Nerve injuries and neurodegenerative diseases such as Parkinson’s disease, amyotrophic lateral sclerosis (ALS), Alzheimer’s disease, Multiple Sclerosis (MS) and glaucoma share some characteristics, one of which is the degeneration of a part of neurons called the axon. Axons are long extensions that branch out of the cell body to allow neurons to connect to other cells, including other neurons, to transmit signals. A team led by SickKids scientist David Kaplan with Freda Miller and their trainees Konstantin Feinberg and Adelaida Kolaj has recently identified a drug, called fortetinib, that protects axons from degeneration in multiple conditions. It may turn out to be a clinically useful therapeutic drug.
Following injury or in neurodegenerative conditions, axons can degenerate by two distinct processes: axons can degenerate by retracting back towards the cell body, or they can undergo a process called Wallerian degeneration. The location, timing and underlying mechanisms differ for these two types of degeneration. To understand these mechanisms, a team of scientists at SickKids hospital set out a screen to identify drugs that can inhibit both types of axon degeneration. To do so, they used a library of anti-cancer drugs known to be safe in humans to test whether any of them could prevent axon degeneration.
Foretinib, currently in clinical trials for treating cancer, was very effective in preventing the degeneration of several different types of neurons. The researchers investigated how this molecule acted, and found that preservation of mitochondria, which are known as the “power plants” of the cell, appeared to be one of the keys to foretinib’s action.
“What is interesting about foretinib is that it inhibited axon degeneration in a variety of neuron types, and in a variety of conditions” explains David Kaplan, senior author of the paper. “For example, it prevented the degeneration of sensory neurons and sympathetic neurons that are vulnerable and damaged in diabetic and chemotherapy-induced neuropathy, and motor neurons that degenerate in ALS. It also inhibited axon degeneration caused by the absence of a necessary survival factor for neurons called Nerve Growth Factor, and delayed the degeneration of axons that were cut off from the rest of the neuron and when the sciatic nerve was crushed. Foretinib could even promote the survival of neurons that express a mutation found in ALS”.
“Foretinib is therefore a clinical candidate for the treatment of many neurological diseases and nerve injuries in which axon degeneration is involved” concludes Dr. Kaplan.