Use of Tyrphostins to Stimulate Neurite Outgrowth
OHSU # 0827
- Chunhe Wang
- Bruce Gold, CR.CROET
- Kim Neve
- Yong-Ping Zhong, ST.Stem Cell Center
- Xiaolin Yu, SM.Neurology
- David Buck, SM.Behavioral Neuroscience
- Robert Johnson
The use of tyrphostin A9 and its pharmaceutically acceptable derivatives as neurotrophin-like agents are able to protect against neurotoxins and to accelerate nerve regeneration, and thus can treat neurodegenerative diseases and nerve injuries in the central and peripheral nervous systems, including (but not limited to) Parkinson's disease (PD), multiple sclerosis (MS), spinal cord injuries and peripheral neuropathies. Tyrphostin A9 has been found to stimulate neurite outgrowth in the presence of nerve growth factor in SK-SY-5Y cells, a human neuroblastoma cell line. The researchers have also discovered that tyrphostin A9 stimulates robust extracellular signal regulated kinases (ERKs) activation in a dose-depdendent and prolonged manner in mouse neuroblastoma cells and primary neuron cultures. In a mouse model for Parkinson's disease (MPTP-treated mice) where MPTP treatment produces an almost complete destruction of tyrosine hydroxylase (TH)-positive nerves, tyrphostin A9 treatment reversed this destructive effect and did not demonstrate some of the side effects produced by other PDGF receptor inhibitors. In SJL mice with EAE, a model for human multiple sclerosis, tyrphostin A9 treatment preserved normal axons and reduced the presence of damaged axons in the CNS.
Many of the compounds previously shown to stimulate nerve regeneration have undesired side-effects, such as immunosuppression, or androgenic or estrogenic stimulation. There is therefore a need to provide a class of nerve growth stimulating compounds that are well tolerated by subjects who take them.
Tyrphostin A9 and its derivatives are small, stable compounds that have obvious advantage over neurotrophins (including NGF, epidermal growth factor, brain-derived neurotrophic factor, and glial cell line-derived neurotrophic factor), peptides for which the delivery in the CNS is complicated, in the protective and restorative treatment of neurodegenerative conditions. In the EAE mouse model studies, A9 was shown to cross the blood brain barrier after oral administration.
Spinal cord injuries : Approximately 250,000 - 400,000 individuals in the US have spinal cord injuries.
Every year, approximately 11,000 people sustain new spinal cord injuries, which equates to thirty new injuries every day. 60 percent of these individuals are 30 years old or younger.
Parkinson's Disease: Estimated that 60,000 new cases are diagnosed each year in the United States. Currently 1.5 million Americans are diagnosed with Parkinson's disease. While the condition usually develops after the age of 65, 15% of those diagnosed are under 50.
MS: Approximately 400,000 Americans acknowledge having MS, and every week about 200 people are diagnosed. Worldwide, MS may affect 2.5 million individuals.
There are a number of medicines that help to ease the symptoms of PD. Several new medicines are being studied that may slow the progression. Many promise to improve the lives of people with PD, but none have been shown to halt or reverse the neuronal damage caused by the disease.
Although there is still no cure for MS, some strategies are available to modify the disease course, treat exacerbations (also called attacks, relapses, or flare-ups), manage symptoms, improve function and safety, and provide emotional support. In combination, these treatments enhance the quality of life for people living with MS, but do not reduce the damage caused by the disease.
Today, there's still no way to reverse damage to the spinal cord following injury. Researchers are working on new treatments, including innovative treatments, prostheses and medications that may promote nerve cell regeneration or improve the function of the nerves that remain after a spinal cord injury, but no successful treatment currently exists.
Patent Status: Pending patent application in the United States.
Licensing Opportunity: OHSU 827 is currently available for exclusive licensing.
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