Gene therapy targeting platform

NextGenRnD® Solution No. 3

Viral vector transduction specificity is of paramount importance for gene therapy applications. Ideally, only a single specific tissue type should be targeted by a viral vector. Methods currently used to improve transduction specificity of adeno-associated virus (AAV) vectors are exclusively “covalent”, i.e., modification is either encoded by viral genetic material or is chemically coupled to viral capsid via a covalent bond. Typically, when the viral capsid is modified a “weaker” than its wild-type prototype virus is produced. The term “weaker” implies that the infectivity of modified virus in absolute majority of cases is compromised. As a consequence, gene expression can be severely decreased, which is not desired in gene therapy applications. Thus, there is a need for a novel approach that would improve AAV transduction specificity considerably without compromising AAV vector infectivity.

For example, the advantages of AAV of serotype 2 (AAV2) are: (i) wild-type virus is nonpathogenic; (ii) it can infect both dividing and non-dividing cells in an organism; (iii) long-term expression of heterologous genes, i.e., genes of interest, is established. The best way to maintain the advantages of gene therapy vectors like that of AAV2 is not to modify its capsid, i.e., protein shell, covalently.

Improved AAV vector transduction specificity will lead to two major advantages: (i) off-target effects reduction; and (ii) AAV vector dose reduction. Reducing the dose of AAV vector is important due to severe toxicity observed recently in large animals.

In this Solution, NextGenRnD reports novel platform technology that should enable improved AAV transduction of lung, intestine, muscle, central nervous system, and eye tissue. This technology platform is based on universal non-covalent modification applicable to AAV1–6,8,9 vectors.

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