Lentivirus Gene Delivery Vector with Modified Sindbis Envelope

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Solution Overview

Problem

Common lentivirus vectors lack cell specificity, leading to extensive off-target effects due to their ability to bind ubiquitously present proteins on most cell surfaces, which hinders efficient and safe in vivo gene therapy applications.

Innovation Solution

A gene delivery system comprising a lentivirus with a modified Sindbis virus envelope protein that ablates native receptor binding, combined with a bispecific polypeptide that specifically targets cell-specific receptor proteins, enhancing the vector's specificity and transduction efficiency.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If common lentivirus vectors are used for gene delivery, then high transduction efficiency is achieved, but cell specificity is lost leading to extensive off-target effects

Engineering Contradiction:

Improvetransduction efficiencyVSAvoidoff-target effects

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent extracts the native envelope protein from the lentivirus vector and replaces it with a modified Sindbis virus envelope protein that has had its native receptor binding capability removed. This extraction of the problematic binding function allows the virus to maintain structural integrity while eliminating off-target binding to ubiquitously present cell surface proteins.

Inventive Principle:

Principle #2Taking out (Extraction)

Solution Approach 2:

The patent introduces a bisspecific polypeptide as an intermediary component that mediates between the modified Sindbis envelope protein and the target cell-specific receptor. This intermediary enables specific target cell recognition and binding while preventing interaction with non-target cells, thus resolving the contradiction between maintaining infectivity and achieving specificity.

Inventive Principle:

Principle #24Intermediary (Mediator)

2Object-affected harmful factors

If ligands or peptides are inserted into viral envelope glycoprotein domains to confer cell specificity, then target cell binding is improved, but viral infectivity is hindered due to structural disruption

Engineering Contradiction:

Improvecell binding specificityVSAvoidviral infectivity

Core Design Contradiction:

Object-affected harmful factorsVSReliability

Solution Approach 1:

The patent segments the viral envelope system into two independent functional components: the modified Sindbis envelope protein that provides structural integrity and fusion capability, and the bisspecific polypeptide that provides target cell specificity. This segmentation allows each component to perform its function without interfering with the other, avoiding the structural disruption that occurs when ligands are inserted into the envelope glycoprotein.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent creates a composite envelope system combining the modified Sindbis virus envelope protein with the bisspecific polypeptide. This composite structure integrates the structural and functional advantages of the Sindbis envelope with the target-specific binding properties of the bisspecific polypeptide, achieving both high infectivity and cell specificity without the trade-offs of traditional modification approaches.

Inventive Principle:

Principle #40Composite materials

3Adaptability or versatility

If viral envelope proteins are modified to alter tropism, then cell specificity is enhanced, but fusion activity and viral titer are reduced

Engineering Contradiction:

Improvetropism alterationVSAvoidviral titer

Core Design Contradiction:

Adaptability or versatilityVSProductivity

Solution Approach 1:

The patent copies the envelope protein structure from Sindbis virus but creates a modified version that lacks native receptor binding capability. This copying approach allows the adoption of a well-characterized envelope structure with known fusion properties while eliminating the problematic tropism, and the bisspecific polypeptide is then added to confer the desired target specificity without affecting the copied structural integrity.

Inventive Principle:

Principle #26Copying

Applied Scientific Principles

This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.

Function Achieved in This Case

The system achieves highly specific and efficient gene delivery to target cells, minimizing off-target effects and maintaining viral infectivity, as demonstrated by enhanced transduction efficiency and specificity in HER2+ cells, while preserving cell viability.

Implementation Method 1

a lentivirus comprising a modified Sindbis virus envelope protein unable to bind a cell surface protein

Methodology Applied

Scientific EffectReceptor binding ablation:

Implementation Method 2

a bisspecific polypeptide configured to bind a viral gene delivery vector particle and target cell-specific receptor protein

Methodology Applied

Scientific EffectSpecific binding:

Data Source

PatentUS20230009161A1Gene transfer system

Publication Date: 2023.01.12 THE UNIV OF NORTH CAROLINA AT CHAPEL HILL

AI summary

The present disclosure relates to a viral gene delivery vector particle and a bispecific polypeptide configured to bind a viral gene delivery vector particle and target cell-specific receptor protein. The disclosure also relates to gene delivery systems, compositions, and methods of use thereof.