AAV capsids with increased tropism to brain tissue
Inventors
Nonnenmacher, Mathieu E. • Hou, Jinzhao • Wang, Wei • Child, Matthew • Li, Shaoyong
Assignees
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Publication Number
US-12577588-B2
Publication Date
2026-03-17
Expiration Date
Abstract
The disclosure relates to compositions, methods, and processes for the preparation, use, and/or formulation of adeno-associated virus capsid proteins, wherein the capsid proteins comprise targeting peptide inserts for enhanced tropism to a target tissue.
Core Innovation
The disclosure concerns an engineered adeno-associated virus (AAV) capsid variant comprising a targeting-peptide sequence in hypervariable loop VIII [procedural detail omitted for safety]. The claims cover a polynucleotide encoding this capsid variant as well as a vector comprising the polynucleotide. This capsid variant exhibits increased tropism for brain cells or brain tissue compared with a wild-type AAV9 capsid.
The disclosure presents AAV particles carrying therapeutic payloads for delivery to the central nervous system and peripheral tissues. Screening results from an RNA-expression platform in non-transgenic animals and nonhuman primates demonstrate enhanced central nervous system tropism, improved blood-brain-barrier penetration, elevated vector-genome levels, and increased payload expression. Certain variants further exhibit reduced targeting to dorsal root ganglia while maintaining delivery to the brain and spinal cord.
Claims Coverage
The patent claims define two inventive features across two independent claims directed to an adeno-associated virus capsid variant with increased brain tropism.
Polynucleotide encoding an AAV capsid variant
Independent claim 1 covers a polynucleotide encoding an AAV capsid variant comprising a targeting-peptide sequence in hypervariable loop VIII [procedural detail omitted for safety], wherein the variant exhibits increased tropism for brain cells or brain tissue compared with a wild-type AAV9 capsid.
Vector comprising a polynucleotide encoding an AAV capsid variant
Independent claim 16 covers a vector comprising a polynucleotide encoding an AAV capsid variant comprising a targeting-peptide sequence in hypervariable loop VIII [procedural detail omitted for safety], wherein the variant exhibits increased tropism for brain cells or brain tissue compared with a wild-type AAV9 capsid.
The two independent claims cover the brain-tropic AAV capsid variant in polynucleotide and vector forms, each requiring hypervariable loop VIII modification and increased tropism for brain cells or brain tissue relative to wild-type AAV9.
Stated Advantages
Increased tropism for brain cells or brain tissue compared with a wild-type AAV9 capsid.
Increased AAV transduction of the central nervous system and other tissues relative to a parent capsid.
Improved blood-brain-barrier penetration.
Broader distribution across brain regions.
Higher brain transgene expression and increased payload expression relative to wild-type AAV9.
Elevated delivery of viral genomes or payloads to brain and spinal-cord regions relative to wild-type AAV9.
Reduced targeting to dorsal root ganglia while maintaining delivery to brain and spinal cord regions.
Documented Applications
Delivery of therapeutic payloads or viral genomes to the brain, central nervous system, and spinal-cord regions using polynucleotides, vectors, and AAV particles.
Selection of capsids in non-transgenic animals using the TRACER RNA-expression screening platform.
Therapeutic use of AAV capsid-variant particles for neurological, neurodegenerative, muscular, neuromuscular, and central nervous system oncological disorders via systemic or direct delivery for protein expression or RNAi.
Brain-directed AAV transduction involving the central nervous system, peripheral nervous system, and muscle, as well as disease treatment.
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