Engineered AAV Capsids for CNS Targeting
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Solution Overview
Problem
Current AAV capsids used in gene therapy exhibit suboptimal targeting to tissues of interest, leading to poor infectivity and liver tropism, and pose immunological challenges, excluding pre-immune patients and limiting repeat dosing.
Innovation Solution
Development of high-throughput engineered AAV capsids with altered tropism, specifically targeting central nervous system (CNS) tissues with increased infectivity and reduced liver tropism, using recombinant viral capsids with amino acid substitutions in the 581-589 region of the VP1 polypeptide.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If naturally-occurring AAV capsids are used for gene therapy, then the treatment can be administered to patients, but the capsids exhibit poor infectivity for CNS tissues and high liver tropism
Solution Approach 1:
The patent applies parameter changes by modifying the amino acid sequence of the AAV capsid protein, specifically in the 581-589 region of the VP1 polypeptide. This sequence modification alters the capsid's biological properties, changing its tissue tropism from liver-preferential to CNS-preferential, thereby resolving the contradiction between achieving high CNS infectivity and reducing liver tropism
Solution Approach 2:
The invention applies local quality by making targeted amino acid substitutions in a specific region (581-589) of the capsid protein rather than modifying the entire capsid structure. This localized modification is sufficient to dramatically alter tissue tropism while maintaining overall capsid function and stability
2Reliability
If the dose is increased to ensure infection of desired tissues, then infectivity for CNS tissues improves, but liver toxicity increases
Solution Approach 1:
By changing the biological parameter of tissue tropism through capsid engineering, the patent enables effective CNS infection at lower doses. The modified capsid's inherent affinity for CNS tissues eliminates the need for high dosing, thereby preventing dose-dependent liver toxicity
3Adaptability or versatility
If naturally-occurring AAV capsids are used, then the therapy can be delivered, but pre-immune patient populations are excluded and repeat dosing is not possible
Solution Approach 1:
The patent applies local quality by introducing specific amino acid substitutions in the 581-589 region of the capsid that alter immunogenicity. These localized changes create a novel capsid variant that is sufficiently different from natural serotypes to evade pre-existing immunity while maintaining functional integrity for gene delivery
Solution Approach 2:
The invention changes the immunological parameter of the capsid by modifying its amino acid sequence, creating a new capsid variant with altered antigenicity. This enables treatment of pre-immune patients and allows for potential repeat dosing by escaping immune recognition
Data Source
AI summary
Disclosed herein are engineered AAV VP capsid polypeptides with the ability to assemble into virus particles and having improved tissue tropism to, for example, CNS tissues or muscle tissues. The capsids are engineered using the high throughput discovery system described herein. In certain embodiments, provided herein are recombinant adeno-associated virus (AAV) VP capsid polypeptides having at least one mutation in a 581-589 region of the VP capsid polypeptide, corresponding to residues 581 to residue 589 of a VP1 polypeptide of SEQ ID NO: 1.