A human brain possesses 100 billion nerve cells or neurons. But only about 400,000 of these nerve cells are dopamine nerve cells that can produce dopamine in the substantia nigra. We depend on dopamine neurons for numerous activities such as movement, motivation, reward, punishment, cognition, mood, memory, attention, and sleep. How can so few dopamine neurons do so many things? The answer is dopamine neurons can sprout massive numbers of branches along its axon. This enables the neuron to link up with many other brain cells and modulate numerous biochemical pathways. To support their massive network activity, dopamine neurons depend on their subcellular power stations called mitochondria for the energy.
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This energy dependence makes dopamine nerve cells vulnerable. Every year, an average of 2,400 dopamine neurons die because of the failure in their power stations. So, half of a healthy adult’s lifetime supply of dopamine cells is dead by age 80. If 70 percent of dopamine cells in the substantia nigra die, symptoms of PD will kick in. A person will hit this threshold at age 120 just by aging. Some people will hit this threshold earlier, like age 60, due to other sources of cell death. Humans are the only animals to get PD because the life spans of other animals are too short to develop the disease.
Because dopamine neurons get “sick” for many reasons, scientists have come up with several neuroprotective strategies.
One idea proposed in 1985 by Walther Birkmayer was to protect dopamine nerve cells from the toxic effect of dopamine itself. Dopamine nerve cells releases dopamine as a neurotransmitter to signal other nerve cells. Once the message is received, the cell needs to clear any leftover dopamine so it doesn’t interfere with future transmissions. Some of the dopamine is reabsorbed by the body. The rest is degraded by an enzyme known as monoamine oxidase, or MAO, releasing free radicals that can destroy brain cells, including the dopamine nerve cells in the substantia nigra. Birkmayer thought treating PD patients with the so-called MAO inhibitors early in their PD might slow the progress of the disease.
In 1985, Birkmayer conducted a study comparing a control group of 377 PD patients (on L-dopa alone) with 594 patients who received L-dopa plus an MAO inhibitor called slegiline over a nine year period. He found the slegiline group lived on average 15 months longer than the control group. Birkmayer interpreted these findings as evidence that selegiline was preventing the death of substantia nigra neurons in PD. But critics believed the selegiline effect was just symptomatic. Researchers had conducted a series of large, expensive placebo-controlled studies to test the efficacy of selefiline and other MAO inhibitors over the last two decades. The results failed to provide definitive evidence that MAO inhibitors can protect neurons and slow the progression of PD.
Meanwhile, scientists have proposed other potential neuroprotection therapies designed to block various disease pathways. Some seek molecule targets that might protect or assist the mitochondria. Others attempt to block calcium channels on the assumption it would help protect the dopamine nerve cells. But these attempts to protect dopamine neurons have been overshadowed by an approach focusing on nourishing dopamine neurons that are damaged but not yet dead.
In 1991, two scientists at the biotech company Synergen isolated a brain protein that appeared to nourish and protect dopamine neurons. They called this protein glial-cell-line-derived neurotrophic factor, or GDNF. They produced a synthetic form of GDNF and tested it on dopamine neurons in test tubes and in monkeys rendered parkinsonian with MPTP. In the test tubes, GDNF turned sick neurons into healthy ones. In the monkeys, the GDNF reduced their PD symptoms. Amgen was so impressed with the experiment they bought the company. Between 1996 and 1999, Amgen carried out trials on 38 humans. The researchers didn’t attempt to reach the striatum, because the available brain catheter was too large. Instead, they delivered the GDNF to the lateral ventricle, hoping the cerebrospinal fluid would carry the GDNF to the striatum. The trial was a failure.
The problem, according to the British neurosurgeon Steven Gill, was that the GDNF had not made it to the striatum because of the size and the design of the catheter. Gill designed his own mini-catheter and mounted an in-house open-label study at the Frenchay Hospital involving five moderately advanced PD patients. After one year, Gill reported that all five patients showed dramatic improvements, and there were no serious side effects. This rekindled Amgen’s interest in GDNF, and the company carried out new animal studies and mounted a blind-placebo-controlled trial. By 2004, Amgen’s second trial had failed. The company announced that it was halting all clinical use of GDNF around the world.
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To this day, Gill believes that his approach worked. With funding from the Cure Parkinson’s Trust, Gill is doing a larger study on GDNF. This trial will allow Gill to determine if direct GDNF infusion has potential as a disease-reversing therapy in PD.
Some neuroscientists argued that a better way to deliver GDNF was to use gene therapy. With gene therapy, you start with a simple common cold virus and replace its gene with the gene of your choice. Here, you can use the gene that encodes the growth factor GDNF or a related cousin called neurturin (NTN). You need to introduce multiple copies of the virus into the patient’s putamen to infect the neurons with the desired gene. Unlike infusion, gene therapy is a one-shot process. Once the genes are inserted and turned on, they should keep working indefinitely.
In 2000, Rush University scientist Jeff Kordower published a paper in Science showing a proof of concept in monkeys. He founded a biotech company in San Diego called Ceregene Inc to undertake a phase I safety trial in humans. Kordower used the NTN gene for the trials because Amgen held the patient on the GDNF gene. After a year, the patients’ UPDRS motor scores had improved by 40 percent with no serious side effects.
In 2008, the results of the phase II double-blind placebo-controlled trial showed no difference between the gene therapy and the placebo groups. Ceregene considered shutting down the NTN gene therapy program. But then two trial patients died of unrelated causes, providing an opportunity to examine their brains. The autopsies revealed that the infusion had fallen short of expectations. Only 15 percent of the putamen expressed the NTN gene; Ceregene researchers had been hoping for 50 percent. With $2.5 million grant from the Michael J. Fox Foundation, Ceregene launched another trial involving 51 patients, infusing four times the viral dose and delivering the NTN to the substantia nigras and putamen. April 2013, after a 15- to 24-month follow-up, the results showed no difference between the treatment group and the placebo group.
- A person has a lifetime supply of 400,000 dopamine nerve cells, of which an average of 2,400 die every year.
- In 1985, Walther Birkmayer attempted to protect dopamine neurons using MAI inhibitors.
- In the late 1990s, Amgen and Steven Gill attempted to nourish damaged dopamine neurons using the growth factor GDNF.
- In 2000, Jeff Kordower attempted to use gene therapy to deliver growth factor NTN to nourish damaged dopamine neurons.
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