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Client Success With Knockin Mouse Model

Point Mutation Knockin Mouse Model Brings Client Success

Point Mutation Knockin Mouse Model Brings Client Success

Dr. Virginia Kimonis started her career as a pediatrician in the UK and United Arab Emirates, where she encountered a number of patients with rare genetic diseases. These experiences motivated her to pursue training as a clinical geneticist at the National Institutes of Health. She also trained in molecular labs with the hope to study and understand the underlying causes of some of these rare diseases, including the identification of the responsible genes. Today, Dr. Kimonis is a Professor of Pediatrics and Chief of the Division of Genetics & Metabolism at University of California, Irvine. She has established UC Irvine as a RDCRN (Rare Diseases Clinical Research Network) site for the Natural History study of Prader Willi and Morbid Obesity syndrome.

Dr. Kimonis studies families with a combination of muscle disease, Paget disease of bone, and dementia (also known as IBMPFD). The disease is characterized by progressive muscle weakness, bone deformities and extensive neuro-degeneration. Patients die of respiratory and cardiac muscle failure.

The responsible gene is Valosin Containing Protein (VCP) gene, which is involved in many important cellular functions associated with degrading proteins. Mutations in this gene have been linked to a variety of muscle disorders, ALS, Parkinsons, dementia and others.

At Boston Children’s Hospital, Dr. Kimonis – then Director of Perinatal Genetics at Beth Israel Hospital, first identified the VCP gene in 2003 – 5 years after encountering the initial patient that prompted her to research the underlying cause of their rare disease further. She raised proper funding and then contracted with ingenious targeting laboratory to generate a point mutation knockin mouse containing a mutation at position R155H, as well as loxP sites flanking exons 4 and 5 for tissue specific deletion of the gene. Since receiving the knockin model in 2007, it has been an excellent model of the human disease and has been utilized for preclinical experiments in the lab for developing new potential therapies.

Among some of the accomplishments using the mouse model, one is the establishment of an exercise study for patients that had shown positive effects in the mouse model. In addition, autophagy was found to be negatively affected in these patients, and a drug upregulating autophagy has shown success in the mouse model, as well as related stem cell models. Based on these results, Dr. Kimonis is working toward a patient treatment trial with a similar drug.

Removing the mutation in the mouse model using the CreLoxP system has also shown benefits in the mouse model. Potential future abilities to knock down the gene in patients carrying the mutation may be a treatment option.

What was the result of generating this one mouse model? Since delivery, there have been 14 publications (see below) and numerous well funded grants over the years. In addition, the model has been used in several preclinical trials with both public and private companies.

Dr. Kimonis stated the following, “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.” Several researchers that graduated from the Kimonis lab continue to work with this mouse model to study the same and other diseases. Each of them have published their findings.

References Related to the Mouse Model:

1) Badadani M, Nalbandian A, Watts GD, Vesa J, Kitazawa M, Su H, Tanaja J, Dec E, Wallace DC, Mukherjee J, Caiozzo V, Warman M, Kimonis VE. 2010. VCP associated inclusion body myopathy and paget disease of bone knock-in mouse model exhibits tissue pathology typical of human disease. PLoS One 5(10).

2) Nalbandian A, Donkervoort S, Dec E, Badadani M, Katheria V, Rana P, Nguyen C, Mukherjee J, Caiozzo V, Martin B, Watts GD, Vesa J, Smith C, Kimonis VE. 2011. The multiple faces of valosin-containing protein-associated diseases: inclusion body myopathy with paget’s disease of bone, frontotemporal dementia, and amyotrophic lateral sclerosis. J Mol Neurosci 45(3):522-31.

3) Yin HZ, Nalbandian A, Hsu C-I, Li S, Llewellyn K, Mozaffar T, Kimonis VE, Weiss J. 2012. A mutant valosin-containing protein (VCP) gene knockin mouse model of ALS. (*co-corresponding author). Cell Death Dis 3:e374.

4) Nalbandian A, Llewellyn KJ, Kitazawa M, Yin HZ, Badadani M, Khanlou N, Edwards R, Nguyen C, Mukherjee J, Mozaffar T, Watts G, Weiss J, Kimonis VE. 2012. The homozygote VCPR155H/R155H mouse model exhibits accelerated human VCP-associated disease pathology. PLoS One 7(9):e46308.

4) Nalbandian A, Llewellyn KJ, Badadani M, Yin HZ, Nguyen C, Katheria V, Watts G, Mukherjee J, Vesa J, Caiozzo V, Mozaffar T, Weiss JH and Kimonis VE. 2013. A progressive translational mouse model of human VCP disease: The VCP R155H/+ mouse. Muscle Nerve 47(2):260-70.

6) Nalbandian A, Nguyen C, Katheria V, Llewellyn KJ, Badadani M, Caiozzo V, Kimonis VE. 2013. Exercise training reverses skeletal muscle atrophy in an experimental model of VCP disease. PLoS One 8(10):e76187.

7) Llewellyn KJ, Nalbandian A, Jung KM, Nguyen C, Avanesian A, Mozaffar T, Piomelli D, Kimonis VE. 2013. Lipid-enriched diet rescues lethality and slows down progression in a murine model of VCP-associated disease. Hum Mol Genet 23(5):1333-44.

8) Nalbandian A, Ghimbovschi S, Wang Z, Knoblach S, Llewellyn KJ, Vesa J, Hoffman EP, Kimonis VE. 2014. Global gene expression profiling in R155H knock-in murine model of VCP disease. Clin Transl Sci 8(1):8-16.

9) Angèle Nalbandian A, Llewellyn KJ, Nguyen C, Monuki ES, Kimonis VE. 2015. Targeted excision of VCP R155H mutation by Cre-LoxP technology as a promising therapeutic strategy for VCP disease. Human Gene Ther Methods 26(1):13-24.

10) Nalbandian A, Llewellyn KJ, Nguyen C, Yazdi PG, Kimonis VE. 2015. Rapamycin and chloroquine: the in vitro and in vivo effects of autophagy-modifying drugs show unexpected results in valosin containing protein multisystem proteinopathy. PLoS One 10(4):e0122888.

11) Llewellyn KJ, Walker N, Nguyen C, Tan B, BenMohamed L, Kimonis VE, Nalbandian A. 2015. A fine balance of dietary lipids improves pathology of a murine model of VCP-associated multisystem proteinopathy. PLoS One 10(7):e0131995.

12) Evangelista T, Weihl CC, Kimonis V, Lochmüller H, on behalf of the VCP related diseases Consortium Workshop report. 2016. A fine balance of dietary lipids improves pathology of a murine model of VCP-associated multisystem proteinopathy. 215th ENMC International Workshop. VCP-related multi-system proteinopathy (IBMPFD), 13–15 November 2015, Heemskerk, The Netherlands. Neuromuscular Disorders.

13) Rodriguez-Ortiz CJ, Flores JC, Valenzuela JA, Rodriguez GJ, Zumkehr J, Tran DN, Kimonis VE, Kitazawa M. 2016. The Myoblast C2C12 Transfected with Mutant Valosin-Containing Protein Exhibits Delayed Stress Granule Resolution on Oxidative Stress. Am J Pathol 186(6):1623-34.

14) Nalbandian A, Khan AA, Srivastava R, Llewellyn KJ, Tan B, Shukr N, Fazli Y, Kimonis VE, BenMohamed L. 2017. Activation of the NLRP3 Inflammasome Is Associated with Valosin-Containing Protein Myopathy. Inflammation 40(1):21-41.

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