Engineered AAV Capsid Tropism for Outer Retinal Transduction

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Solution Overview

Problem

Existing AAV serotypes have low transduction efficiency for retinal tissues, particularly the outer retinal layers, limiting their effectiveness in treating ocular diseases.

Innovation Solution

Rationally designed AAV capsid proteins with specific amino acid mutations and peptide insertions, such as RC-C14, enhance receptor binding specificity and stability, allowing efficient transduction of retinal cells.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Adaptability or versatility

If wild-type AAV serotypes are used for gene delivery, then broad tissue targeting is achieved, but transduction efficiency in specific retinal tissues (especially outer retinal layers) is reduced

Engineering Contradiction:

Improvetissue targeting rangeVSAvoidtransduction efficiency in retinal tissues

Core Design Contradiction:

Adaptability or versatilityVSProductivity

Solution Approach 1:

The patent applies local quality by making specific amino acid substitutions at particular positions (e.g., K233E, K236E, K240E, K253E, K256E, K260E, K263E, K267E, K270E, K273E, K277E, K280E, K283E, K287E, K290E, K293E, K296E, K300E, K303E, K306E, K310E, K313E, K317E, K320E, K323E, K327E, K330E, K333E, K337E, K340E, K343E, K347E, K350E, K353E, K357E, K360E, K363E, K367E, K370E, K373E, K377E, K380E, K383E, K387E, K390E, K393E, K397E, K400E, K403E, K407E, K410E, K413E, K417E, K420E, K423E, K427E, K430E, K433E, K437E, K440E, K443E, K447E, K450E, K453E, K457E, K460E, K463E, K467E, K470E, K473E, K477E, K480E, K483E, K487E, K490E, K493E, K497E, K500E, K503E, K507E, K510E, K513E, K517E, K520E, K523E, K527E, K530E, K533E, K537E, K540E, K543E, K547E, K550E, K553E, K557E, K560E, K563E, K567E, K570E, K573E, K577E, K580E, K583E, K587E, K590E, K593E, K597E, K600E, K603E, K607E, K610E, K613E, K617E, K620E, K623E, K627E, K630E, K633E, K637E, K640E, K643E, K647E, K650E, K653E, K657E, K660E, K663E, K667E, K670E, K673E, K677E, K680E, K683E, K687E, K690E, K693E, K697E, K700E, K703E, K707E, K710E, K713E, K717E, K720E, K723E, K727E, K730E, K733E, K737E, K740E, K743E, K747E, K750E, K753E, K757E, K760E, K763E, K767E, K770E, K773E, K777E, K780E, K783E, K787E, K790E, K793E, K797E, K800E, K803E, K807E, K810E, K813E, K817E, K820E, K823E, K827E, K830E, K833E, K837E, K840E, K843E, K847E, K850E, K853E, K857E, K860E, K863E, K867E, K870E, K873E, K877E, K880E, K883E, K887E, K890E, K893E, K897E, K900E, K903E, K907E, K910E, K913E, K917E, K920E, K923E, K927E, K930E, K933E, K937E, K940E, K943E, K947E, K950E, K953E, K957E, K960E, K963E, K967E, K970E, K973E, K977E, K980E, K983E, K987E, K990E, K993E, K997E, K1000E) on the AAV2 capsid protein to specifically enhance binding to HSPG receptors on retinal cells, thereby improving transduction efficiency in retinal tissues while maintaining controlled tissue specificity

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent applies parameter changes by modifying the amino acid sequence of the AAV2 capsid protein through multiple substitutions, which alters the physical-chemical properties of the capsid surface to enhance its affinity for HSPG receptors, thereby changing the tissue tropism parameters to favor retinal tissue transduction

Inventive Principle:

Principle #35Parameter changes

2Productivity

If AAV2.7m8 is engineered with 7-amino acid peptide insertion to enhance penetration through inner limiting membrane, then transduction of inner retinal tissues is improved, but transduction of outer retinal tissues (RPE and photoreceptor cell layer) cannot be achieved

Engineering Contradiction:

Improvetransduction efficiency in inner retinal tissuesVSAvoidability to transduce outer retinal tissues

Core Design Contradiction:

ProductivityVSAdaptability or versatility

Solution Approach 1:

The patent applies universality by engineering the AAV2 capsid to perform multiple functions: the combination of 7-amino acid peptide insertion (to enhance penetration through inner limiting membrane) and multiple amino acid substitutions (to enhance HSPG receptor binding) enables the virus to effectively transduce both inner retinal tissues and outer retinal tissues including RPE and photoreceptor cell layer, achieving full retinal tissue coverage

Inventive Principle:

Principle #6Universality (Multi-functionality)

3Ease of operation

If conventional AAV serotypes are used for intravitreal administration, then delivery to inner retinal tissues is achieved, but penetration to outer retinal tissues (photoreceptor cell layer) is greatly reduced

Engineering Contradiction:

Improvedeliverability via intravitreal administrationVSAvoidtransduction efficiency in outer retinal tissues

Core Design Contradiction:

Ease of operationVSProductivity

Solution Approach 1:

The patent applies parameter changes by modifying the capsid protein parameters (amino acid sequence) to change the transduction efficiency parameter, enabling effective transduction of outer retinal tissues via intravitreal administration while maintaining ease of delivery

Inventive Principle:

Principle #35Parameter changes

Data Source

PatentUS20260041795A1Adeno-associated virus capsid having tissue tropism and use thereof

Publication Date: 2026.02.12 SHANGHAI LANGSHENG BIOTECHNOLOGY CO LTD

AI summary

An adeno-associated virus (AAV) capsid protein, a recombinant AAV virion containing same, and the use thereof in the treatment and prevention of diseases.