Objective/Rationale:
Available treatments for PD offer relief of symptoms, but none are able to restore the neural structures that have degenerated. Neuroscientists have long believed that surviving mature neurons are incapable of new axon growth. However, there is emerging evidence that this belief is not true, that surviving neurons may be induced to re-grow axons by re-activation of molecular processes that are active during normal brain development. Our proposal will explore a gene therapy approach to re-activation of these axon growth processes.
Project Description:
We have assessed the ability of dopamine neurons to re-grow their axons in the mature brain by use of a neurotoxin pre-clinical model. At a period of three weeks after the lesion, after axon degeneration has occurred, we use a gene therapy approach to insert axon growth genes into the surviving neurons. Of these axon growth genes, we have found two in particular that induce robust new axon growth and achieve partial restoration of function. The goal of this proposal therefore is to develop this approach and achieve greater potency and while minimizing potential adverse effects.
Relevance to Diagnosis/Treatment of Parkinson’s Disease:
At the time of first diagnosis of PD, 70% of the neurons of the substantia nigra still survive. If they can be induced to re-grow their axons, such that they re-contact their target, the striatum, and re-establish their ability to release dopamine, it may be possible to offer substantial neurorestoration with clinical benefit. The promise of this approach is that this benefit will be achieved by restoring dopamine neurons, in their normal locations, with intact connections and with normal regulatory mechanisms in place, rather than transplanting neurons into the brain that would then have to integrate.
Anticipated Outcome:
Based on our very promising results with these two axon growth genes, we anticipate that this ‘next generation’ approach will also achieve new axon growth with restoration of function.
Final Outcome
A goal in the treatment of PD is to develop therapies that restore neural structures that have degenerated due to the disease. Most efforts have focused on restoration of neurons. However, when PD is first diagnosed, only about 30% of the neurons have been lost. There has been a much greater loss of the neuron connections, called axons, and this loss is probably responsible for the symptoms. Neuroscientists have long believed that neurons in the adult brain cannot grow new axons. However, there is new evidence that this is not true, that surviving adult neurons may be induced to re-grow axons by re-activation of processes that occur during brain development. We have shown that two mediators of axon growth during development, Akt and Rheb, when administered as gene therapy, can induce re-growth of dopaminergic axons in pre-clinical models. However, these molecules may play a role in cancer, so they are unlikely to be used in patient treatment. We investigated whether another protein, downstream to Akt and Rheb, called p70S6K, could also induce axon re-growth. Our evidence suggests that it can. It may therefore be possible to develop gene therapy treatments that can safely induce new axon growth.