Compositions and methods for the treatment of Parkinson's disease
Inventors
Ravina, Bernard • Kells, Adrian Philip
Assignees
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Publication Number
US-12319929-B2
Publication Date
2025-06-03
Expiration Date
Abstract
The present disclosure relates to methods, formulations and devices for the delivery and therapeutic administration of polynucleotides encoding AADC. The present disclosure relates to methods, formulations and devices for the delivery and therapeutic administration of AAV vectors which include polynucleotides encoding AADC. The present disclosure relates to methods, formulations and devices for the delivery and therapeutic administration of polynucleotides encoding AADC in the treatment of neurological diseases, disorders and conditions, including Parkinson's Disease.
Core Innovation
The invention relates to administering a pharmaceutical composition comprising an adeno-associated virus (AAV) with an AAV2 capsid and a vector genome. The vector genome comprises a nucleotide sequence having at least 99% nucleotide sequence identity to SEQ ID NO: 979, and the disclosure relates to AADC-related genetic material and AADC (DDC) polynucleotides in the context of Parkinson’s Disease treatment.
The document also describes vector genome architecture concepts including promoter and polyA components, payload-region architecture associated with inverted terminal repeats (ITRs), and AAV vector genome formats such as self-complementary AAV and single-stranded AAV. It further describes AAV manufacturing and formulation approaches for generating rAAV2 particles, including bacterial/bacmid co-transfection with viral replication cells and mammalian transient transfection in HEK293, together with downstream processing and purification approaches such as ion exchange chromatography and ultracentrifugation.
For administration and use, the disclosure targets treatment in the central nervous system, including the putamen, in the context of Parkinson’s Disease. It also describes pharmaceutical formulation composition and administration routes directed to CNS regions, with formulation targets including salts, an excipient component, and a pH between 7.0 and 7.5, together with quantitative delivery attributes within disclosed ranges.
Claims Coverage
The consolidated claim coverage centers on two core methods: administering a pharmaceutical composition comprising an AAV2 capsid and a vector genome with at least 99% nucleotide sequence identity to SEQ ID NO: 979, and treating Parkinson’s Disease using the same type of composition. Across the claim set, the inventive features emphasize the AAV2 capsid and the high-identity nucleotide sequence constraint to SEQ ID NO: 979, with dependent refinements focusing on specific sequence and administration constraints.
AAV2 capsid with high-identity vector genome sequence
The pharmaceutical composition comprises an adeno-associated virus (AAV) which comprises an AAV2 capsid and a vector genome, wherein the vector genome comprises a nucleotide sequence which has at least 99% nucleotide sequence identity to SEQ ID NO: 979.
Parkinson's Disease treatment using AAV2 and high-identity vector genome
Administering a pharmaceutical composition comprising an adeno-associated virus (AAV) which comprises an AAV2 capsid and a vector genome, wherein the vector genome comprises a nucleotide sequence which has at least 99% nucleotide sequence identity to SEQ ID NO: 979.
Nucleotide sequence embodiment as SEQ ID NO: 980
A nucleotide sequence that has at least 99% sequence identity to SEQ ID NO: 979, wherein the sequence is SEQ ID NO: 980.
Transfrontal surgical infusion into putamen with coverage
Administering the pharmaceutical composition via transfrontal surgical infusion into at least one putamen, achieving an average total putaminal coverage of 30-50%.
Per-putamen administration volume ceiling
Administering the pharmaceutical composition at a volume of up to 1800 μL per putamen.
Total viral dosage range
Administering the pharmaceutical composition at a total viral dosage ranging from 2.0×10^12 vg to 9.4×10^12 vg.
Formulation with specified excipients and pH range
Using a pharmaceutical formulation containing sodium chloride, sodium phosphate, and pluronic acid F-68 with a pH between 7.0 and 7.5.
Claim coverage is centered on administration and treatment methods using an AAV2 capsid and a vector genome defined by at least 99% nucleotide sequence identity to SEQ ID NO: 979. Dependent refinements further narrow specific sequence embodiments, route and target constraints, quantitative delivery limits, and formulation composition with a specified pH window.
Stated Advantages
Minimal SAEs are reported in the document.
Pharmacodynamic effects are described, including AADC enzyme activity measured by 18F-DOPA PET and dopamine increases.
Clinical outcomes are described as improvements, including UPDRS changes and levodopa dose reductions.
Documented Applications
Parkinson’s Disease treatment in a subject using a pharmaceutical composition comprising an AAV2 capsid and a vector genome having at least 99% nucleotide sequence identity to SEQ ID NO: 979.
Parkinson’s disease clinical delivery/regimens, including posterior bilateral putaminal infusion approaches and alternative CNS targets such as SNpc, VTA, STN, or intrastriatally.
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