Redirection of tropism of AAV capsids
Inventors
Nonnenmacher, Mathieu E. • Hou, Jinzhao • Wang, Wei • Child, Matthew • Li, Shaoyong
Assignees
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Publication Number
US-12630842-B2
Publication Date
2026-05-19
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 tor enhanced tropism to a target tissue.
Core Innovation
The disclosure describes a method of delivering a payload to a cell or tissue by administering an adeno-associated virus (AAV) particle comprising an AAV capsid variant and a payload. The capsid variant possesses at least 95% sequence identity to a specified reference capsid region and comprises a specified targeting peptide, amino-acid motif, or consecutive portion thereof positioned in a capsid loop, particularly hypervariable loop VIII. Payload types encompass proteins, antibodies, enzymes, and inhibitory RNA agents.
The targeting-peptide capsid variants exhibit increased transduction and tropism across central nervous system, peripheral nervous system, dorsal root ganglion, and muscle tissues relative to parent reference capsids. Comparative evaluation against AAV9 in nonhuman primates identifies variants, including TTD-001 through TTD-005, with broad biodistribution and elevated payload expression across brain and spinal cord regions. A screening result identifies multiple variants demonstrating enrichment over AAV9, and the TRACER platform selects capsids based on cell-specific capsid mRNA expression.
Claims Coverage
The provided claims identify one independent claim directed to an AAV-mediated method of payload delivery comprising three inventive features.
AAV-mediated payload delivery using a defined capsid variant
The independent claim recites administering an AAV particle comprising a payload and a capsid variant to deliver the payload to a cell or tissue, wherein the capsid variant possesses at least 95% sequence identity to a reference capsid region and comprises a specified targeting peptide, amino-acid motif, or at least five consecutive amino acids thereof.
Targeting-peptide location in hypervariable loop VIII
Dependent claims specify that the targeting-peptide sequence or amino-acid motif is present within hypervariable loop VIII of the AAV capsid variant via insertion or substitution.
Payload, administration routes, and target tissue refinements
Dependent claims further specify payload types including proteins, antibodies, enzymes, and inhibitory RNA; target tissues including central nervous system, brain, spinal cord, or dorsal root ganglion regions; and administration routes including intra-cisterna magna injection, intracerebral, intrathecal, intracerebroventricular, intraparenchymal, or intramuscular administration.
The independent claim centers on payload delivery using an AAV particle with a sequence-defined capsid variant, with dependent claims refining the peptide loop location, payload types, target anatomical regions, and administration routes.
Stated Advantages
The disclosure reports enhanced blood–brain barrier penetration, broader distribution across brain regions, and increased central nervous system payload expression, transduction, and tropism compared with parent capsids, including preferential brain transduction over dorsal root ganglia.
Variant TTD-001 exhibits increased enrichment over AAV9 in brain and spinal cord, markedly increased brain payload mRNA expression after intravenous dosing, and produces mRNA expression approximately 1,007–14,227 times higher than AAV9 across tested brain regions.
Variants TTD-003 and TTD-004 demonstrate increased brain transduction, with TTD-004 further reported to exhibit reduced dorsal root ganglia targeting and increased heart transduction.
Documented Applications
Delivery of payloads, including proteins, antibodies, enzymes, and inhibitory RNA agents, to target cells and tissues such as central nervous system, peripheral nervous system, dorsal root ganglion, and muscle tissues.
Targeted delivery to specific brain and spinal cord regions, including frontal, sensory, and motor cortices, caudate, dentate nucleus, cerebellar and cerebral cortices, brain stem, hippocampus, thalamus, putamen, and cervical, thoracic, and lumbar spinal cord.
Therapeutic delivery of payloads for neurological, neuromuscular, and central nervous system oncological disorders.
Administration of AAV particles via intra-cisterna magna, intracerebral, intrathecal, intracerebroventricular, intraparenchymal, or intramuscular routes for systemic or direct delivery.
Evaluation and selection of AAV capsid variants for brain and spinal cord delivery using the TRACER platform, non-human primates, and human brain microvascular endothelial cells.
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