Del Mar professor of medicine and neuroscience honored for discoveries made on diseases such as Huntington’s, ALS

Honoree Don Cleveland in the lab.

By Kathy Day

Don Cleveland’s career path took a turn when he was in graduate school at Princeton, veering from physics to biochemical sciences.

The Del Mar resident was married then to a biologist who used to come home and talk excitedly about her experiments.

In physics, experiments take about 50 people; in biology it takes two or three, he said. Soon, he changed directions and earned a Ph.D. in biomedical sciences. Today he is a professor of medicine and neuroscience and heads the Laboratory of Cell Biology at The Ludwig Institute for Cancer Research at UCSD. He is also chair of UCSD’s Department of Cellular and Molecular Medicine.

His change of focus may well turn out to be a very good thing for people suffering from neuromuscular and neurogenetic diseases, such as Huntington’s, amyotrophic lateral sclerosis (Lou Gherig’s disease) and spinal muscular atrophy – a fatal disease affecting children who are born with little muscle tone and never develop muscle control.

He has teamed up with Dr. Frank Bennett, senior vice president of research at Carlsbad-based Isis Pharmaceuticals, and Holly Kordasiewicz, who used to be a member of Cleveland’s research team and now is at Isis, to work on a way to treat these diseases. In the June edition of the journal Neuron, they reported that they had found a gene that can silence the mutated gene that causes Huntington’s disease. In animal models, they found that a single infusion of a DNA-based drug built on Isis’s antisense gene-blocking technology slowed and even partly reversed the progression of the debilitating disease.

On Nov. 16, the Huntington’s Disease Society of America ( honored the trio and their research teams at the annual Celebration of Hope Gala & Auction at the Manchester Grand Hyatt. According to a press release “The honorees have made discoveries into the causes and treatment of human neurodegenerative diseases, especially ALS and Huntington’s diseases. Their efforts are pioneering the development of stem cell and gene silencing therapies for both of these disorders.”

Huntington’s is a fatal genetic brain disorder that results in the loss of all mental and physical capabilities. It affects about 30,000 people a year, Cleveland said.

For him, the “aha moment” was the realization that DNA-based drugs could be used to treat disease. It came after the concept was repeatedly championed by Richard Smith, a neurologist and director of La Jolla’s Center for Neurologic Study.

“He came by and said, ‘Don, you should try it,’” Cleveland recalled, adding with a wry smile, “He was very pushy and very annoying.”

Then Smith met Bennett, one of the founders of Isis, and told him the same thing.

Finally, Cleveland said, “We just told him we would do it.”

Initially, they didn’t think that if you infused the DNA into a single gene that it would transfuse throughout the body. But their experiment showed otherwise.

“It broadly delivers an effective drug into the nervous system,” he said, noting that the approach is being applied to several diseases and has already entered clinical trials in three. They hope to move into the clinic with Huntington’s patients within a year. “The last 14 months have been the most exciting time in ALS (research) in history.”

Thirteen months ago they discovered the cause of that disease. Cleveland read the original description in a scientific journal on a Wednesday; on Thursday he and the team started talking about “likely clinical strategies” and off they went into their labs. Today Isis has a drug for spinal muscular atrophy, using the antisense technology, in clinical trials.

Meanwhile, Cleveland still is focused on “establishing the feasibility of trying to truly treat the primary causes of cancer,” but his excitement over the efforts in neuromuscular and neurodegenerative diseases is hard to hide.

Huntington’s disease is a “monogenetic disease,” meaning that a single gene causes the damage, in this case producing a toxic protein called the huntingtin that damages and ultimately destroys brain cells. Because of that, the antisense approach to silence the gene “makes great sense,” he said. It’s a technique already proven safe in trials and there are already antisense drugs approved for other uses.

In research to date, Cleveland’s researchers and the Isis team have been able show the mutated gene’s instructions can be turned off for short periods and that the effects can actually be reversed for a period of time.

It could be that a monthly or quarterly infusion could prove to be the answer for those who suffer from this type of genetic disease, Cleveland noted.

As the team pursues the latest discoveries into the clinic – his former student Kordasiewicz left for a job at Isis to do just that – Cleveland leads his team of 15 post-doctoral students at the Ludwig Institute. It’s the largest of the centers funded by the global non-profit founded by Daniel K. Ludwig, a business magnate who pledged $1 billion to support cancer research after his wife died of the disease. Cleveland left Johns Hopkins University School of Medicine in 1994 to head up the center.

He enjoys the teaching part of his work and, like many of his colleagues, he said, “I teach all day every day.”

He gets major satisfaction from seeing his students succeed -- 25 have left for jobs all over the country and one is running a clinical trial for an ALS drug.

“I’m proud of lots of them,” he said. “They’re going to replace me one day. That’s the goal.”

He tries to impart to them something he began to learn at Princeton about the keys to success.

“Smart is nice, being experimentally talented is helpful and perseverance helps.”

But it is the process of discovery that is the key part, he added. “If you enjoy it, it’s a great life. If not, get out.”

A native of New Mexico who did his undergraduate work in physics at New Mexico State University, Cleveland says he lives his hobby, spending nearly 12 hours a day on campus.

Occasionally he finds time to take a run, enjoys spending time with his wife and their two cats, and gets a kick out of traveling all over the world to talk about his work.

“My mother said, ‘You have to have a hobby,’” said Cleveland, whose father was a physicist. “I get paid for my hobby. I’m engrossed in it. I like what we do.”