Ocular neurodegenerative diseases, like glaucoma, represent a significant and growing public health concern for the US, particularly with an aging population.
Last year, a team at Stanford Medicine, Palo Alto, CA discovered that a mutation in optineurin (OPTN) – a multifunctional protein responsible for helping to control autophagy (cell breakdown and recycling) and mitochondrial transport, as well as regulating inflammation – leads to degeneration in the brain and an increased risk of neurodegenerative disease development.
Based on their discovery, the Hu Lab — headed by Yang Hu, Professor of Ophthalmology at the Byers Eye Institute at Stanford – has now developed a gene therapy in mouse models that aims to tackle the OPTN mutation, providing strong evidence that this new type of approach could be used to treat neurodegenerative diseases in human patients.
Yang Hu spoke with The Ophthalmologist about the next steps in further developing neuronal repair therapies that can be effective and safe for patients suffering from ocular neurodegenerative diseases.
How did you discover that OPTN mutations disrupt mitochondria delivery?
It was a total surprise! We used a mitochondria sensor to evaluate the known function of OPTN, but accidentally found the total mitochondria in the optic nerve decreased dramatically after OPTN truncation.
How does your research reframe our understanding of OPTN’s role in diseases?
It’s been known for a while that OPTN mutation causes human glaucoma and amyotrophic lateral sclerosis (ALS), but the mechanism was never clear. Now we have a clearer understanding that OPTN participates in axonal mitochondria transport, the dysfunction of which leads to axon degeneration due to the lack of mitochondria. Furthermore, our research demonstrates that boosting axonal mitochondria transport achieves significant neuroprotection and axon regeneration, indicating a novel therapeutic strategy for treating these CNS axonopathies.
What makes AAV (adeno-associated virus) an ideal delivery method for this therapy?
AAV is a benign virus that has been chosen as a delivery vehicle for gene therapies. There are existing AAV-based gene therapies that have been approved by the FDA and are already used in clinics. We have proof-of-concept data on AAV-mediated enhancement of axonal mitochondria transport and associated neuroprotection in mouse glaucoma models, and so the next steps would be to further optimize the AAV vectors to make them suitable for human use.
What are the safety considerations as you move into preclinical testing?
There are many important aspects that need to be carefully considered and addressed: such as the selection of an AAV capsid that is safe and potent when targeting retinal ganglion cells, the profiling of transgene expression and its dynamics, the minimizing of immune responses, the long-term effect of boosting axonal mitochondria transport, and the side effects/function of the transgenes.
Do you think this therapy could also improve symptoms for those already suffering from neurodegenerative ophthalmic diseases?
Current data from animal glaucoma model studies suggest a potent neuroprotection effect of this strategy. Therefore, we expect it will halt or delay the progression of neurodegeneration. We also found that boosting axonal mitochondria transport induces optic nerve regeneration, suggesting that this treatment may also improve neurodegeneration by stimulating axon regeneration. But how the regeneration affects visual functional recovery needs to be further investigated.
How would it be delivered to patients in the future?
For gene therapy, AAV intravitreal injection would be the most effective way to target retinal ganglion cells and the optic nerve. However, if we can find small molecule enhancers of axonal mitochondria transport, that would mean it could be delivered in many other ways as well.
If the therapy proves successful in humans, what could be its impact over the next decade?
Neuronal retina and optic nerve are CNS tissues, and the success of this therapy in retina and optic nerve diseases will indicate its effectiveness in other CNS neurodegenerative diseases, especially in ALS. We are currently testing this therapy in ALS animal models, which will give us more evidence.
What are the next steps in translating these findings into therapeutic applications?
Firstly, the molecular mechanism we identified in this study needs to be validated by other labs in other glaucoma models or other neurodegenerative diseases’ animal models. Secondly, we are working on identifying the most potent and safe strategies – including gene therapy strategies, small molecule strategies, and protein/cell therapy strategies – to enhance axonal mitochondria transport, in order to develop effective and safe neural repair therapies.
