AAV capsid variants and uses thereof
Inventors
Nonnenmacher, Mathieu Emmanuel • Moyer, Tyler Christopher • Li, Jiangyu • Laks, Dan Richard
Assignees
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Publication Number
US-12419969-B2
Publication Date
2025-09-23
Expiration Date
Abstract
The disclosure relates to compositions and methods for the preparation, use, and/or formulation of adeno-associated virus capsid protein variants.
Core Innovation
The disclosure relates to adeno-associated virus (AAV) capsid variants and encoding polynucleotides for tissue-directed delivery and altered organ tropism. The variants comprise an amino acid sequence at least 95% identical to amino acids 203–742 of SEQ ID NO: 981 and include the SPHSKA motif in variable region IV, or comprise SEQ ID NO: 981. These variants are incorporated into AAV particles, conjugated to therapeutic agents, or associated with delivery carriers.
The capsid variants exhibit enhanced central nervous system tropism, demonstrated by blood–brain barrier penetration and elevated brain and spinal-cord enrichment relative to AAV9 in non-human primates and mice. Experimental characterization indicates increased brain transgene expression alongside reduced liver and dorsal root ganglia biodistribution. Because the background section is omitted from the available text, the specific underlying technical problem is not explicitly described in patent.
Claims Coverage
The claims identify four independent claims covering four inventive features: an AAV capsid variant containing a specified motif in variable region IV, a sequence-defined AAV capsid variant, a polynucleotide encoding a capsid variant, and an AAV particle comprising a capsid variant.
AAV capsid variant with a variable region IV motif
Claim 1 covers an AAV capsid variant comprising an amino acid sequence at least 95% identical to amino acids 203–742 of SEQ ID NO: 981, wherein the amino acid sequence comprises SPHSKA (SEQ ID NO: 941) in variable region IV (VR-IV).
Sequence-defined AAV capsid variant
Claim 19 covers an AAV capsid variant comprising the amino acid sequence of SEQ ID NO: 981.
Polynucleotide encoding an AAV capsid variant
Claim 22 covers a polynucleotide encoding an AAV capsid variant comprising an amino acid sequence at least 95% identical to amino acids 203–742 of SEQ ID NO: 981, wherein the amino acid sequence comprises SPHSKA in variable region IV.
AAV particle comprising a capsid variant
Claim 25 covers an AAV particle comprising an AAV capsid variant comprising an amino acid sequence at least 95% identical to amino acids 203–742 of SEQ ID NO: 981, wherein the amino acid sequence comprises SPHSKA in variable region IV.
The independent claims cover sequence-defined AAV capsid variants, an encoding polynucleotide, and an AAV particle comprising the variant, while dependent claims address sequence modifications, payload delivery, production methods, administration routes, and target tissues.
Stated Advantages
The reported capsid variants show greater brain and spinal-cord enrichment than AAV9, including blood–brain barrier penetration, broader brain distribution, and increased payload expression.
TTM-001 shows increased brain expression and higher brain transgene mRNA and viral DNA levels across cynomolgus macaques, African green monkeys, marmosets, and mice after intravenous administration.
TTM-002 shows enhanced central nervous system biodistribution and expression in African green monkeys following intravenous delivery.
Reported variants such as TTM-002 show reduced liver biodistribution and dorsal root ganglia targeting alongside increased heart expression relative to AAV9.
Mouse maturation screening results associate retention of the specified motif with up to approximately eightfold enrichment over the parent TTM-001 in mouse brain, while certain variants provide liver-preferential tropism or reduced CNS tropism.
The TRACER screening result provides selection of cell-specific capsids.
Documented Applications
Delivery of payloads, including proteins, antibodies, enzymes, or inhibitory RNA, to central nervous system cells or tissues such as neurons, motor neurons, astrocytes, glial cells, oligodendrocytes, brain tissue, and spinal-cord tissue for treating neurological, neuromuscular, genetic, and neuro-oncological disorders.
Tissue-directed transduction involving neural cell types, endothelial cells, liver, heart, skeletal muscle, and dorsal root ganglia.
AAV particle payload delivery via intravenous, intra-cisterna magna, intracerebral, intrathecal, intracerebroventricular, intraparenchymal, or intramuscular administration.
Making an AAV particle using a host cell containing a viral genome and a polynucleotide encoding the capsid variant, and applying TRACER screening results for selecting cell-specific capsids.
Conjugation of peptides to therapeutic or diagnostic agents and association of peptides with delivery carriers, including exosomes and lipid nanoparticles.
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