Where Are They Now from GeneTargeting.com

Kimonis, Virginia from GeneTargeting.comDr. 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 is still being actively utilized for preclinical experiments in the lab for potential therapy today.

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.

Nine years after the model was delivered by ingenious targeting laboratory to Dr. Kimonis, it is still her sole research focus. The mouse model has resulted in 12 publications (see below) and numerous well funded grants over the years. In addition, the model is being 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. VCP Associated Inclusion Body Myopathy and Paget Disease of Bone Knock-In Mouse Model Exhibits Tissue Pathology Typical of Human Disease. 2010. PLoS ONE 5(10): e13183. doi:10.1371/journal.pone.0013183.

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. 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. 2011 Nov;45(3):522-31. Epub 2011 Sep 3.

3) Yin HZ, Nalbandian A, Hsu C-I, Li S, Llewellyn K, Mozaffar T, Kimonis VE*, Weiss J. A mutant valosin-containing protein (VCP) gene knockin mouse model of ALS (* co-corresponding author). Cell Death Dis. 2012 Aug 16;3:e374. doi: 10.1038/cddis.2012.115.

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. A Progressive Translational Mouse Model of Human VCP Disease: The VCP R155H/+ Mouse. Muscle Nerve. 2012 Jul 12. doi: 10.1002/mus.23522. [Epub ahead of print].

5) 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. The Homozygote VCPR155H/R155H Mouse Model Exhibits Accelerated Human VCP-Associated Disease Pathology. PLoS One. 2012;7(9):e46308. doi: 10.1371/journal.pone.0046308. Epub 2012 Sep 28.

6) Nalbandian A, Nguyen C, Katheria V, Llewellyn KJ, Badadani M, Caiozzo V, Kimonis VE. Exercise Training Reverses Skeletal Muscle Atrophy in an Experimental Model of VCP Disease. PLoS One. 2013 Oct 9;8(10):e76187. doi: 10.1371/journal.pone.0076187.

7) Llewellyn KJ, Nalbandian A, Jung KM, Nguyen C, Avanesian A, Mozaffar T, Piomelli D, Kimonis VE. Lipid-enriched diet rescues lethality and slows down progression in a murine model of VCP-associated disease. Hum Mol Genet. 2013 Oct 24. [Epub ahead of print]

8) Nalbandian A, Ghimbovschi S, Wang Z, Knoblach S, Llewellyn KJ, Vesa J, Hoffman EP, Kimonis VE. Global Gene Expression Profiling in R155H Knock-In Murine Model of VCP Disease. Clin Transl Sci. 2014 Nov 12. doi: 10.1111/cts.12241. [Epub ahead of print]

9) Angèle Nalbandian A, Llewellyn KJ, Nguyen C, Monuki ES, Kimonis VE. Targeted Excision of VCP R155H Mutation by Cre-LoxP Technology as a Promising Therapeutic Strategy for VCP Disease. Human Gene Ther Methods 2014 Dec 29. [Epub ahead of print]

10) Nalbandian A, Llewellyn KJ, Nguyen C, Yazdi PG Kimonis VE. 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. 2015 Apr 17;10(4):e0122888. doi: 10.1371/journal.pone.0122888. eCollection 2015.

11) Llewellyn KJ, Walker N, Nguyen C, Tan B, BenMohamed B, Kimonis VE, Nalbandian A. A fine balance of dietary lipids improves pathology of a murine model of VCP-associated multisystem proteinopathy. PLoS One. 2015 Jul 2;10(7):e0131995. doi: 10.1371/journal.pone.0131995.

12) Evangelista T, Weihl CC, Kimonis V, Lochmüller H, on behalf of the VCP related diseases Consortium Workshop report: 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. 2016

13) Kimonis VE, Dec E, Vesa J, Badadani M, Watts DG, Nalbandian A, Caiozzo V, Martin B, Smith C. Clinical spectrum of VCP myopathy, Paget’s disease and fronto-temporal dementia; experimental models and potential treatments for : Muscle Aging, Inclusion-Body Myositis and Myopathies, eds. Valerie Askanas and W. King Engel. 2012 Wiley-Blackwell Publishing; 1 edition (March 6, 2012).

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Dr. Vadim Arshavsky

VadimArshavsky from GeneTargeting.comDr. Vadim Arshavsky, Scientific Director of the Albert Eye Research Institute at Duke University, was one of ingenious targeting laboratory’s very first clients. In 1999, ingenious generated a Phosducin knockout mouse model for Dr. Arshavsky, who had just started his lab at Harvard University a few years prior. Phosducin, in addition to regulating light and dark adaptation of photoreceptors, is involved in the regulation of blood pressure, likely through similar mechanisms based on modulation of G protein signaling. The mouse model resulted in three publications and has significantly contributed to the research direction the lab has taken since. Dr. Arshavsky deposited the line at Jackson Laboratory in 2010. He believes the model is useful for researchers studying cardiovascular health. We’ve reconnected with Dr. Arshavsky recently to understand how this mouse model has contributed to his research.

At what point in your career were you at the time the model was first created, and subsequently published? Something like transitioning from a “young” to “mid-career”. I started my lab in 1995.

How has your lab evolved and grown since? We almost doubled in size and now explore a few new directions, one of which was launched upon characterizing this mouse.

What was the focus of your research back then? We were primarily interested in  signal transduction mechanisms underlying the ability of rod and cone photoreceptor cells to translate the information they receive as photons into the language of neuronal electrical activity.

How has the model helped to address your research questions at the time? We had just discovered a novel and very unusual mechanism by which rod photoreceptors adapt to ambient light. The mechanism consists of massive translocation of signaling protein into and out of the light-sensitive compartment of the photoreceptor cell. Phosducin was previously known to interact with one of these translocating proteins, the beta/gamma subunit complex of G protein, transducin. Transducin beta/gamma is a membrane-associated protein, and our hypothesis was that binding to phosducin facilitates its partitioning from membrane to cytosol, which enables its translocation across the cell. The first paper in JBC showed it was indeed the case.

From the three papers you were able to publish due to this model, what findings about Phosducin’s role were you able to identify? It turned out that phosducin is a multi-faceted

protein regulating a whole array of photoreceptor functions, both in rods and cones. In addition to assisting light-driven translocation of transducin in rods, it is involved in the regulation of transducin expression level in both photoreceptor types. Furthermore, phosducin regulates signal transmission across the first synapse in the retina, which photoreceptors form with their downstream bipolar interneurons. Normally, these synapses adjust neurotransmitter release according to conditions of ambient illumination. However, this adaptation is impaired by phosducin knockout so that these synapses behave as if they are constitutively light-adapted. We published these additional findings in The Journal of Neuroscience in 2010.

Furthermore, this knockout allowed us to reject a hypothesis about phosducin’s functional role that was dominating the literature in the decade preceding our publications. Phosducin was hypothesized to participate in photoreceptor light adaptation by sequestering a fraction of transducin from the phototransduction cascade, but electrophysiological recording from the knockout rods showed that this is not correct.

How has your research progressed and changed since? Are you still studying phosducin? We do not study phosducin at this time. Our mice were deposited at the Jackson Labs. However, our current direction addressing a broader picture of intracellular targeting and trafficking of photoreceptor-specific proteins was inspired by the studies of light-driven protein translocation in this cells, including elucidating the role of phosducin in this mechanism.

16 years later, Dr. Arshavsky no longer studies Phosducin. However, his current direction addressing a broader picture of intracellular targeting and trafficking of photoreceptor-specific proteins was inspired by the studies of light-driven protein translocation in these cells, including elucidating the role of phosducin in this mechanism.  His lab has doubled and he is now the Scientific Director of the Albert Eye Research Institute at Duke University.