Compositions and methods for treating Huntington's disease
Inventors
Sah, Dinah Wen-Yee • Hou, Jinzhao • Zhou, Pengcheng • Wang, Xin • Deckert, Jochen • Hossbach, Markus
Assignees
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Publication Number
US-11951121-B2
Publication Date
2024-04-09
Expiration Date
Abstract
The present invention relates to small interfering RNA (siRNA) molecules against the HTT gene, adeno-associated viral (AAV) vectors encoding siRNA molecules and methods for treating Huntington's Disease (HD) using the siRNA molecules and AAV vectors.
Core Innovation
The disclosed subject matter includes HTT-targeting modulatory polynucleotides comprising the nucleotide sequence of SEQ ID NO: 349, including siRNA duplexes and pri-miRNA or shRNA expression constructs. It describes an adeno-associated viral (AAV) vector genome comprising a nucleic acid sequence positioned between two inverted terminal repeats (ITRs) encoding the modulatory polynucleotide. These constructs are configured to reduce HTT gene, mRNA, and protein expression within central nervous system cells, including medium spiny neurons, cortical neurons, and astrocytes.
The disclosure further encompasses vector-genome design options, capsid variants, inverted terminal repeat arrangements, regulatory components, and delivery systems to facilitate the treatment of Huntington's disease. Experimental summaries report huntingtin suppression by adeno-associated viral constructs in cultured human cell models and animal striatal tissue. Because the background section is not included in the supplied material, the specific problem being solved is not explicitly described in patent.
Claims Coverage
The claims define four inventive features across independent claims directed to compositions and methods for HTT modulation.
Modulatory polynucleotide comprising SEQ ID NO: 349
A modulatory polynucleotide comprising the nucleotide sequence of SEQ ID NO: 349.
AAV vector genome encoding a modulatory polynucleotide
An AAV vector genome comprising a nucleic acid sequence positioned between two inverted terminal repeats (ITRs), wherein the nucleic acid sequence encodes a modulatory polynucleotide comprising the nucleotide sequence of SEQ ID NO: 349.
Inhibition of HTT expression in a cell
A method of inhibiting HTT gene, mRNA, and/or protein expression in a cell comprising contacting the cell with an AAV vector genome encoding a modulatory polynucleotide comprising the nucleotide sequence of SEQ ID NO: 349.
Treatment of Huntington's disease in a subject
A method of treating Huntington's disease in a subject comprising administering an effective amount of an AAV vector genome encoding a modulatory polynucleotide comprising the nucleotide sequence of SEQ ID NO: 349.
Together, the four inventive features cover the specified modulatory polynucleotide, an AAV vector genome encoding it between two ITRs, and associated methods for inhibiting cellular HTT expression and treating Huntington's disease in a subject.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treatment or amelioration of Huntington's disease in a subject using the HTT-targeting modulatory polynucleotide and AAV vector genome.
Inhibition of HTT gene, mRNA, and/or protein expression in a cell, including silencing wild-type or mutant HTT in central nervous system cell types such as medium spiny neurons, cortical neurons, and astrocytes.
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