Gene therapy aims to recover the normal function of the cells of a patient to obtain a therapeutic benefit by introducing genetic material. The benefit being, for example, in improving the immune system response to fight cancer or correcting a genetic disorder by rescuing gene function.
Scientists harness the natural ability of viruses to transfer their genetic material to infected cells. For decades, they have developed modified viruses as vectors to deliver genes of interest into a tissue or cell type, in a precise and efficient manner.
Luxturna, the first gene therapy approved as a treatment for a form of retinal dystrophy, is based on an adeno-associated virus (or AAV) as a vector. Even though they are the most widely used vectors for gene delivery, conventional AAVs have some limitations, such as the length of the gene they can accomodate and their tissue specificity.
To obtain optimized AAV vectors, different research groups such as those of David V. Schaffer and John G. Flannery at UC Berkeley (United States) and Hildegard Büning and Sylianos Michalakis (in Germany) have generated AAV vectors with the ability to transfer genes to retinal photoreceptors cells after an intravitreal injection. This is a simpler and safer route of administration than subretinal injection and potentially it can target a larger area of the retina.
To deliver large genes, such as ABCA4, the gene responsible for Stargardt disease, dual AAV vectors have been designed. The coding sequence of the ABCA4 gene is divided in two fragments that are packaged into two AAV vectors. Once the two DNA fragments are present in the same cell, the complete coding sequence of the gene is reconstituted by recombination, allowing the synthesis of a functional ABCA4 protein.
Other initiatives are based on virus-independent methods. Code Biotherapeutics, Anjarium Biosciences, and Generation Bio are investigating novel approaches with synthetic DNA coated by lipid nanoparticles. One of the advantages of these methods is that, unlike viral vectors, they do not trigger an immune response. and moreover they could be administered to patients who have developed immunity against AAVs.
The use of non-viral vectors is currently being investigated to transfer one or more large genes simultaneously or as an option to administer several doses of gene therapy to extend their effects throughout the patient’s life.
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