|Growing a New Antidepressant|
Nine years ago, Rusty Gage shattered a neuroscience dogma when he showed human brains give birth to new neurons. Today, a company is eager to take those findings to the clinic.
ARTICLE EXTRAS1 and Liz Gould and Bruce McEwen at Rockefeller had published a suite of studies on the effects of stress on neurogenesis in rodents.2 But the field was sparkling with newness, and huge questions remained. "At the time there was speculation about the modulatory factors of neurogenesis. Kempermann already showed exercise and an enriched environment increased it. But what are the molecular components?"
There were hints that serotonin might be involved. A year earlier, in 1998, Gould, now at Princeton, teamed up with her next-door laboratory neighbor, Barry Jacobs - known to some as Mr. Serotonin - to see if the neurotransmitter might have an effect on neurogenesis. They applied 8-OH DPAT, an agonist to the 5-HT1A serotonin receptor, or fenfluramine, which stimulates massive serotonin release. "And lo and behold we had loads of proliferation,"3 Jacobs says. Shortly following, two French investigators showed that depleting serotonin decreases neurogenesis in the hippocampus.4
At the same time Santarelli had begun work on a knockout mouse whose 5-HT1A serotonin receptor was lost. Though he had not published the work yet, Santarelli found that these mice did not respond to a number of antidepressants. He began to put pieces of the puzzle together: "I started wondering whether or not antidepressants could have some of their efficacy by changing the process of neurogenesis," Santarelli says. "And I thought, maybe my mouse is going to tell me something. Not only do I have a mouse where there's a disruption in the serotonin system, but also a disruption in the response to drugs." When Santarelli brought his ideas back to René Hen, "he thought I was crazy."
NEUROGENESIS, MEET ANTIDEPRESSANTS
René Hen sits in his corner office on the seventh floor of the New York State Psychiatric Institute in upper Manhattan. Leaning forward with his elbows on his knees, Hen remembers that he didn't want to invest too much time in Santarelli's neurogenesis project, and says that his hesitation was warranted. "When you think of classic hippocampal functions, you think [of] learning and memory," says Hen. "You wouldn't have thought changes in the hippocampus could change mood."
Nevertheless, Hen agreed. The plan was to ablate neurogenesis and test whether antidepressants still worked. Santarelli and a graduate student, Michael Saxe, went for a cheap trick: They decided to use low doses of radiation to kill dividing cells in the hippocampus.
Searching around Columbia's medical campus, they found a 35-year old Siemens Stabilopan X-ray System that had been retired from use in breast cancer treatments. What they needed next was a lead apron that would fit over the mouse and allow only the hippocampus to be irradiated. Next door to the radiation room was a carpentry shop run by an expert in probe design for radiation research. In exchange for mouse-sized aprons with tiny slits above the hippocampus, Santarelli would buy him Jack Daniel's bourbon or 12-packs of beer. "He didn't drink on the job!" Santarelli jokes.
Meanwhile, the stirrings of a new theory in depression were beginning to emerge. In 2000 Gage and Jacobs, who took a sabbatical from Princeton to join Gage's laboratory for a year, proposed a theory of depression in which decreases in neurogenesis in the dentate gyrus precipitate depression, and pharmaceutical interventions that increase serotonin improve neurogenesis and relieve depression.5 In the meantime, Ron Duman's group at Yale, who assisted Santarelli on his project, found that antidepressant treatment increases neurogenesis.6
The findings confirmed some of Santarelli's suspicions, but Hen reminded him it was merely an association. The ablation experiments would show whether neurogenesis was necessary for antidepressants to be effective. After some time spent getting the radiation protocol optimized, the experiments worked. In August 2003 Santarelli and his collaborators published an article in Science showing that antidepressants do indeed require neurogenesis to change behavior.7 "I was thrilled," says Gage, who was anxious to learn more about the functional role of neurogenesis. "I thought it was great."
A MARKET FOR NEUROGENESIS
"From the moment we found neurogenesis was necessary for antidepressants, one of the natural consequences of that finding was, if we identify compounds that stimulate neurogenesis, we could maybe get new antidepressants," says Hen. There is certainly a market out there for new therapeutics, he adds. Though dozens of antidepressant drugs are on the market, there is still room for more, agrees John Rush, a professor of psychiatry at the University of Texas Southwestern Medical Center. "Our current therapeutic armamentarium certainly leaves a lot to be desired," Rush says. "A lot of the drugs out there are similar." He says about one-third of patients with depression are resistant to antidepressant treatments.8
Moreover, Rush says, about 10%-15% of patients switch drugs because of side effects such as insomnia, anxiety, and sexual dysfunction. Hen says that stimulating neurogenesis might bypass the serotonergic system (thought to be responsible for the side effects) and perhaps improve the tolerability of the drug. Still, Rush says, "most of the drugs are pretty well tolerated ... even a new drug, even if it doesn't affect those neurotransmitters, could affect other brain functions and have [its own] side effects."
As Hen and Santarelli recruited cofounders (including Nobel laureate Eric Kandel) and began discussing their business plans, another group was also hatching plans to capitalize on neurogenesis. Oxford Biosciences, a venture capital group based in Boston, knew there was opportunity in neurogenesis, but they weren't sure what it was. In 2003 they hosted a neurogenesis think tank in Westport, Conn., at which Kandel, Gage, Hen, Santarelli, and a few others attended and presented ideas. Gage had developed protocols for positive neurogenesis controls, optimal neural stem cell cultures, and for labeling and measuring proliferation, differentiation, and survival of new neurons; Santarelli had already received his results from the neurogenesis ablation experiments. Essentially two business ideas shook out of the meeting: Hen and Santarelli wanted to stimulate neurogenesis to treat depression, and Gage had developed in vitro assays that could be used to screen compounds for their effects on the different stages of neurogenesis.
Gage's assays could be used in a general way to measure a drug's neurogenic effects, but Hen's proposal would give those screens focus. "What every good venture capitalist tries to do is to put the best of the best under one tent," says Ellen Baron, a partner at Oxford Bioscience. She and another partner, Jonathan Fleming, offered to develop one "supercompany" that would target Gage's screening tools toward depression. Oxford Biosciences attracted other investors, including Bay City Capital, Technology Partners, and Pappas Ventures, and raised $17.7 million for their initial investment.
Baron and Fleming also thought that BrainCells could bring drugs back to life - drugs that other companies had developed and abandoned. "One way one uses these [screening tools] are as new eyes for existing compounds, because then you can leapfrog the potential of that compound into the clinic," Baron says. By choosing drugs that have already passed through safety trials, BrainCells could potentially shave years off drug development and save millions of dollars as well.
Leasing drugs from companies hasn't been an easy process, however. Before BCI540 surfaced in BrainCells' screens, several other drugs showed promising results. BrainCells approached a handful of companies to begin negotiations on in-licensing their compounds, but when BrainCells presented the neurogenesis data from the potential drug, "they no longer wanted to give us the compound," says Carrolee Barlow, BrainCells' chief scientific officer. The problem, she says, was the size of the companies they were talking to. "A company that is very small and only has two drug assets, if one is on the shelf, it's more valuable on the shelf than if it's gone." In-licensing is like a permanent lease, and Barlow says that once companies discover that their compound might have useful properties, they are not willing to give it away. What those companies would eventually do with those compounds was a mystery. "We stopped looking to repurpose drugs from very small biotech companies," Barlow says.
TO THE CLINIC
BCI540 resulted from that shift in strategy. The owner is $2 billion-a-year Mitsubishi Pharma, which tried the drug for a nonpsychiatric neurologic disorder on more than 300 patients in the United States. Citing competitors who may want to take advantage of their technology, BrainCells won't disclose the identity of the compound or its mechanism of action. Barlow will say only that it does not act upon serotonin, norepinephrine, or dopamine pathways as traditional antidepressants do. She says that patients took the drug for six months with side effects no different from placebo. None of the patients were assessed for changes in mood. Ultimately the drug failed in Phase II trials for lack of efficacy for its original indication.
Once Morse's in vivo results showed that BCI540 was neurogenic and acted like an antidepressant in the novelty-suppressed feeding assay, BrainCells decided to go after the compound. "It was really exciting because we knew it was already safe in humans," says BrainCells' Carter. BrainCells approached Mitsubishi Pharma with a proposal that each company would disclose information about the compound to one another and decide if in-licensing was desirable. Five months of negotiations followed to establish the terms of an in-licensing agreement, which BrainCells' CEO Schoeneck says is a fast turn around. Oxford Biosciences' Baron says the money that was raised originally for the company in the first round was sufficient to cover the costs of in-licensing. Of the $25 million raised for the company so far, they've spent $18 million. Now the company is working on raising another $37 million to bring the drug to humans. Barlow says the board agreed to pursue BCI540 because of the excitement of finding a drug that acts as well as antidepressants in their assays, but doesn't work on serotonin.
BrainCells plans to enter Phase IIA clinical trails once the funds are in hand. A little less than one hundred patients with major depressive disorder will be given a dose of BCI540 either once or three times per day for six weeks. The pills have already been manufactured and if all goes as planned the results should be available sometime in 2008. Barlow says that if BCI540 can meet efficacy goals, the idea is to collaborate with a large pharmaceutical company in the development of a new antidepressant.
BrainCells has a few back-up plans in case BCI540 fails. Schoeneck says BrainCells' screening platform can be used to partner with other companies that want to uncover neurogenic properties of their compounds. The company has already partnered with Organon, a division of Akzo Nobel, to screen Organon's compounds that stalled along the clinical pipeline for neurogenic properties. Barlow says BrainCells' technology might have other applications, such as a treatment for macular degeneration or hearing loss. BrainCells also continues to screen compounds for potential antidepressants. Still, success is no guarantee. As Hen says, "We proved [neurogenesis] is necessary. Now what they are trying to do is prove it's sufficient."
IS NEUROGENESIS ENOUGH?
Fritz Henn, at Brookhaven National Laboratory, is skeptical. At the same time Santarelli and his colleagues were demonstrating the role of neurogenesis in antidepressants, Henn was looking at whether a decrease in neurogenesis could induce depression. Henn hypothesized that every animal with impaired neurogenesis should show a change in behavior. But when he induced a decrease in neurogenesis by exposing animals to the same stress, only a fraction of the animals exhibited depressive behaviors.9 "Given our findings ... I've argued that looking for drugs that specifically increase neurogenesis doesn't seem to be the right approach," says Henn.
Henn's hunch is that the key to relieving depression lies in synaptogenesis. "What really matters in depression is not how much you knock down neurogenesis, but how many cells really integrate into the system." Where and how is unknown. "There is more to depression than just neurogenesis," says Bruce McEwen at Rockefeller. A suite of changes occurs in the brains of people with depression: hippocampal volume reduction, decreased density in glial cells and neuronal size in the prefrontal cortex, and changes in blood flow and glucose metabolism in the hippocampus and amygdala. Stress also causes extensive dendritic remodeling in the hippocampus. "So the question is," McEwen says, "whether these small molecules that work on neurogenesis in the hippocampus also work on these other parts of the brain involved in depression. I don't think neurogenesis is the be-all and end-all of depression, but it's certainly very important."
As BrainCells brings its compound to humans, the experiment could help answer a looming question that Princeton's Jacobs has posed: "Do any of these animal models have anything to do with human clinical depression?" Investigators at BrainCells admit behavioral assays in rat are imperfect models for human mood disorders. Irwin Lucki at the University of Pennsylvania points out that one of BrainCells primary models, novelty-suppressed feeding, is more a proxy for anxiety than depression. "It remains to be demonstrated that models of depressive behavior and neurogenesis are related," Lucki says.
Still, Lucki says screening compounds for their neurogenic properties is appropriate for determining their effects as a chronic antidepressant (he's currently working on a similar project with Wyeth). Santarelli, who is no longer involved in BrainCells because of a potential conflict with Roche, where he now works, says going after neurogenesis is worth a shot, simply to try something new. "There isn't much novelty in depression in the pipeline," Santarelli says. "The only way to break out the mold is to do things like this."
1. P.S. Erikkson et al., "Neurogenesis in the adult human hippocampus," Nature, 4:1313-7, 1998. | [PubMed]
2. E. Gould et al., "Neurogenesis in the dentate gyrus of the adult tree shrew is regulated by psychosocial stress and NMDA receptor activation," J Neurosci, 17:2492-8, 1997. | [PubMed]
3. B.L. Jacobs et al., "Serotonin stimulates the production of new hippocampal granule cell neurons via the 5HT1A receptor in the adult rat," Soc Neurosci Abstr, 24:1992, 1998.
4. J.M. Brezun, A. Daszuta, "Depletion in serotonin decreases neurogenesis in the dentate gyrus and the subventricular zone of adult rats," Neuroscience, 89:999-1002, 1999. | [PubMed]
5. B.L. Jacobs et al., "Adult brain neurogenesis and psychiatry: a novel theory of depression," Mol Psychiat, 5:262-9, 2000. | [PubMed]
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9. B. Vollmayr et al., "Reduced cell proliferation in the dentate gyrus is not correlated with the development of learned helplessness," Biol Psychol, 54:1035-40, 2003. | [PubMed]