AAV Vectors with Peptide Insertions for Retinal Transduction
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Solution Overview
Problem
Current adeno-associated virus (AAV) vectors face challenges in efficiently transducing photoreceptors due to physical barriers and limited bioavailability, requiring invasive subretinal injections and resulting in potential collateral damage, especially in degenerated retinas.
Innovation Solution
Development of novel AAV vectors with specific peptide insertions between positions 587 and 588 of the AAV capsid, allowing for efficient intravenous delivery and targeting of retinal cells, including photoreceptors, by overcoming natural barriers and improving bioavailability and target cell specificity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If invasive subretinal injections are used to deliver AAV vectors to photoreceptors, then transduction efficiency is improved, but risk of collateral damage increases
Solution Approach 1:
The patent introduces a peptide mediator (inserted at positions 587-588 of the AAV capsid) that enables indirect delivery of AAV vectors to photoreceptors. This peptide acts as an intermediary that facilitates crossing of the blood-retina barrier and specific binding to photoreceptor cells, replacing the need for direct invasive injection while maintaining transduction efficiency.
Solution Approach 2:
The patent modifies the AAV capsid parameters by inserting specific peptide sequences at positions 587-588, which changes the vector's ability to interact with biological barriers and target cells. This parameter change enables systemic delivery via intravenous injection while maintaining photoreceptor-specific transduction, thus avoiding invasive procedures.
2Ease of operation
If AAV vectors are designed for systemic delivery, then ease of administration is improved, but target cell specificity deteriorates
Solution Approach 1:
The patent applies local quality by inserting a specific peptide sequence at a precise location (positions 587-588) in the AAV capsid structure. This localized modification confers specific properties to the vector, enabling it to recognize and bind to photoreceptor cells while circulating systemically, thus maintaining target cell specificity despite ease of systemic administration.
3Manufacturing precision
If peptide insertions are added to AAV capsid, then target cell specificity is improved, but device complexity increases
Solution Approach 1:
The patent applies partial action by inserting a relatively small peptide sequence (6-8 amino acids) at a specific location in the capsid, rather than extensively modifying the entire capsid structure. This minimal modification is sufficient to confer photoreceptor-specific targeting while maintaining overall capsid integrity and minimizing structural complexity.
Data Source
AI summary
The present invention relates to an adeno-associated virus (AAV), comprising an insertion of at least 6-8 amino acids between the positions corresponding to position 587 and 588 of SEQ ID NO: 1. Also envisioned are AAVs of the present invention for use as a medicament and pharmaceutical compositions comprising the AAV of the present invention. Further, the present invention relates to an in vitro use of AAV of the present invention for transduction of the nucleus of retinal cells. Also concerned is a method for screening an insertion sequence as well as a peptide obtainable by the method for screening. Also contemplated are kits comprising the AAV of the present invention.