New Interview: Lab of Dr. Kimonis from UC Irvine–Promises Rare Research

Global Genes: Can you tell me a little bit about your personal drive for answers in the field of rare disease? What brought you to work with these kind of diseases and patients?

Dr. Kimonis: I was always interested in challenging unusual syndromes as a pediatrician in training in the UK. My interest in genetic rare diseases became solidified when I started working in the United Arab Emirates (UAE) as a pediatrician, following my pediatric training in England to become a Member of the Royal College of Physicians.

While in the UAE I saw a lot of patients with genetic problems because of the high blood relation rate there. There were almost no resources available to me except for a lot of time to pose questions, research and write articles on cases I saw in the clinics and with the help of metabolic geneticist Dr. Philip Benson, who was writing a book on Metabolic Disorders in Sharjah, (one of the emirates) at the time, and I was able to write up a series of four patients with Sanfilippo, a mucopolysaccharidosis syndrome.

I gained more insights from writing up case reports and this led to my decision to train as a clinical geneticist. I took a number of tests in order to gain a visa and pursue my training in the US. My first step was to repeat my residency in the Harvard training program in pediatrics at Massachusetts General Hospital (MGH) in Boston, a requirement then for fellowship training in Clinical Genetics.

At MGH I was exposed to several genetic diseases and syndromes. I saw a girl with Niemann Pick type A with Dr. Edwin Kolodny and a young boy with Cystinosis with Dr. Julie Engelfinger, which boosted even more my determination to pursue a career in clinical genetics. I was lucky to be accepted into the program at the NIH and trained with Dr. Bill Gahl in clinical research in Cystinosis. I also wanted to pursue training in a molecular lab so that I may one day take my work from the clinic to the lab, because so little was known at the time about so many rare diseases.

My top choice was Ed Ginns/Ellen Sidransky’s lab in Gaucher disease however for various reasons I decided to pursue training with Sherrie Bale/John Compton. This lab was one of the best molecular labs for understanding the molecular basis of rare skin disorders.

Global Genes: Is there any particular rare disease that you would cite as your main puzzle? There are several varied diseases that will be the focus of this new lab’s research. In which disease(s) do you feel the largest mystery or challenge lies?

Dr. Kimonis: My training at the NIH set me up with the tools to be able to identify disease genes in familial genetic disorders by linkage analysis. My first position was as an Assistant Professor at Southern Illinois University, in Springfield, Illinois. I was the sole geneticist for a wide area in the Midwest. In one of my genetics clinics in 1998, a family was referred by the MDA clinic with limb girdle muscular dystrophy and Paget bone disease. Recognizing that what they had was unique; I undertook the task of trying to identify the gene causing their problem.

I raised the funding, set up my lab and I undertook a linkage analysis which meant collecting samples of DNA from all affected and unaffected members of the family. I moved to Boston Children’s Hospital in 2001 and while there, I recruited new families in order to take advantage of chromosomal crossovers to narrow the location of the gene.

We narrowed the locus to one of 84 genes on chromosome 9 and with the help of collaborators we undertook sequencing of the genes in affected individuals. In 2003, my laboratory identified VCP (Vasolin Containing Protein), as the disease causing gene because all affected individuals carried the mutation whereas the unaffected relatives did not.

This protein constitutes 1% of all the protein in the body and is now known to be extremely important in carrying out many important cellular functions mainly associated with degrading proteins. Thus a significant finding derived from the study of a very rare disease. This disease is called VCP multisystem proteinopathy. Mutations have been identified in patients and families diagnosed with other muscle disorders, ALS or Lou Gehrig disease, Parkinsons, and frontotemporal dementia among others.

Dr. Kimonis with staff from her lab.

Global Genes: You’ve transcended past just lab experience, and are working with patients face to face—what has your experience been like working with these patients and their families as they struggle through their day-to-day symptoms?

Dr. Kimonis: The transcendence has been a seamless transition from the clinic to the lab and back to the clinic. My work has always been in response to a very real clinical translational need. I have always worked with patients throughout my career, first as a primary care physician then as a pediatric specialist and as a clinical geneticist since 1995. One of the most challenging and rewarding aspects of my job has always been to diagnose patients with a previously undiagnosed condition and provide hope even where no treatment was available. We live in a very opportune time where testing is available to be able to diagnose patients, with the availability of exome sequencing. Identifying the gene helps families connect with the larger community of patients which is not only therapeutic in itself but it also opens them up to resources, researchers and provides recognition of their condition and hope of a better quality of life irrespective of how long it takes. There is power in numbers and if patients with rare diseases band together to try and drive research for their personal rare disease much can be achieved faster. Big Pharma companies are beginning to express an interest in rare disorders. So these are promising times for patients with rare diseases. 

Global Genes: Can you help explain to us: what exactly is translational research? What is the process like for you as a scientist to go from theory to animal trials to human application?

Dr. Kimonis: Translation research refers to the process of going from lab bench research to the patient. I will provide you an example of how this has been achieved for patients with VCP disease which I have been researching since 1998. With the help of funding from the National Institute of Health, the Muscular Dystrophy Association, and the Paget foundation we have studied cells from patients and have created a knock-in mouse model that replicates the human disease. Additionally we have made stem cells from patient fibroblasts which have been made into neurons and muscle cells or myoblasts. These models have been crucial in studying mechanisms and quantifying the results of novel treatments.

Successes include studying the effects of uphill exercise in our mouse model which has been translated to an exercise study for patients. We have identified that autophagy, a mechanism for degrading and recycling proteins, is affected in patients and have shown that Rapamycin treatment which upregulates autophagy, results in benefits in the cells and the mouse model. I am working towards a treatment trial in patients using a similar drug.

We have also shown benefits in the mouse model after removal of the mutation using Cre technology. This has led to potential treatments involving technology to knock down the VCP gene carrying the mutation. My dream is to have trials for my patients using a variety of drugs and other strategies. I have studied this disease for over 15 years and there is nothing more satisfying than to be able to offer a treatment.

I have also established UC Irvine as a center of excellence for Prader Willi syndrome and morbid obesity. I am currently involved with three drug trials for Prader Willi syndrome where none previously existed and also for lysosomal storage disorders, in particular Pompe and Fabry disease–all with the help of collaborators.

Global Genes: How large will the focus be in your future research on studying how these treatments affect human patients?

Dr. Kimonis: There are over 7000 different genetic disorders and it is hard for any one researcher to study more than a handful of conditions. Research in one disorder however does benefit other disorders as my study in VCP disease has clearly shown. Funding is the driving force behind all research. I have been very fortunate that my VCP research has been funded continuously for over 15 years and without the help of the funding agencies, we may not have made so much progress. It is very gratifying that pharmaceutical companies are now interested in rare disorders. My dream is to have a research center of excellence at UC Irvine for Translational Research and Treatment of Rare Genetic Disorders.

Global Genes: We know the focus of these studies will be rare disease—but what kind of ramifications do you think this research might have on larger groups of diseases like Parkinson’s or cardiac diseases?

Dr. Kimonis: We know that common disorders are due to variations in genes associated with the rare disorders. Therefore researching rare diseases is very cost-effective because we learn so much about common disorders.

We are currently working on a project that involves a rare disease affecting two girls whose story is told at thelifewelivedoc.com. We have identified that the gene that causes their disorder is important in Parkinson’s disease which, as you know, is a common disorder. We have made stem cells from skin fibroblasts which will be made into neurons for testing a variety of drugs. There are many other examples of benefits for common disorders resulting from research in rare genes.  Studying this rare gene (VCP) has given us great insight into the mechanisms of more common disorders such as ALS, inclusion body myositis and frontotemporal dementia.

Global Genes: What sources do you look to for following the latest in rare disease research? Are there any journals or other scientists you might suggest that patients or their parents follow?

Dr. Kimonis: Joining support organizations and reading their websites will provide a lot of information to patients. Additionally there are free magazines such as Genome which provide useful information for patients and their families. Because there are so many rare disorders, scientists and clinicians have to specialize, and organizations such as Global Genes are a very valuable resource for information for patients and for putting them in touch with researchers throughout the globe.

The first step in research however, is an accurate diagnosis. A clinical or metabolic geneticist has special training in recognizing and diagnosing rare disorders and initiating more targeted investigations in undiagnosed disorders, harnessing the best labs for testing. Once a diagnosis is made it is important to involve a community of specialists to help address the problem.

Global Genes: What advice do you have for patients who feel they might be at a standstill without some form of personalized research and treatment? What would be the first steps in bringing a disease forward to the research community?

Dr. Kimonis: The advice I would give is to be proactive, and reach out to other patients, and researchers. Often disorders that affect very few individuals might not attract federal funding to move the research forward. Thus my recommendation is for families of patients is to jump start the research in their disorder by fundraising in order to start the preliminary research process and to maintain their activism throughout. I would also encourage patients to participate in research protocols so one can scientifically assess the benefits of new treatments for rare diseases.

For more information about Dr. Kimonis and The Kimonis Laboratory, please visit https://www.pediatrics.uci.edu/kimonis/

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