[转贴]a therapy for neurodegener

[em15] Intracranial delivery protections and peptides as a therapy for neurodegenerative diseases.

Grondin R, Zhang Z, Ai Y, Gash DM, Gerhardt GA.

Department of Anatomy & Neurobiology and the Morris K. Udall Parkinson's Disease Research Center of Excellence, 305 Davis-Mills Bldg, University of Kentucky Medical Center, Lexington, KY 40536-0098, USA. rcgron0@mky.edu

Parkinson's disease is characterized by a progressive degeneration of the substantia nigra pars compacta dopamine neurons that innervate the striatum. Unlike current treatments for PD, GDNF administration could potentially slow or halt the continued degeneration of nigral dopaminergic neurons. GDNF does not cross the blood-brain barrier and needs to be administered directly into the brain. Due to the progressive nature of PD, sustained delivery of trophic factors may be necessary for optimal, long-term neuronal effects. Novel methods for sustained delivery of GDNF into the nigrostriatal pathway are currently being studied in non-human primates, including computer-controlled infusion pumps. Using this approach, we have demonstrated that chronic infusions of nominally 7.5 or 22.5 microg/day GDNF into the lateral ventricle, the putamen or the substantia nigra, using programmable pumps, promotes restoration of the nigrostriatal dopaminergic system and significantly improves motor functions in MPTP-lesioned rhesus monkeys with neural deficits modeling the terminal stages of PD and in aged rhesus monkeys modeling the early stages of PD. Based on the promising studies of the chronic effects of GDNF in non-human primate models of PD, a study was recently conducted in England on five advanced PD patients. Chronic GDNF infusion into the dorsal putamen, via programmable pumps, resulted in improved motor function in all patients and limited side effects were observed. However, while the data from this intraparenchymal clinical trial in humans look encouraging, extensive blinded efficacy trials will need to be conducted before it can be determined if chronic treatment with GDNF or other trophic molecules will prove useful in treating patients with PD.

Delivering a Cure
UK researchers design brain implants to fight neurological disorders

Parkinson's is a disease that affects more than a million people in North America. It progressively impairs control of body movement and often leads to immobility. Although current treatments with oral medications can almost completely restore normal movement to people in the early stages of Parkinson's, the drugs lose effectiveness as the disease progresses.

Greg Gerhardt, anatomy and neurobiology professor in the UK College of Medicine, is searching for a way to improve the quality of life for people with Parkinson's disease beyond the current limits of drug therapy. He can now treat the disease, but that doesn't mean the person's life is like it was before they developed Parkinson's. He says quality of life, after all, should be the ultimate concern.

Improving the lives of those with Parkinson's has also been a career-long goal for Don Gash, chair of UK anatomy and neurobiology department. Gash has studied Parkinson's in animal models since 1985. He and Gerhardt have known each other for nearly 20 years, but it wasn't until 1991 when Gash was working at the University of Rochester and Gerhardt was at the University of Colorado that they officially began to collaborate.

Gash and Gerhardt's collaboration led to a five year, $5 million grant in 1999 from the National Institute of Neurological Disorders and Stroke (NINDS), part of the National Institutes of Health. The NINDS grant established a Morris K. Udall Parkinson's Disease Research Center of Excellence at UK, one of only eight centers funded that year. The grant supports a collaborative project by center director Gerhardt, Gash and Zhiming Zhang, a neurosurgeon from China, who is working on site-specific delivery of proteins called trophic factors. Their research has laid the foundation for treating Parkinson's disease direct delivery of a key protein to the brain to repair damaged cells.

This is where Gerhardt's amazing chip comes in. Using the same technology that created the microchip, Gerhardt has created a device that can potentially help determine how to restore motor function to people with Parkinson's disease. In addition, implanting the high-tech microsensors and electrodes may one day allow doctors to measure neurotransmitters and deliver powerful proteins directly to the brain to treat people with devastating neurological disorders.

The sensors are very tiny, about half the thickness of a human hair. (A human hair is approximately 0.003 inches or 75 microns.) These microelectrodes can be implanted in various regions of the brain to measure neurotransmitters ?molecules involved in brain signaling ?such as dopamine, norepinephrine, serotonin, glutamate, choline, and nitric oxide. Previous studies in animals revealed that disruption of dopamine regulation in the brain is the primary cause of the movement problems associated with drug-induced Parkinson's disease. So for his initial study of Parkinson's, Gerhardt designed a sensor that counts dopamine molecules.

Gerhardt's research team has already tested the sensors by listening in on brain activity in animals with drug-induced Parkinson's disease. Implanted sensors allow researchers to monitor what is going on in the animals' brains. were discovered that these procedures are relatively non-invasive, because they cause minimal damage to brain tissue, and they're safe,he says.

The research team is currently focused on studying a protein called glial cell-line derived neurotrophic factor (GDNF). These proteins are manufactured by cells, and are used in cell programming, differentiation, growth, and maintenance,?Gerhardt explains. Perhaps the most widely studied is Nerve Growth Factor. Lack of that protein seems to play a fundamental role in Alzheimers disease.GDNF is found in low levels in the adult human brain. Reintroducing this protein into the brain may allow these researchers to turn back the clock?on dopamine neurons sabotaged by Parkinson's. If we re-administer this protein in an adult brain that's damaged, it looks like we can potentially arrest further degeneration and even repair some of those neurons,?says Gerhardt.

The problem was in getting the proteins where they were supposed to go. It involves the fact that not all molecules or drugs can penetrate the brain from blood vessels, says Gerhardt. The blood-brain barrier is not really a physical barrier, but it's clear that many drugs or proteins, like GDNF, can't cross it.Direct-delivery technology allows these proteins to bypass the blood-brain barrier.

The delivery system is based on a modified Medtronic SynchroMed Infusion System, an implantable, programmable pump invented by Dennis Elsberry. This device is currently approved to deliver drugs directly to the fluid around the spinal cord in patients with chronic and intractable pain, cancer pain, and severe muscle spasticity, as well as deliver chemotherapy agents to treat colorectal cancer that has spread to the liver. When modified, it can also deliver drugs directly to the brain.

Medtronic began working with Gerhardt and his Center for Sensor Technology at the suggestion of the National Science Foundation in 1994. The team was able to gather safety data to take to the FDA based on the technological contributions of Amgen and Medtronic provided at no cost to UK. Amgen, an international drug company headquartered in California that makes GDNF from E. coli, is supplying UK with the purified protein. Without cooperation from Medtronic and Amgen, and a whole host of other companies and biotech firms, it would have been another three or four years before we could even begin thinking about clinical trials,?Gerhardt says.

In March 2002 Gerhardt, Gash, UK hospital chief of staff Byron Young, UK Movement Disorders Clinic director John Slevin, and neurologist Charles Smith began a Phase-I FDA-approved clinical trial in 10 patients with advanced Parkinson's disease. The Medtronic pump, about the size of a hockey puck, was implanted in the abdomen of the patients to deliver GDNF to the brain through tiny tubes. Results of this trial will be released in early 2004, says Gerhardt. Efficacy trials, with a much larger pool of patients, are under development.

Gerhardt points out that the biggest challenge of using this new technology is fear. Most people don't want to us stick a tube in their brain. But the reality is that the medical community has very successfully been putting tubes in the human brain for about 80 years. While it sounds a little like something out of Star Trek, the insertion of tubes ?most clinicians refer to them as shunts ?is actually a very safe procedure, Gerhardt says.

Success in adapting this direct-delivery pump may have a ripple effect on technology and medicine, says Gerhardt. not inconceivable to think of a pump that would eventually fit behind your ear, like a hearing aid. Every day we use technology thats more complicated than this little pump, and the reason we can afford it is millions of people are buying the technology,?he says. If we can prove this technology has widespread use, we can look forward to a whole new generation of micromachines that will revolutionize the way we treat diseases.