with SEQ ID NO: 2
A polynucleotide comprising a nucleotide sequence encoding an shRNA capable of inhibiting the silencing of a paternal UBE3A gene, wherein the nucleotide sequence encoding the shRNA consists of SEQ ID NO: 2.
Based on the provided independent claim, the principal inventive subject matter is an shRNA-encoding polynucleotide with a specified nucleotide sequence (SEQ ID NO:2) that inhibits silencing of the paternal UBE3A gene.
Stated Advantages
Restoring paternal UBE3A expression in neurons for treating Angelman syndrome.
Reducing or inhibiting the UBE3A-ATS that mediates silencing of the paternal UBE3A gene.
Documented Applications
Treating human Angelman syndrome by restoring paternal UBE3A expression in neurons.
Administering viral particles or pharmaceutical compositions to the brain in patient treatment (as stated for certain method claims).
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