Dual AAV NF1 Vectors for Oversized Gene Delivery

Resolve Bottlenecks,
Find Innovative SolutionsGenerate Solutions

Solution Overview

Problem

The NF1 gene, which is 8,540 bp, exceeds the packaging capacity of recombinant AAV vectors, making gene therapy to correct NF1 gene mutations difficult for conditions like Neurofibromatosis type I, which causes skin lesions, benign neurofibromas, malignant tumors, and cognitive deficits.

Innovation Solution

Development of recombinant AAV vectors engineered to express functional NF1 protein, including mini-NF1 and full-length NF1 proteins, using dual AAV vector systems to deliver the protein to target cells, and administration methods to achieve effective gene therapy.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If the full-length NF1 gene (8,540 bp) is used for gene therapy, then complete gene replacement is achieved, but the packaging capacity of recombinant AAV vectors is exceeded

Engineering Contradiction:

Improvegene therapy effectivenessVSAvoidvector packaging capacity

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The full-length NF1 gene is divided into multiple coding regions (first coding region and second coding region) that can be separately packaged into different AAV vectors. The first coding region is packaged in a first AAV vector and the second coding region in a second AAV vector, allowing the complete gene to be delivered through multiple smaller packages that fit within the vector capacity limits.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent transitions from a single-gene delivery approach to a multi-vector system, adding the dimension of using multiple vector molecules to deliver the complete genetic information. This allows the total genetic payload to exceed the capacity of a single vector while maintaining compatibility with AAV packaging constraints.

Inventive Principle:

Principle #17Another dimension (Dimensionality change)

2Ease of manufacture

If recombinant AAV vectors are used to deliver NF1 protein, then gene therapy is enabled, but the coding sequence length exceeds packaging capacity

Engineering Contradiction:

Improvegene therapy feasibilityVSAvoidcoding sequence length

Core Design Contradiction:

Ease of manufactureVSQuantity of substance

Solution Approach 1:

The NF1 coding sequence is segmented into multiple regions that can be distributed across different vector molecules. This segmentation allows each vector to contain only the necessary portion of the coding sequence, making the overall delivery system feasible while accommodating the total quantity requirement.

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

Multiple AAV vectors containing different portions of the NF1 coding sequence are combined within the target cell through recombination, merging their contents to reconstruct the full-length functional gene. This combining process enables the delivery of substantial genetic material that would be impossible in a single vector.

Inventive Principle:

Principle #5Merging (Combining)

Data Source

PatentUS12522845B2Aav vectors encoding NF1 and uses thereof

Publication Date: 2026.01.13 UNIV OF MASSACHUSETTS

AI summary

Aspects of the disclosure relate to compositions and methods of treating certain genetic disease (e.g., Neurofibromatosis type I) by delivering functional neurofibromin 1(NF1) protein (e.g., mini-NF1 protein and/or full-length NF1 protein) to target cell (e.g., cells and/or tissue of a subject). The disclosure is based, in part, on isolated nucleic acids (e.g., rAAV vectors) and rAAVs engineered to express a functional NF1 protein (e.g., mini-NF1 protein and/or full-length NF1 protein) or variants thereof.