AAV Capsid Variants for Joint Delivery
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Solution Overview
Problem
Current treatments for osteoarthritis primarily focus on alleviating symptoms, with no cure or method to stop its progression, and existing delivery methods for therapeutic agents often elicit a neutralizing immune response, limiting their effectiveness.
Innovation Solution
The use of recombinant adeno-associated virus (rAAV) vectors with specific capsid protein variants that are efficiently packaged and tropic to arthritic tissues, allowing for intra-articular delivery of anti-inflammatory transgenes to reduce inflammation in joints without eliciting a neutralizing immune response.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If wild-type AAV vectors are used for delivering therapeutic agents to joints, then delivery can be achieved, but a neutralizing immune response is elicited that limits effectiveness
Solution Approach 1:
The patent applies parameter changes by modifying the capsid protein sequence of AAV vectors to create variants with altered immunogenicity properties. Specific amino acid substitutions in the capsid protein are designed to reduce recognition by pre-existing neutralizing antibodies while maintaining viral function and transduction efficiency, thereby resolving the contradiction between delivery effectiveness and immune response
2Quantity of substance
If existing delivery methods are used to deliver therapeutic agents to arthritic tissues, then some delivery is achieved, but the neutralizing immune response limits therapeutic effectiveness
Solution Approach 1:
The invention modifies the capsid protein parameters (amino acid sequence) to create variants that are less immunogenic. This allows for adequate delivery quantity of therapeutic agents to arthritic tissues while avoiding the neutralizing immune response that would otherwise limit therapeutic effectiveness
3Ease of manufacture
If standard AAV capsid proteins are used, then packaging and delivery can proceed, but immune recognition occurs that reduces treatment success
Solution Approach 1:
The patent employs parameter changes by introducing specific amino acid substitutions in the capsid protein sequence that reduce immune recognition. These modified capsid proteins maintain their ability to be packaged into rAAV particles and deliver therapeutic cargo, but exhibit reduced immunogenicity, thus resolving the contradiction between ease of manufacture and immune recognition
Data Source
AI summary
Aspects of the disclosure relate to compositions and methods for delivering a transgene (e.g., an anti-inflammatory transgene encoding one or more gene products) to a joint. The disclosure is based, in part, on adeno-associated virus (AAV) capsid protein variants characterized by tropisms for joint tissues (e.g., cartilage, skin, muscle, and bone cells). Methods of treating arthritis in a joint by administering an rAAV comprising the AAV capsid protein variants are also described by the disclosure.