AAV capsids with increased tropism to brain tissue
Inventors
Nonnenmacher, Mathieu E. • Hou, Jinzhao • Wang, Wei • Child, Matthew • Li, Shaoyong
Assignees
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Publication Number
US-11859200-B2
Publication Date
2024-01-02
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 disclosed invention is an adeno-associated virus (AAV) capsid variant comprising a targeting peptide insert [procedural detail omitted for safety] in hypervariable loop VIII. The variant exhibits increased tropism for brain cells or brain tissue compared with a wild-type AAV9 capsid. The disclosure further describes alternative capsid backgrounds, hybrid capsids, encoding polynucleotides, and modifications outside the specified insertion region.
The disclosure reports enhanced central nervous system transduction and payload delivery, showing preferential brain transduction over dorsal root ganglia. Transgene expression and vector-genome abundance exceed wild-type AAV9 levels across selected cortical and subcortical tissues, demonstrating blood-brain barrier penetration and elevated transduction signals. Because the background section is omitted in the provided content, the background problem being solved is not explicitly described in the patent.
Claims Coverage
The claims identify two inventive features directed to an AAV capsid variant and isolated cells containing the variant.
AAV capsid variant with increased brain tropism
An adeno-associated virus (AAV) capsid variant comprises a targeting-peptide sequence [procedural detail omitted for safety] in hypervariable loop VIII, wherein the variant has increased tropism for brain cells or brain tissue compared with a wild-type AAV9 capsid.
Isolated cell from specified brain or spinal-cord regions or a neuron
An isolated mammalian or insect cell containing the AAV capsid variant is from one or more specified brain or spinal-cord regions, or is a neuron, sensory neuron, or motor neuron.
The claims cover the specified AAV capsid variant exhibiting enhanced brain tropism relative to wild-type AAV9, as well as isolated cells comprising the variant. Dependent claims further specify capsid sequences, payload delivery particles, increased tropism thresholds after intravenous injection, and specific central nervous system tissue transduction.
Stated Advantages
The claimed AAV capsid variant has increased tropism for brain cells or brain tissue compared with a wild-type AAV9 capsid, with a dependent claim specifying at least five-fold greater tropism.
The disclosure describes increased central nervous system and brain-region transduction, payload delivery, enhanced blood-brain barrier penetration, and preferential brain transduction over dorsal root ganglia.
The variant provides substantially higher transgene expression and vector-genome abundance than wild-type AAV9 across selected brain regions.
Peptide inserts can increase AAV transduction of central nervous system, peripheral nervous system, dorsal root ganglia, and muscle cells or tissues relative to a parent capsid.
Documented Applications
Transduction of brain cells or brain tissue, including the cerebral cortex, cerebellar cortex, brain stem, hippocampus, thalamus, putamen, and dentate nucleus, following intravenous or direct central nervous system administration.
AAV particles carrying genetic payloads, including therapeutic protein, antibody, gene-editing, or RNAi payloads such as APOE, SMN1, SMN2, AADC, and ASPA, for neurological, neurodegenerative, neuromuscular, and neuro-oncological disorders.
Transduction of central nervous system, peripheral nervous system, dorsal root ganglia, and muscle cells or tissues via intravenous injection into a subject.
Isolated mammalian or insect cells comprising the AAV capsid variant, including sensory neurons, motor neurons, and cells from brain or spinal-cord regions.
Use of the TRACER platform for selecting capsid variants in non-transgenic animals.
Interested in licensing this patent?