Inherited mitochondrial diseases are a group of rare genetic disorders that affect the mitochondria, the energy-producing organelles in the cells. The most commonly affected organs by inherited mitochondrial diseases are the ones that have high energy requirements, like the liver and the central nervous system (CNS). These group of disorders have no cure and current treatments are focused on managing symptoms and supporting overall health.

Gene therapies using recombinant adeno-associated virus (rAAVs) have revolutionized the treatment of some monogenic diseases. However, their application to multisystem indications, like inherited mitochondrial diseases, requires optimization. On one hand, the use of vectors with constitutive promoters administered systemically can trigger immune responses that cause significant adverse effects. On the other hand, using vectors with specific promoters for each affected tissue would require the development of independent rAAVs. Therefore, this project proposes the development of rAAVs carrying a hybrid promoter, specific to more than one organ, that could overcome these drawbacks.

First, we tested different constructs combining a neuro-specific and a hepato-specific promoter driving the expression of a reporter transgene in hepatic and neuronal cell lines. We selected the two most efficient combinations for in vivo testing by systemic administration in wild-type mice, using rAAV9 and a rAAV9 synthetic variant with an increased CNS transduction. The results indicate that our tandem promoter allows for selective expression of the transgene in the target tissues, which has potential application to diseases with hepato-neurological pathology, including inherited mitochondrial diseases.