A cellular therapy for epilepsy developed at UC San Francisco has been employed for the first time in a sea lion with intractable seizures caused by ingesting toxins from algal blooms. The procedure is the first-ever attempt to treat naturally occurring epilepsy in any animal using transplanted cells.
The 7-year-old male sea lion, named Cronutt, first beached in San Luis Obispo County in 2017 and was rescued byThe Marine Mammal Center(TMMC), based in Sausalito, Calif. His epilepsy is due to brain damage caused by exposure to domoic acid released bytoxic algal blooms. Each year, domoic acid poisoning affects hundreds of marine mammals, including both sea lions and sea otters, up and down the West Coast, a problem that is on the rise as climate change warms the worlds oceans, making algal blooms more common.
Like many of these animals, Cronutt cannot survive in the wild due to his epilepsy, and he was transferred by TMMC in 2018 to Six Flags Discovery Kingdom in Vallejo, Calif., which has facilities to care for wildlife with special veterinary needs.
In recent months, Cronutts health has declined due to increasingly frequent and severe seizures. With all other options exhausted, his veterinary team sought help from epilepsy researcherScott C. Baraban, Ph.D., in a last-ditch effort to save the sea lions life. For over a decade, Baraban, who holds the William K. Bowes Endowed Chair in Neuroscience Research in UCSFsDepartment of Neurological Surgery, has been developing the cell-based therapy, which has been shown by his research team to be highly effective in experimental lab animals.
This method is incredibly reliable in mice, but this is the first time it has been tried in a large mammal as a therapy, so well just have to wait and see, said Baraban, a member of the UCSF Weill Institute for Neurosciences. Over the years Ive come to learn how many marine mammals cant be released into the wild due to domoic acid poisoning, and its our hope is that if this procedure is successful it will open the door to helping many more animals.
On Tuesday, Oct. 6, a team of 18 specialists, including veterinarians from Six Flags and neurosurgeons and researchers from UCSF, successfully completed a precisely targeted injection of brain cell precursors taken from pig embryos called neural progenitor cells into Cronutts hippocampus, the brain region responsible for seizures. Based on extensive observations in rodents, Baraban said, the injected embryonic cells should migrate through his damaged hippocampus over the course of days and weeks, integrating and repairing the brain circuitry causing his seizures.
It was a remarkable convergence. Every year there are many animals suffering from epilepsy for which there isnt any treatment available, while, just across the bridge from The Marine Mammal Center, we at UCSF are trying to develop this new form of therapy and looking for ways to one day translate it to the clinic, saidMariana Casalia, Ph.D., a postdoctoral researcher who joined Barabans lab in 2015 to work ontranslating the groups successes in rodentsinto therapies, and who has taken the helm of the sea lion epilepsy project. It seemed very natural for us that these animals could be first patients to hopefully benefit from this therapy.
Domoic acid poisoning in marine mammals causes hippocampal damage very similar to that seen in temporal lobe epilepsy, the most common form of epilepsy in humans. In this disease, damage to hippocampal inhibitory interneurons removes the brakes on electrical activity, leading to seizures. In a vicious cycle, seizures can further damage brain circuitry, which is why epilepsy often worsens over time.
Since 2009, theBaraban labhas been developing a way to replace these damaged interneuronsby transplanting embryonic MGE (medial ganglionic eminence) progenitor cells into the hippocampus. As discovered two decades ago by Barabans UCSF colleaguesArturo lvarez-Buylla, Ph.D., andJohn Rubenstein, Ph.D., MGE cells normallymigrate into hippocampus during brain developmentandintegrate themselves into the local circuitry as inhibitory neurons.
Barabans group has shown that its possible to transplant embryonic MGE cells into the brains of adult rodents with temporal lobe epilepsy, wherethey quickly spread through the hippocampus and repair its damaged circuitry. The procedure reliably reduces seizures in these animals by 90 percent, along with other side effects of epilepsy, such as anxiety and memory problems.
Our laboratorys work has been inspired by the desire to find new solutions for the 30 percent of temporal lobe epilepsy patients who dont respond to available drug treatments, and for whom no new medicines have emerged over the past 50 years. Baraban said. For a number of reasons, including regulatory hurdles, cellular therapies for people with epilepsy are probably still a long way off. However, marine mammals with brain damage from domoic acid poisoning are in a very similar boat with no effective treatments that would let them ever be returned to the wild.
Baraban learned about the hundreds of annual domoic acidrelated strandings of marine mammals from long-time colleague Paul Buckmaster, D.V.M., Ph.D., of Stanford University. Buckmasters seminal studies in collaboration with TMMC in Sausalito had found that these animalssuffer from hippocampal damage almost identical to human temporal lobe epilepsy.
As soon as Mariana and I learned about this issue it was clear that our approach could be a perfect solution to help rehabilitate these animals, Baraban said.
Casalia had spent four years developing and testing a pig source of MGE cells pig tissue is often used for transplants into humans in collaboration with colleagues at UC Davis, work the lab intends to publish soon. On learning about the plight of domoic acidpoisoned sea lions, she partnered with TMMC and the California Academy of Sciences to study sea lion skulls to begin planning an eventual transplant surgery. She ultimately worked with UCSF neurosurgery chairEdward Chang, M.D., and collaborators at the medical software firmBrainLabto create a custom targeting system for the sea lion brain.She had even spent months working closely with the Hamilton Company to create a custom needle for delivering the stem cells to the right spot in a sea lions hippocampus.
All that remained was to find the right patient. And then, in September, 2020, they got a call from a veterinarian at Six Flags asking if they could help save the life of a sea lion named Cronutt.
After rescuing Cronutt in 2017, TMMC had attempted three times to rehabilitate him and release him back into the wild. Each time he would beach himself again, emaciated, disoriented, and approaching humans. Then he began to have seizures. Most marine centers dont have facilities for the long-term care of marine mammals with special needs, but Six Flags volunteered to give Cronutt a new home.
We have cared for a lot of special needs animals over the years, said Dianne Cameron, director of animal care at Six Flags. We adore Cronutt and are committed to providing him a forever home. He has his own apartment in our Sea Lion Stadium with a pool and dry resting area. When hes doing well, he comes out and participates in training sessions. Unfortunately, recently it has been hard to get him to come out of his apartment.
Over this spring and summer, Cronutt had begun a serious decline his seizures were increasing, he was losing weight, and he often seemed disoriented. To oversee Cronutts care, Six Flags hiredClaire Simeone, DVM, a founder and CEO of Sea Change Health, who hadstudied the neurological effects of domoic acid poisoningduring her six years working with TMMC. But it soon became clear that no treatment was working for Cronutt.
Despite our best efforts and all the tools that we have, his seizures were becoming more prolonged and more frequent over time, Simeone said. His brain damage and the effects on his body were getting worse. His decline has been gradual, but we reached a point several months ago where we were questioning what quality of life he had. We had run out of options for how we could successfully manage Cronutts disease and knew that we were going to have to make some hard decisions soon.
Then Simeone recalled a talk Baraban had given at TMMC several years ago about the potential of MGE transplants for marine mammals with domoic acid poisoning. In September, she reached out to ask if the lab might be willing to attempt the procedure as a last-ditch effort to save Cronutts life.
Cronutts health was slipping fast, but Casalias years of preparation for this moment allowed her and her colleagues to quickly assemble everything that would be needed in just one month.
In a bit of serendipity that would prove crucial, Cronutts brain had already been imaged in 2018 by Ben Inglis, Ph.D., of UC BerkeleysHenry H. Wheeler Jr. Brain Imaging Centeras part of an ongoing study ofhow domoic acid poisoning affects the sea lion brain. These MRI images provided critical guideposts that made it possible for UCSF neurosurgeons to plan how they would inject stem cells at just the right spot in Cronutts hippocampus.
Cronutts surgery, conducted in accordance with COVID-19 protocols at the SAGE Veterinary Centers in Redwood City, Calif., went smoothly, and he was returned to Six Flags. In the days after the surgery his veterinary team reported that he had been sleeping and eating well.
Based on prior experiments transplanting pig MGE cells into rats, the researchers expect it to take about a month or so for the cells to fully integrate into Cronutts hippocampus. They will be following up to see if his seizures decrease and his health and behavior improves, and whether his antiseizure medications can be reduced.
This first-ever attempt has been made possible by funding from a Javits Award from the National Institutes of Health and from the UCSFProgram in Breakthrough Biomedical Research. Without these funds, this kind of high-risk, high-reward science would never have gotten off the ground, Baraban added. It also depended on Marianas fearlessness and perseverance in pursuing this very uncertain project.
Casalia, who has degrees in applied science and neurobiology from Universidad National de Quilmes and the University of Buenos Aires in Argentina, says the surgery felt like a culmination of everything shed been working on in her career so far. Ive always wanted to apply what we are doing in the lab to the clinical setting, she said. For me the ability to do this in reality to help these animals who are suffering is a dream come true.
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