AADC polynucleotides for the treatment of Parkinson's disease
Inventors
Kotin, Robert • Kells, Adrian Philip • Ravina, Bernard
Assignees
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Publication Number
US-11975056-B2
Publication Date
2024-05-07
Expiration Date
Abstract
The disclosure relates to compositions and methods for the preparation, manufacture and therapeutic use of polynucleotides encoding AADC for the treatment of Parkinson's Disease.
Core Innovation
The invention describes a polynucleotide encoding aromatic L-amino acid decarboxylase (AADC), comprising a sequence at least 95% identical to SEQ ID NO: 17 and 5′ and 3′ inverted terminal repeats (ITRs) each at least 130 nucleotides in length. Described expression-cassette components include CMV enhancer and promoter sequences, IE1 and human beta-globin elements, an AADC coding region, and an hGH poly(A) signal. Contemplated delivery utilizes a recombinant adeno-associated virus (rAAV) vector.
The described technology applies to gene therapy for Parkinson’s disease and AADC deficiency, including brain infusion targeting the putamen to address motor symptoms and dyskinesia. Examples report that the phAADC_3k construct produces up to 200% greater striatal AADC expression in rats relative to a standard construct. A study of full and empty AAV particles reports comparable distribution across ratios and a trend toward lower expression when empty particles exceed 30%.
Claims Coverage
The relevant claims identify one independent claim directed to an AADC-encoding polynucleotide, reciting one inventive feature.
AADC-encoding polynucleotide with specified sequence identity and ITRs
The claim covers a polynucleotide encoding an AADC protein comprising a sequence at least 95% identical to SEQ ID NO: 17, a 5′ ITR at least 130 nucleotides in length, and a 3′ ITR at least 130 nucleotides in length.
The independent claim centers on the AADC-encoding polynucleotide, its sequence identity to SEQ ID NO: 17, and the minimum lengths of its 5′ and 3′ ITRs. The claim summaries further describe expression-cassette regions, rAAV capsids, pharmaceutical compositions, and methods for increasing AADC protein levels or addressing specified clinical effects.
Stated Advantages
The described methods are intended to increase AADC protein levels.
The described treatment is intended to reduce periods of dyskinesia and address Parkinson’s motor symptoms.
Examples report up to 200% greater striatal AADC expression in rats with the phAADC_3k construct than with a standard construct.
Documented Applications
AAV-mediated gene therapy for Parkinson’s disease and AADC deficiency, including central nervous system delivery and brain infusion directed to the putamen.
Administration of an rAAV-containing pharmaceutical composition to increase AADC protein levels, treat insomnia, or reduce periods of dyskinesia.
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