By Dan Fost
When a child is diagnosed with a rare and life-threatening disease, the parents often don’t know where to turn.
Mark Dant was told his toddler, Ryan, wouldn’t make it to his tenth birthday. Ryan had a rare genetic disorder, the doctors called it, Mucopolysaccharidosis (MPS I).
Not only was there no cure, but the disease was so rare that no one was even looking for a cure. There would be no money in finding a cure. But Mark Dant didn’t give up. He found Emil Kakkis, MD, PhD, at the time a young scientist and now a biotechnology legend, who worked tirelessly to find a treatment for MPS I. Today, Ryan Dant is 28 years old and on the verge of graduating from college.
“Not a day goes by that I don’t wonder what my son’s life would have been like without this medicine,” Mark Dant says.
Mark Dant and Emil Kakkis provided the emotional and inspirational bookends to a remarkable Rare Disease Symposium at UCSF on March 3rd titled “Negotiating the Challenges of Therapeutics Discovery for Rare Diseases.” The event, hosted by the UCSF Catalyst program, presented a mix of speakers, from family members passionately advocating for research into rare and so-called “orphan” diseases, to scientists giving hopeful talks about cutting edge developments that provide those families with that all-important quality, hope.
“It's an interesting time for rare diseases. It's been an area that no one would touch for a long time, because there’s no money in it due to the small patient populations” said Cathy Tralau-Stewart, PhD, interim director of the Catalyst Program. But now, with new technologies, she said, “There's massive enthusiasm about working in the rare disease space. If you can define your drug mechanism and linked patient population, you have a significantly higher chance of creating a successful therapy and moving our understanding of the disease biology forward.”
That’s because targeting a rare disease enables a scientist to focus on a narrow area, ruling out many other factors. The knowledge gleaned from such efforts can then be applied to a better understanding of the molecular mechanisms underlining a vast array of genetic variations that play a role in more common diseases.
“We can use research into rare diseases to understand something you couldn't understand in any other way in human patients,” said Kakkis. “Rare disease research will also open the door of insight into common diseases. We think rare disease treatments will translate to larger markets, either with the drug itself or the understanding and insight.”
Individually Rare, But Affecting Millions
Kakkis has a foot in both the for-profit and nonprofit world as president and chief executive officer of Ultragenyx Pharmaceutical in Novato, California, and as founder and president of the nonprofit EveryLife Foundation for Rare Diseases. “Rare disease research matters because 10 percent of Americans are affected by a rare disease,” he said. Although the diseases themselves are individually rare, the National Organization for Rare Disorders estimates that 30 million people in the U.S.—half of them children—have one of 7,000 rare diseases.
“Many of them are lethal and devastating,” Kakkis said. “The fact that there's so many of them has made it hard for people to focus and execute.”
One ray of hope is found in collaborations between academia and industry. “Academia offers the longest time frame to incubate creative ideas, which is hard to do in a company where the urgency is timed for the next quarter,” Kakkis said. “Linking those two allows the seed to be planted in academia, things can start to grow, and then the company can pick them up and actually take them to the marketplace.”
“In the rare disease space, it's extremely important for there to be collaboration,” he added. “No one person and no one company usually knows enough. You have to pull bits of information from all kinds of different people. You have to be able to tap into all the knowledge, brains and creativity to find solutions for rare disease patients.”
Tralau-Stewart couldn’t agree more. “My driver here is to cure and treat more diseases,” she said. “I genuinely believe that linking industry and academia is a key part of the answer. If we can make these collaborations work, we can get more treatments to patients. That's the game.”
UCSF’s Cutting Edge Science
Some of UCSF’s top scientists presented their research at the symposium, demonstrating the potential for new advances.
Wendell Lim, PhD, chair of the Department of Cellular and Molecular Pharmacology, painted an ambitious picture of how the emerging science of reprogramming cells may someday make a major impact in rare disease research. “It would be wonderful and like something out of science fiction if we could engineer cells the way we engineer molecules—but that’s what we’re working on.”
Lim said scientists have been working on “synthetic biology” for quite some time. In this case, the goal would be to manufacture “little robots,” in which “we could change or modify what programs the cells execute and apply it to disease.”
Some modified cells have already shown promise in fighting certain cancers, he said, but there are stumbling blocks. “You can see how powerful a cell is if it’s modified in the right way,” he said. “We put cells in patients and they do amazing things, but we lack a way to talk to the cells once they’re in there.”
Nadav Ahituv, PhD, a professor in the Department of Bioengineering and Therapeutic Sciences, revealed preliminary research that he has not yet even published. Ahituv’s research suggests that CRISPRa is showing promise as a therapeutic strategy for diseases linked to haploinsufficiency.
The genome editing tool CRISPR/Cas9 has received a lot of attention in the scientific community for making it possible to alter DNA and possibly thwart diseases. CRISPRa can be used to activate a gene promoter or enhancer and increase gene expression. Ahituv showed dramatic slides in which he used CRISPRa to reduce the weight of obese mice which were overweight due to being haploinsufficient for an obesity-related gene. “It worked,” he declared, which will keep him conducting experiments to see what else might work.
It’s somewhat rare for a so-called basic scientist to come across something that might be translatable to the clinic, and Ahituv finds it thrilling. “As a basic scientist, I can't make a therapeutic,” he said. He noted that for all of his scientific expertise, he has no experience with such agencies as the federal Food and Drug Administration (FDA). “I want to get into the clinic. I don't know the FDA, I don't know much about clinical trials. Catalyst is a great system” for enabling collaboration, he said.
“As a geneticist, until recently, we were mainly able to find the causes of diseases, but CRISPRa now actually provides us a way to develop therapeutics for these diseases,” Ahituv said. “That's one of the most exciting things we've found.”
Ophir David Klein, MD, PhD—a research scientist and also a clinical geneticist—wears many hats at UCSF, including chief of the Division of Medical Genetics, chair of the Division of Craniofacial Anomalies, medical director of the Craniofacial Center and director of the Program in Craniofacial Biology. He said he’s been taking “the first steps on a long road” to finding medical approaches to structural birth defects.
He said that 3 percent of all births have birth defects, accounting for a large fraction of infant illnesses and deaths, and he mused, “Can we treat or prevent birth defects in utero?” Studies are challenging: “To enroll six to 10 infants with a rare disorder into a study is amazingly difficult,” he said, considering they need a prenatal diagnosis and must have a known mutation in their family. For some diseases, there may be only a handful of patients around the world.
Klein worked with a company in the U.S. on a clinical trial for a promising drug, but the company ran out of money before it got FDA approval. The same drug is now being investigated by a doctor in Germany, where there are easier rules, and the drug can be injected prenatally. “It has shown promise,” he said. “My hope is that, with further study, it’ll work.”
Klein and Ahituv both used the word “fun” to describe their collaboration with industry partners. “I'm on the scientific advisory board for one company, Encoded Genomics,” Ahituv said. “I meet with them every two months. That's one of the most fun things I do. The scale is much bigger than what we can do.”
Industry Partners Join the Fight
The value of that sort of collaboration was very much in evidence at the symposium. Companies that sponsored the event included BioMarin, Genentech, Sanofi Genzyme, Ultragenyx Pharmaceuticals and, Charles River Associates and executives from those and others participated on panels at the symposium, declaring their support for research into rare diseases.
Whether an industry giant or bold new startup, companies proclaimed an appetite for tackling the tough problems of rare diseases.
Scott Clarke, senior vice president of Product Development at BioMarin Pharmaceutical, moderated a sponsor panel discussion: How Does Rare Disease Research Fit Into Company Strategies/Approaches? Scott joined Emil’s startup BioMarin in 2005 when the company only had enough in reserves to cover the next two payrolls. Over the last ten years, BioMarin has grown into a rare disease therapeutic giant with five products on the market and over $1 billion in revenue. According to Scott, half of the revenue goes back to invest in rare disease research. Scott emphasized that future successes are “depending on institutions like UCSF to take new technologies like CRISPR and oligonucleotides moving forward to enable new therapies”.
Angelika Jahreis, MD, PhD, FAAD, group medical director, Genentech, said her company has “quite a few drugs with orphan drug approval.” “We focus on diseases with high unmet medical needs,” she said. “We don’t want to make an incremental impact, but a big impact on patients.”
Her colleague, Jeffrey Siegel, MD, who wears two hats at Genentech Roche—senior group medical director in product development immunology and global lead for rheumatology and rare diseases—spoke to the challenges of getting approval for a new drug from the FDA. Because of the small population that suffers from any individual rare disease, Siegel said, scientists wanting to test a new treatment must overcome hurdles such as “finding enough patients for a clinical trial, a lack of validated endpoints, showing efficacy in a reasonable time frame, and the challenges of randomizing to a placebo.”
At the other end of the spectrum from the giant Genentech Roche, Neil Kumar, PhD, CEO and founder of BridgeBio, a small new startup, is studying genetic diseases and genetic-driven cancer. “We see ourselves as an emerging company that sits on top of what’s already been done with clinical genetics, molecular biology, and where they intersect.”
BridgeBio was founded by venture capitalists focusing on 300 of the 7,000+ identified rare diseases, and a concept of finding scientists doing interesting work and bringing them in-house where they can benefit from centralized expertise. “If something looks promising, we’ll try to move it forward,” Kumar said.
Many of the companies said they look to academia for those new ideas. “All of our programs to date have been brought in from academic partners, with whom we’re still working,” said Natalie Holles, senior vice president and chief operating officer of Audentes Therapeutics.
Holles identified some of the tricky challenges confronting companies working to cure rare diseases. The people who have a disease are often so desperate for any help that they are eager to sign up for clinical trials. Yet the population with any given disease is so small that, “if you treat them in a clinical trial, you could lose them as a customer” when the drug is approved, Holles said.
“How do we get the therapy to the patient early, which is needed, and still get rewarded for our efforts?” she said. “It’s got to be a viable business model. I don’t know how, but we’ll get there.”
Holles doubled down on her optimism, declaring, “We’re really at an inflection point for our field. Eighteen months ago, we decided to build our own plant in South San Francisco.”
Similarly, Arcturus Therapeutics has occupied a former Pfizer campus in La Jolla, Calif., where it works to apply RNA technologies to the treatment of rare diseases. Fortune magazine described how Arcturus, founded in 2013, turned a $50,000 startup investment into nearly $2 billion in deals with industry heavyweights like Johnson and Johnson. “We’re sitting on some fantastic gene-editing data,” Joseph Payne, Arcturus’s president, CEO and chairman, said at the UCSF forum. “We want to define ourselves as the messenger RNA rare disease company.”
“This is why we do it,” Payne said, showing a slide of six babies diagnosed with rare diseases in the past six months. “If we don’t do our job, they could all die by age 12.”
Many scientific symposia can feel abstract, with talk of molecules and slideshows full of mice and worms. In contrast, the Rare Disease Symposium featured flesh and blood stories that related the human toll these diseases take.
Ben Lenail, 51, of Palo Alto, a successful Silicon Valley executive, told of a five-year odyssey begun when he was 40 to get a diagnosis for his mysterious disease—a common story for people with rare ailments. In Lenail’s case, that turned out to be the neuro-metabolic disease X-linked adrenoleukodystrophy (X-ALD), a deadly genetic brain disorder that affects 1 in 18,000 people, mostly boys and men.
Dean Suhr told how two of his three daughters had been diagnosed with MLD, or metachromatic leukodystrophy, a degenerative brain disease that affects one in every 40,000 babies. It took six years to diagnose it in his oldest daughter, when she was 14; his youngest was affected as well.
Amer Haider said some scientists offered him a ray of hope when he bemoaned the fiscal realities of finding a cure for an orphan disease. Haider, who had a successful career in finance and technology, cofounded two nonprofits when he had one child with clubfoot and another with dwarfism.
“I asked a researcher, ‘How much money would it take to move the ball in your field?’” Haider said. “I thought he would say $100 million. He said, ‘A couple of $100,000.’ I asked, ‘How is that possible?’ He said, ‘I have a lab. All I need is a couple of postdocs. If I can show promise, I can get grants.”
Perhaps most powerfully, Karen Park told of the struggles parents face when doctors can’t diagnose a disease, as often happens with rare disorders—the case with her son Milo.
“Being a parent to an undiagnosed child with complex special needs is a very challenging thing to go through,” she said. “We desperately need your help.”
Having a child with special needs is isolating, she said, but at least there are special needs communities. Within those groups, specific disorders like Down syndrome have their own communities; even children diagnosed with rare diseases have foundations and support groups. “When you’re undiagnosed, there is no tribe,” Park said. “You’re completely isolated. You’re on your own.”
Her son Milo is six years old now, and while she was told he might end up no better than a vegetable, he is actually attending school in a general education classroom and doing well. “He’s considered on grade level academically,” she said. The Milo’s Journey website says that Milo has had six surgeries and global developmental delays. It notes: “He started walking on his own in summer of 2015 and still requires close spotting to do this safely. His fine motor skills are delayed but he is making progress and slowly taking to writing with a traditional pencil. He is also able to use alternative pencils to write (and he is pretty good at spelling!). He has significant speech delays but understands everything we say. He is quite adept at expressing himself using an alternative communication system known as the PODD.”
Genetic testing finally lifted some of the isolation, pointing to a variant of the KDM1A/LSD1 gene. Park started the Milo’s Journey website, and almost immediately heard from another parent. She now knows of two others—a total of four—with a mutation of the gene. And that gives scientists something to work with.
“I don't have a huge degree of confidence that we're going to find some gene therapy that will 'cure' this disorder during my son's lifetime,” Park said, “but I want us to be in a place where we've been doing enough research along the way that we can participate if there starts to be breakthroughs in these kinds of therapies.”
Park looked up and addressed the scientists and biotech executives in the audience, and put the question to them that many must have been thinking: “How can all of you help?”
“Be collaborative,” she said. “Offer hope and perspective and compassion to special needs families. Try and inform parents of the resources available to them.”
“I hope,” she said, “that through all of this, you can help us bring the promise and the vision of precision medicine, and make it a reality for families like mine.”
Watch videos of the event below:
- Welcome & Keynote: by Emil Kakkis
- Sponsors Panel: How Does Rare Disease Research Fit Into Company Strategies/Approaches?
- Presentation: Orphan Drug Discovery Using Whole Animal Disease Models by Ethan Perlstein / Panel: Role of Disease Foundations
- Presentation: Transformative Cellular Technologies in Rare Disease Research by Wendell Lim / Case Study: Building Life: A New Era of Nucleic Acid Therapeutics to Treat Orphan Diseases by Joseph Payne
- Presentation: Challenges in rare Disease Development: Navigation the Regulatory Environment by Jeffrey Siegel / Panel: Challenges in Rare Disease Development & Clinical Research in Small Patient Populations / Parent Perspectives: by Karen Park & Mark Dant
- Excerpt: Parent Perspective: Milo’s Journey by Karen Park