Parkinson's transplants emerge as stem cell pioneer Jeanne Loring joins R&D race
Jeanne Loring hadn’t studied Parkinson’s in 22 years when she got an email from a local neurologist.
The neurologist, Melissa Houser, didn’t know Loring had ever published on the disease. She was just looking for a stem cell researcher who might hear her out.
“I think I was just picked out of a hat,” Loring told Endpoints News.
At a meeting in Loring’s Scripps Research office, Houser and a Parkinson’s nurse practitioner, Sherrie Gould, asked her why there was so much research done in stem cell transplants for other neurodegenerative diseases but not Parkinson’s. They wanted to know if she would work on one.
“Funding,” Loring told them, get me the funding — $200,000 — and I’m yours.
That was in 2011. The decade that ensued saw scientists on three continents and both North American coasts work, sometimes collaboratively, to use new technology to resurrect a vision once discarded for reasons that extended well beyond scientific. Now, researchers are closely watching for the results of the first such transplants in Japan while Bayer-backed BlueRock is awaiting only a final FDA go-ahead to start its trials. And after nearly 10 years of patient and public-backed research, Loring is today launching her company, Aspen Neuroscience, from stealth mode with a technology others saw as unworkable and an eye toward its own trials next year.
Some are even toying around, cautiously, with the word “cure,” even as others – including the first doctor to execute a transplant for Parkinson’s – see more exciting developments elsewhere.
“We’ve developed symptomatic treatments,” BlueRock development VP Mike Scott told Endpoints. “But with this regenerative medicine approach, you’re talking about reversing lost function. It’s transformative. It has the potential to be a functional cure.”
Aspen enters with one of the most famous names in stem cell research. Loring did her PhD on stem cells before most Americans had heard of them and was dubbed by the late science journalist Bradley Fikes, “a stem cell evangelist” for her work over the ensuing decades. In 2001, she developed 9 of the embryonic cell lines George W. Bush approved for research.
“She’s one of the godmothers of stem cell therapy,” Scott said.
Loring’s first attempt at applying her cell work in biotech came at Hana Biologics in 1987, where she tried to graft dopamine neurons into rats engineered with Parkinson’s. Parkinson’s symptoms are caused by these dopamine neurons decaying — which affect not only pleasure, but also movement and body control — and it had been theorized that a transplant could curb or even reverse the disease. The longstanding carbidopa levodopal, or “L-dopa,” treatments supplement the lost dopamine but can vary in their effectiveness and don’t reverse the damage.
“There’s no turning back,” Loring said. “The only way to turn back the clock is to replace those neurons.”
The experiment proved promising, but the company failed. Loring published a paper and moved onto GenPham and Alzheimer’s mice.
At the same time, Curt Freed and Robert Breeze at the University of Colorado implanted a patient for the first time with human fetus-derived dopamine cells. From 1988 through 1999, they implanted 61 patients and published results showing some patient improvement, but the therapy went nowhere. The problem, Freed said, had little to do with efficacy.
“It was almost impossible to find the right kind of human fetal tissue from abortion,” Freed, who is not affiliated with Aspen or BlueRock, told Endpoints.
The technology for an alternative emerged in 2006, when Shinya Yamanaka demonstrated how any living cell could be chemically induced into stem cell state, effectively untethering stem cell research from its political and sourcing quandaries. In 2011, Lorenz Studer, founder of the Memorial Sloan Kettering Center for Stem Cell Biology, published a Nature paper showing how dopamine neurons from these induced human stem cells, also called induced-pluripotent stem cells (iPS), could be engrafted onto rats. Studer would go on to build that work into BlueRock in 2016.
Loring’s work leading up to that 2011 meeting had largely been in genomics — including founding Arcos Biosciences, the forerunner of diabetes cell transplant Viacyte — and after Gould and people with Parkinsons’ raised the necessary lab funds through a summit of Mt. Kilimanjaro, she took a different approach than Studer and top researchers in Japan and Sweden took.
Loring sought to do an autologous as opposed to an allogeneic transplant: Rather than take cells from another human, build up a large bank and then implant a certain number into a patient, she wanted to take a patient’s own skin cells, turn them into stem cells and then dopamine neurons and finally implant them into the brain.
“We’re the only company doing autologous,” Kim Kamdar, a Novartis alumn and partner at Domain Associates, which provided seed funding, told Endpoints. “The beauty in a way is the personalized medicine.”
There were scientific and economic reasons, though, that no other company pursued that goal. They may be part of why BlueRock launched with $245 million from Versant Ventures and Bayer, while Loring’s work was kept going through patient funding and emerges now with $6.5 million in seed cash. (They are hoping to close on a Series A in the first quarter of 2020.)
BlueRock over years developed billions of cells they keep in cryogenic storage in a New York lab. That costs money, as Aspen execs noted, but Freed and Scott suggested that having to build a new cell line for each patient would, like individualized CAR-T therapies, cost far more and introduced more potential production problems.
“You would need to have a highly robust, bulletproof, cell replication system,” Scott said.
Loring says she’s developed that. Leaning on her genomics background and a machine learning, she says she’s built technology to standardize the process. She argues that she can save money by manufacturing far fewer cell lines.
The platform will also allow them to predict and prevent mutations in the cell lines, Loring said, and because the cells are from the patient, their body will accept them.
“We won’t have to immunosuppress them,” she said.
Scott acknowledged Aspen’s immunosuppression benefits. BlueRock plans to immunosuppress patients in its first clinical trial. But it’s not actually clear that patients need the ubiquitous post-transplant drugs for a stem cell brain procedure because the immune system operates differently beyond the blood-brain barrier. BlueRock hopes to eventually stop giving the drugs.
Freed gave immunosuppressants to every other patient early on, and then stopped giving them entirely. His team has done 15 autopsies of former patients, he said, and not one showed a transplant wiped out by rejection.
“Our studies have shown immunosuppression is not required,” Freed said.
The key question, though – will any of this be effective – may take a while to answer.
Does it work?
At the end of last year, researchers at Kyoto University implanted the first of seven patients with allogeneic stem cells. Scientists are still eagerly waiting for the procedure’s results as it can take up to 6 or even 12 months before the implant cells will fully connect with the others and patients begin to show response.
That delay, among other issues, has some in the Parkinson’s community looking towards other solutions. David Sulzer, a neurobiology professor at Columbia University who last year received a grant to help research the role of autoimmunity in Parkinson’s, said transplants have potential – one day.
“It’s going to need a lot of work,” Sulzer told Endpoints, noting skepticism about cell lines and where cells will be inserted.
Among other possible obstacles is the fact that researchers don’t understand what causes Parkinson’s at the deepest level.
It’s possible, Scott said, that whatever killed the first neurons will kill the new ones.
Freed for his part has moved on. He says most of his research on transplants showed they work essentially the same as an l-dopa. It didn’t return lost function but pumped out dopamine at a steady pace, saving patients from having symptoms oscillate throughout the day. He’s moved on to phenylbutyrate, a drug he thinks can halt the disease. Other researchers are working on gene therapies.
The newer transplants, though, promise improvements on Freed’s work and patients backed it hoping for a significant remedy in their lifetime. After the Kilimanjaro fundraiser for Loring, Gould founded Summit for Stem Cell to continue backing her. Jennifer Raub, who has Parkinson’s, later became president, turned it into a 501c(3) and once raised over $1 million in a night to help find something that had broader, more consistent and long-lasting effects than the l-dopa she was taking.
“I made a conscious choice, as many do, to seek an alternative to carbidopa levodopa rather than wait until I can no longer function,” she wrote to Endpoints
For Loring, now in her 60s, Aspen represents a unique opportunity. Her work has changed medicine, but so far she’s directly developed no new FDA-approved drugs. She hopes to begin testing a potential one next year. They’ve already begun finding patients.
“It would be the culmination of my career,” she said, “and I’ve invested most of my life.”