Method for using alternative splicing to control specificity of gene therapy

Unmet Need
Viral-based gene therapy holds tremendous promise for the treatment of human diseases. Using genetically engineered carriers called vectors to deliver genes into cells, gene therapy can help replace a mutated gene with a healthy copy or even introduce a new gene into the body to fight a disease. However, an important concern when designing these vectors is to ensure that genes are only delivered and expressed in the intended cell type. Since off-target delivery and expression can lead to side effects, current methods attempt to address these concerns by selecting virus serotypes (for vector) or constructing cell-specific promoters. Collectively, these current methods have significant limitations and as a result, gene therapy treatments have not succeeded in reaching their full therapeutic potential. As such, there is a need to create gene therapy vectors that will be able to specifically deliver and express into a defined cell type.

Technology Overview
Johns Hopkins researchers have developed a novel platform methodology for gene therapy. This method exploits alternative RNA splicing in order to precisely restrict gene expression to defined cell types. The technology uses cell type-specific alternative exons to drive cell type-specific gene expression (independent of any other sequence in the vector). Cell type-specific exons can be incorporated into gene expression constructs for viral-based gene therapies. By coupling cell type-specific splicing events to a desired translational reading frame, the technology ensures that the viral vector will only express encoded proteins in the target cell type.

Additionally, this vector technology is independent from other methods of controlling gene expression and can be easily used in conjunction with other strategies. Unlike current methods, this technology platform resolves the issues of viral serotype cell selection and weak gene expression, while simultaneously solving the important problem of off-target side effects.

Stage of Development
Proof-of-concept technology has been developed and is currently being tested in mice and higher order animal models. In vitro and in vivo data are available.

Publications
Ling JP, Wilks C, Charles R, Ghosh D, Jiang L, Santiago CP, Pang B, Venkataraman A, Clark BS, Nellore A, Langmead B, Blackshaw S. ASCOT identifies key regulators of neuronal subtype-specific splicing. bioRxiv 501882 (accepted in Nature Communications).
 

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