Making rare diseases their common cause

By the time families meet with Dr. Virginia Kimonis, hope is about all they have left.

Her pediatric patients are afflicted with debilitating diseases caused by mutations in an alphabet soup of genes – VCP and NUBPL among them. Prader-Willi, Rett, Paget’s and the like are difficult to diagnose and even harder to treat. But with cutting-edge genomic sequencing and old-fashioned scientific sleuthing, physician-researchers such as Kimonis are on the vanguard of modern medicine, finding therapies where none seemed possible.

Kimonis specializes in one of the most challenging areas: rare genetic diseases. What she and others in her field are learning about disorders that impact only a few is paving the way to a greater understanding of diseases that impact millions.

“It’s wonderful to show in the lab and in the clinic that we can offer these patients some hope,” says Kimonis, a UC Irvine pediatrician and clinical geneticist.

A rare disease is defined as one diagnosed in no more than 200,000 people worldwide; 70 percent, though, affect fewer than 6,000. And of the nearly 7,000 known rare diseases, half involve children, and 80 percent are linked to genetic flaws. These are Kimonis’ focus.

According to UC Irvine’s Dr. J. Jay Gargus, an expert in genetic metabolic diseases, rare disease research can be a springboard to understanding and treating more common ailments.

“We have a special opportunity with rare genetic diseases to provide an insight into how common diseases arise,” says Gargus, who directs the campus’s Center for Autism Research & Translation. “This is an important venue for drug discovery. The National Institutes of Health and the Food & Drug Administration recognize this and have programs established for target diseases. UC Irvine has a great strength in diagnostics, and we should be very involved in this.”

Gargus himself is making a breakthrough on a rare genetic disease. He recently held the first U.S. clinical trial of a treatment for Wolman disease, a cholesterol storage disorder, at UC Irvine Medical Center – with promising results.

Kimonis is also helping the campus establish itself as a leader in the field. She manages a section of the NIH’s Rare Diseases Clinical Research Network dedicated to Prader-Willi, Rett and Angelman syndromes.

Children with Prader-Willi – which is caused by the loss of several genes on chromosome 15 – are characterized by obesity, low muscle tone and cognitive disabilities. In addition to treating Prader-Willi patients with novel approaches, Kimonis is building a national database of those with the disease and designing studies to identify promising therapies.

In one project, she plans to partner with Daniele Piomelli – UC Irvine’s Louise Turner Arnold Chair in the Neurosciences, who examines the endocannabinoid system – to see how marijuana-like chemicals called OEAs created in the body can help curb the insatiable appetites of Prader-Willi children. By creating mice models with Prader-Willi gene mutations, the two hope to learn if the hunger-curbing signal provided by OEA is missing and whether compounds that boost OEA can aid satiety.

“If successful, our experiments will achieve two important objectives,” Piomelli says. “First, they will help us understand why Prader-Willi causes hunger; second, and more importantly, they will suggest new possible therapies to reduce appetite.”

Another focus of Kimonis’ work centers on disorders triggered by mutations in the valosin-containing protein gene. VCP programs enzymes that help maintain cell health by breaking down and clearing away old and damaged proteins that are no longer necessary. Mutations in the VCP gene have been discovered in people who have a muscle-weakening disease called inclusion body myopathy, early-onset Paget’s disease of the bone or frontotemporal dementia.

Kimonis was the first scientist to map and identify mutations in the VCP gene in inclusion body myopathy, and in 2012, she developed the first genetically modified mouse model that exhibits many of the clinical features of diseases largely caused by VCP gene mutations.

“Mouse models like these are important because they let researchers study how these now-incurable, degenerative disorders progress in vivo and will provide a platform for translational studies that could lead to lifesaving treatments,” says Kimonis, who co-directs UC Irvine’s MitoMed laboratory, which offers testing for many rare diseases.

Her research breakthroughs are coinciding with greater public recognition of rare genetic diseases. The NIH has established an Office of Rare Diseases Research, and nonprofit groups such as the Orange County-based Global Genes Project are increasing awareness, advocating and soliciting philanthropic aid on behalf of this issue. (The GGP is hosting a patient advocacy summit Sept. 11 and 12 in Huntington Beach.)

Parents of children with rare genetic diseases are also speaking out. Cristy and Rick Spooner of Rancho Santa Margarita, who’ve endured a long quest to identify a disabling condition affecting two of their three daughters, have gone public with their story, hoping to raise the profile of such diseases.

After the Spooners spent years seeking help from doctors, Kimonis contacted them about a new technique, called exome sequencing, that examines the tens of thousands of genes in the human body for disease-causing mutations. Aliso Viejo-based Ambry Genetics, which partners with Kimonis’ research group, provided the sequencing services.

Test results showed that Cali and Ryann Spooner harbored mutations in the NUBPL gene. This defect prevents their mitochondria – the power generators in cells – from efficiently producing energy. Armed with this information, Kimonis developed dietary and drug treatments for the Spooner sisters.

“What’s even more satisfying about our work is that it has huge implications for other diseases,” she says.

Kimonis is seeking funding to determine whether mitochondrial defects caused by mutated NUBPL genes underlie the onset of Parkinson’s disease. She hopes to partner with UC Irvine neurologist Dr. Neal Hermanowicz, who manages the movement disorders program, to establish a clinical research network for this effort.

“In our lab, we don’t give up,” Kimonis says. “If people are reaching out, you have to do all you can about rare diseases.”