Surface-Bound Peptide AAV Particles for BBB Transduction
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Solution Overview
Problem
The blood-brain barrier poses a significant obstacle for the systemic delivery of adeno-associated virus (AAV) vectors, limiting their efficacy in transducing neurons across the central nervous system due to low transduction efficiency in adults.
Innovation Solution
The use of AAV particles modified with surface-bound peptides such as Angiopep-2, GSH, HIV-1 TAT (48-60), ApoE (159-167), Leptin 30 (61-90), THR, PB5-3, PB5-5, or PB5-14 enhances transduction across the blood-brain barrier, improving delivery to brain and central nervous system cells.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If AAV vectors are administered systemically to deliver genes across the blood-brain barrier, then the ability to treat neurodegenerative disorders is improved, but the transduction efficiency is reduced due to the BBB obstacle
Solution Approach 1:
The patent uses transcytosis mediators (such as antibodies, peptides, or other molecules that bind to BBB transport receptors) as intermediaries to facilitate AAV vector crossing of the blood-brain barrier. These mediators temporarily enable the AAV particles to traverse the BBB through receptor-mediated transcytosis, thereby improving brain delivery efficiency while maintaining systemic administration capability.
2Adaptability or versatility
If AAV9 is used to transduce parenchymal brain cells after intravenous injection, then the ability to cross the BBB is improved, but the neuron transduction efficacy is reduced in adults compared to neonates
Solution Approach 1:
The patent modifies parameters of the AAV vector system by combining AAV9 with transcytosis mediators, altering the physical-biological parameters of vector-BBB interaction. This enables adult brains to achieve transduction efficacy comparable to or exceeding neonatal levels by changing how the vector interacts with BBB transport mechanisms, rather than relying solely on the inherent properties of AAV9 alone.
3Manufacturing precision
If intraparenchymal injection is used to deliver AAV vectors, then the delivery to local brain area is improved, but the ability to treat disorders involving multiple brain areas is reduced
Solution Approach 1:
The patent makes the AAV vector system universal for treating multiple brain disorders by enabling systemic administration to effectively deliver vectors to multiple brain regions simultaneously. The combination with transcytosis mediators allows a single intravenous injection to achieve widespread brain distribution, making the system adaptable for treating neurodegenerative disorders that affect multiple areas rather than requiring separate injections for each target region.
Data Source
AI summary
Disclosed herein is an adeno-associated virus (AAV) particle comprising a surface-bound peptide that enhances transduction of cells across the blood-brain barrier (BBB). Also disclosed herein is a modified AAV capsid protein comprising an insertion of a polypeptide that enhances transduction of cells across the BBB, and an AAV particle comprising the modified AAV capsid protein. Specific peptides are provided. Pharmaceutical formulations and method of administering/delivering a nucleic acid to a cell of the brain and/or central nervous system are also disclosed.