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I’m Melanie Gillingham, and this is why I research.Melanie Gillingham started her career as a clinical dietitian prior to earning her PhD in Nutrition and becoming a professor at Oregon Health Science University (OHSU). Dr. Gillingham’s laboratory research focuses on the development of novel treatments for fatty acid oxidation disorders. For the past 20 years her research group has performed both clinical and basic research on fatty acid oxidation disorders with a primary focus on long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) deficiency. One recent clinical trial examined the effects of an odd-chain fatty acid supplement, triheptanion, on myopathy and cardiac function in patients with long-chain fatty acid oxidation disorders. This study was the largest randomized controlled trial on these disorders. Furthermore, it led to Melanie’s 2018 Archibald Garrod Award by the Society for the Study of Inborn Errors of Metabolism (SSIEM) for best paper in the field, published in the Journal of Inherited Metabolic Disease for the article Triheptanoin versus trioctanoin for long-chain fatty acid oxidation disorders: a double blinded, randomized controlled trial. Dr. Gillingham has been honored with multiple Teaching Excellence Awards in Graduate Education during her time as a professor at OHSU. Bio-Techne is proud to have Dr. Gillingham as one of our 2020 Rare Genomics Institute BeHEARD Competition awardees.
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Would you tell us what sparked your interest in science? I initially became interested in nutrition science in my undergraduate basic nutrition class. It combined the science of physiology, biochemistry, and food. My science classes were always my favorites but sometimes the material was too abstract. I like the application of nutrition science with such a fundamental human activity – eating – that spans different cultures, societies, and environments. What is Long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency (LCHADD) retinopathy and why did you become interested in studying this rare disease? LCHADD is an inherited disorder which impacts the ability to burn fatty acids to make energy or ATP. It is one of a family of disorders in this pathway. Infants and children with a fatty acid oxidation disorder can have hypoglycemia, cardiomyopathy, and rhabdomyolysis with fasting or exercise but only patients with LCHADD develop a retinopathy that leads to vision loss. In graduate school, I was following a young patient with LCHADD as part of a neurodevelopmental fellowship, LEND. She had remarkably low plasma levels of docosahexaenoic acid or DHA. When I researched the function of DHA, it was essential in the retina for normal vision. From those observations, we started a DHA supplementation trial to determine if DHA supplements could slow or halt the progressive retinal deterioration with LCHADD retinopathy. DHA supplements did not halt the progression of retinopathy and we are continuing to look for a treatment. Which new advances in flow cytometry technology are you or have you been most excited about? Anything that expands what we can do. We use only one of a whole series of single cell technologies, each of which can supply us with some unique perspective on the cells under study. We are now less limited by the slight downsides of flow - we use a zero-resolution technique so there is no morphological information, but we now have imaging flow cytometry. The problems with needing more targets have been addressed by mass cytometry. Each new technology gives us a little more edge and capability. What are the current therapies or modalities of treatment for this disease? There are no treatments for LCHADD retinopathy specifically. Early diagnosis with newborn screening, along with good management and prevention of metabolic crises slows the progression of vision loss but does not halt it. Children, adolescents, and adults with LCHADD experience progressive vision loss despite current treatments to manage other aspects of their disorder. The corner stone of treatment for all long-chain fatty acid oxidation disorders is to minimize fat oxidation with small frequent meals and the avoidance of fasting. Patients are advised to consume a low-fat diet and often supplement with medium-chain triglycerides or MCTs that bypass the long-chain fatty acid oxidation enzyme defects. Recently, a novel triglyceride, triheptanoin, was approved to treatment of these disorders. We conducted a randomized controlled trial of triheptanoin and demonstrated that it improved cardio-respiratory function at rest and during exercise compared to standard of care. This might be particularly important for patients who are struggling with cardiomyopathy. The brand name is Dojolvi and it is the first FDA approved treatment for long-chain fatty acid oxidation disorders in general. As mentioned in your BeHEARD proposal, you and your lab have created two models for LCHADD retinopathy. Tell me more about how you propose to use these models to develop novel treatments for this disease. We have developed a cell culture model using patient fibroblasts, de-differentiated to induced pluripotent stem cells and the re-differentiated to retinal pigment epithelium. The LCHAD-deficient RPE do not make ketones, accumulate triglycerides and other partially oxidized fatty acid products and do not oxidize fatty acids. The cells are susceptible to oxidative stress induced by hydrogen peroxide and die in the presence of added fatty acids more rapidly than wild-type cells. We are now testing a gene replacement approach of introducing a normal copy of the gene, HADHA, into the LCHAD deficient cells to see if the normal gene can rescue the phenotype. We also used CRISPR-Cas9 and introduced a common point mutation into the mouse genome to create an LCHADD deficient mouse. Previous attempts to knockout the entire gene, HADHA, were neonatal lethal. Our LCHAD mutant mice die more frequently during the immediate post-natal period but some have survived into adulthood. We looked at the adult LCHAD deficient mouse eyes and found they have decreased visual acuity and accumulate lipid droplets in the retinal pigment epithelium suggesting they will be a good animal model of the human retinopathy. Eventually, we plan to test our gene replacement approach in the mice. Tell me about what exciting research projects are happening in your lab. There are several exciting projects happening in the lab right now. We are currently testing the plasmid to add the wild-type HADHA gene in transfected cells. This is an important step because LCHADD is one enzyme function of a complex protein, mitochondrial trifunctional protein. Trifunctional protein has two subunits, HADHA and HADHB. Four alpha and four beta combine inside the mitochondria to form the holo-enzyme. We need to determine if an exogenous alpha can combine with endogenous beta subunits and restore fatty acid oxidation before proceeding with more complex experiments. It is a rather critical step in our research program. We are also working to further characterize our mouse model. We are breeding mice to test their ability to exercise on a treadmill, measure how they burn fat, look at their cardiac function and continue to examine their eyes. If the mouse can recapitulate the muscle, cardiac and retinal phenotypes observed in human patients, it will be a very valuable model in which to study potential novel treatments. It seems the fatty acid oxidation pathway is involved in a variety of metabolic disorders in humans. What area of metabolic research, outside of studying LCHADD, are you most fascinated by? What developments in the field are most exciting to you? I’m very interested in the interplay of fatty acid oxidation and glucose oxidation in the development of insulin resistance or metabolic syndrome. There are several competing hypotheses about the role of fatty acid oxidation and insulin resistance. One theory, the Randle glucose-fatty acid cycle, proposes that when fat oxidation is high, there is adequate ATP for the cell and glucose oxidation is downregulated. If that is true, then subjects and mice with low fat oxidation such as patients with LCHAD deficiency would be less likely to develop insulin resistance. Another theory, the lipotoxicity theory, proposes that as fat accumulates in the cytosol due to decreased oxidation and increased intake, the fat intermediates inhibit the insulin signal and induce insulin resistance. If that is true, then patients with LCHAD deficiency would be more likely to develop insulin resistance. We are currently completing a study in human subjects to look at this very question. It could provide new insights into this debate within the insulin resistance field. Describe why your research is important to the ordinary citizen. Our primary research focus is on developing novel treatments for a rare disease in fatty acid oxidation. If we are successful, the lives of patients suffering with LCHAD deficiency will be greatly improved. However, beyond developing treatments for LCHAD, we are learning about the role of fatty acid oxidation in retinal health and in the development of insulin resistance and metabolic syndrome. We learn so much in biology by studying rare cases rather than only studying the routine or normal condition. For instance, statins were developed by studying patients with familial hypercholesterolemia. Our insights into the role of fatty acid oxidation in the retinal pigment epithelium may provide new ideas about more common eye disorders like macular degeneration. Our study of insulin sensitivity in patients with fatty acid oxidation disorders may provide new ideas for targets to manage insulin resistance. Do you have any advice for young scientists interested in pursuing a research career? Research is an exciting career opportunity but requires a lot of perseverance. You have many failed experiments and repeated attempts to get things to work in the lab. However, the breakthroughs and ability to impact people to improve human health is thrilling. If you enjoy problem solving and thrive in environments where there are new challenges each day, research is a good option for you. And finally, if you could meet any scientist from the past, who would you meet and why? I would like to meet Dennis McGarry. He was an endocrinologist and scientist who described the regulation of fatty acid oxidation and glucose metabolism. His former students and post-docs have become influential researchers in the field and speak so highly of their training with Dr. McGarry. Select Publications by Dr. Gillingham: Elizondo, G., Matern, D., Vockley, J., Harding, C. O., & Gillingham, M. B. (2020). Effects of fasting, feeding and exercise on plasma acylcarnitines among subjects with CPT2D, VLCADD and LCHADD/TFPD. Molecular genetics and metabolism. Advance online publication. https://doi.org/10.1016/j.ymgme.2020.09.001 Gillingham, M. B., Elizondo, G., Behrend, A., Matern, D., Schoeller, D. A., Harding, C. O., & Purnell, J. Q. (2019). Higher dietary protein intake preserves lean body mass, lowers liver lipid deposition, and maintains metabolic control in participants with long-chain fatty acid oxidation disorders. Journal of inherited metabolic disease. https://doi.org/10.1002/jimd.12155 Gillingham, M. B., Heitner, S. B., Martin, J., Rose, S., Goldstein, A., El-Gharbawy, A. H., Deward, S., Lasarev, M. R., Pollaro, J., DeLany, J. P., Burchill, L. J., Goodpaster, B., Shoemaker, J., Matern, D., Harding, C. O., & Vockley, J. (2017). Triheptanoin versus trioctanoin for long-chain fatty acid oxidation disorders: a double blinded, randomized controlled trial. Journal of inherited metabolic disease. https://doi.org/10.1007/s10545-017-0085-8 Gillingham, M. B., Harding, C. O., Schoeller, D. A., Matern, D., & Purnell, J. Q. (2013). Altered body composition and energy expenditure but normal glucose tolerance among humans with a long-chain fatty acid oxidation disorder. American journal of physiology. Endocrinology and metabolism. https://doi.org/10.1152/ajpendo.00225.2013 Rare Genomics Institute BeHEARD Competition Contacts: Danielle Fumagalli Back to Faculty Interview Archive |
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