NEW YORK — The introduction of levadopa therapy more than 40 years ago marked a milestone in the treatment of Parkinson’s disease. The dopamine replacement drug helps control the motor symptoms associated with the neurodegenerative disease, but it does not prevent the further loss of dopamine-producing neurons, so researchers have been on the hunt for more neuroprotective treatment options.

At the Parkinson’s Disease Therapeutics Conference here last week — hosted by the Michael J. Fox Foundation (MJFF) and the New York Academy of Sciences — a who’s who of Parkinson’s researchers met to discuss some of the more promising approaches, ranging from small molecules that hit novel drug targets to the first vaccine to enter clinical testing.

One lead involves blocking Cav1.3, a subunit of a calcium channel that enables the channel to stay open and facilitates dopamine-dependent neuron activity. Two years ago, James Surmeier, a physiologist at Northwestern University in Chicago, first linked calcium signaling, particularly through Cav1.3 channels, to the selective degeneration of dopaminergic neurons. Building on those findings, at the meeting last week Surmeier reported the results of a high-throughput screen showing that a compound called pyrimidine 2,4,6 trione blocks the Cav1.3 channel in cell culture. These findings dovetail with a paper published earlier this year by another group at Northwestern University showing that similar compounds were also neuroprotective in a cultured cell model of amyotrophic lateral sclerosis, suggesting that the drug candidates may be useful across neurodegenerative diseases.

Surmeier’s group is now following up his unpublished cell-based findings with experiments in rodent models of Parkinson’s. Despite the results being very preliminary, they are already creating quite a buzz. “This is a totally different idea,” says Anders Björklund, a neuroscientist from Lund University in Sweden who was not involved in the research.

Another new strategy involves activating the glutamate receptor mGluR4. Last year, researchers at Vanderbilt University in Nashville, Tennessee reported the synthesis of a new mGluR4-potentiator compound, dubbed VU0364439. And at the meeting, Vanderbilt’s Jeffrey Conn presented unpublished work showing that another compound had acute effects on motor functions in animal models.

“This will be a brand new drug with a brand new target,” says Conn, noting that he’s in late-stage discussions with a commercial partner to further develop the drug and launch clinical trials. But the Vanderbilt group is not the only one working on mGluR4 drugs. In January, for example, Merck Serono announced a $178 million deal with the French company Domain Therapeutics to develop mGluR4 activators.

Nurr-oprotective effects

Meanwhile, other drugmakers are advancing different approaches. For instance, San Diego-based Acadia Pharmaceuticals is attempting to modulate the Nurr1 transcription factor, which is essential for the growth, development and survival of dopamine-producing neurons.

Since Nurr1’s discovery nearly 15 years ago, pharmaceutical companies have desperately sought to find a ligand that can bind to Nurr1, but to no avail. So instead, Acadia decided to target the receptor indirectly, through its binding partner, the retinal receptor RXR. The company’s molecule, AC-838, binds to the Nurr1-RXR complex and is able to reverse loss of dopamine-producing neurons and improve motor function in animal models of Parkinson’s disease. “There are many others searching for a Nurr1 ligand, but I think we’ve got a little hook,” says Acadia’s head of biosciences Ethan Burstein, who presented a poster showcasing the work.

However, Acadia might have competition. Earlier this year, researchers at the National Yang-Ming University in Taiwan published a paper showing that docosahexaenoic acid, another ligand for the Nurr1-RXR heterodimer, caused a similar increase in dopamine release of neurons in rats. And according to Björklund, who studies Nurr1, larger pharmaceuticals such as Sanofi and Abbott Laboratories have an active interest in Nurr1 complexes as well.

Beyond new therapeutic targets, some companies are also trying new therapeutic approaches. Various groups — including the Austrian company AFFiRiS, the University of Texas Health Science Center and the University of California-San Diego — are currently competing to develop the first Parkinson’s vaccine targeted at reducing pathological build-up of alpha-synuclein, a characteristic marker of the disease.

But AFFiRiS might have a leg up. Last month, MJFF awarded the company $1.5 million to begin a clinical trial that is slated to launch by the end of the year. At the October meeting, Markus Mandler, the company’s head of neurodegeneration, also reported preclinical data showing that vaccinated mice performed better on functional memory tests and produced antibodies against alpha-synuclein that managed to cross the blood-brain barrier and even enter neurons in the brain.

Results like those presented last week seem to indicate that the field is moving away from easing symptoms of the disease and toward a more preventive approach. Let’s hope that this is more than just a tremor in the research force.