Gene Therapy for mitochondrial optic neuropathies (LHON, DOA)

Research type

Laboratorium onderzoek

Start date


Participating coworkers


Mutations in mitochondrial genes can lead to mitochondrial optic neuropathies, such as LHON and DOA. These diseases are characterized by degeneration of the optic nerve, which often appears at young age and eventually leads to blindness. A therapy is desperately needed.

Description research

We are exploring gene therapy for treatment of mitochondrial optic neuropathies, including LHON (Lebers Hereditary Optic Neuropathy) and DOA (Dominant Optic Neuropathy). Gene therapy has the potential to hit these diseases in the heart, by targeting the basis of the disease: the mutated DNA. 

We and others have obtained proof-of-concept on using gene therapy for treatment of LHON. Using adeno-associated virus (AAV) as a delivery vehicle, we were able to introduce the correct ND4 protein in cells, which was shuttled into mitochondria via a mitochondrial targeting sequence. Improved respiration capacity of the mitochondria was observed. These results corroborate on the results of others, demonstrating the potential of the therapy. Efficiency and safety studies in patients are ongoing at different locations worldwide.

Gene therapy also has great promises for treatment of DOA. In contrast to LHON (caused by a defect in the mitochondrial genome), DOA is caused by a defect in the nuclear genome (mutated OPA1 gene). This offers opportunities for genome editing, using engineered nuclease proteins that specifically target and correct mutated sequences in the nuclear genome.

We have developed an extensive toolkit of gene therapeutics, both virus-based and non-virus based (e.g. exosomes). These therapeutics are analyzed and compared on patient-derived cell systems (e.g. “retinas in a dish”) that faithfully mimic the clinical situation in patients (3D tissue architecture, genetic and cellular diversity, presence of therapy-blocking immune components). The most promising approaches are further studied in animal models, and will eventually be tested in patients.

This research is supported by Ride4Kids.