Especially Beautiful Fundraising Update

04 May Especially Beautiful Fundraising Update

Virginia Kimonis, MD
Especially Beautiful Fundraising Update
April 2016

NUBPL is a “rare” mitochondrial disease. Research activities represent hope for the lovely Spooner girls and others with this rare condition. In fact, the field of clinical genetics represents a promising pathway to new and better treatments for many rare diseases. And, what this means is that every child with NUBPL disease today has a reason to hope. Nothing is more thrilling than to successfully slow or treat a disease.
The funds raised so far ($12,000) have helped to establish UC Irvine as the hub for research activities in NUBPL disease. The following is an update on the progress of the research so far.
1. Dr. Kimonis has gathered several researchers at UC Irvine and other institutions to study NUBPL disease
2. The Kimonis Laboratory has studied the skin fibroblasts from the girls for the mitochondrial function at UC Irvine using the Seahorse instrument in collaboration with Dr. Christina Kenney’s lab.
3. We theorize that a mitochondrial disease may manifest when a person’s body is stressed –with infection or exposure to a toxin, for example. So, we are introducing paraquat a mitochondrial complex 1 poison and hydrogen peroxide to the cells in order to study mitochondrial function under conditions of stress.
4. Dr. Kimonis is working with Dr. Moyra Smith in further analysis of the exome data in the two girls to understand the cause of the differences between the two girls
5. A stem cell line has been made with skin fibroblasts from Calynn. These stem cells will be used to make brain cells to study how mutations in the gene causes the problems in the girls and to study the effect of novel treatments
6. Our collaborator, Dr. Janneke Balk, at the University of East Anglia, UK, has shown in her lab that treating yeast cells with peptones improves mitochondrial function. Therefore, we now recommend treating patients with NUBPL disease with a high-protein diet. As a result of our collaboration Dr, Balk has treated the cells and yeast mutants with components of the mitochondrial cocktail to identify specific drugs that may be beneficial. She has identified that coenzyme Q10 treatment has resulted in improvement in the activity of mitochondrial complex 1. She has also introduced the various mutations found in patients in the yeast in order to study the effect on mitochondrial complex 1 in order to conclusively establish that the mutations are the cause of the disease.
7. Dr. Kimonis has recruited several other patients and families with NUBPL disease in order to expand knowledge of the disease. To date, we have 5 new patients in 4 families with definite NUBPL disease. These new participants will help us understand the spectrum of manifestations of the disease to identify and genotype-phenotype correlation in NUBPL disease.
8. In collaboration with Peggy Eis of Population Diagnostics we have identified that relatives of the NUBPL families have a higher incidence of Parkinson’s disease, essential tremor or restless leg syndrome. Sample collection of the relatives from the 4 new families is in progress in order to conclusively make the connection with being carriers of mutations in the NUBPL gene.

With the $20,000 raised from the Especially Beautiful event in 2016 we are planning the following experiments:
1. We plan to create stem cells from two additional NUBPL patient’s skin samples. Our goal is to convert these stem cells into neurons that represent the cerebellum and cortex of the brain. We would then study the cells to try and identify the defective mechanism in patients with the disease.
2. We will test the effects of different drugs on these brain cells in the hopes of finding a drug that would halt or reverse the progression of the disease. Other partners engaged in this work include stem cell researchers at the California Institute for Regenerative Medicine, and Dr. Phil Schwartz at CHOC Children’s. Stem cell work is very intensive and expensive however the potential rewards is enormous because the work is done using cells from the girls. This truly represents personalized medicine
3. We will also continue all the experiments already started in year 1.

Future studies:
With the CRISPR technology being readily available we are also proposing an animal model of the NUPBL gene mutation that would allow us to study the brain and in particular the cerebellum function. These models, stem cells and other tools are all ways to pursue different treatment strategies at the same time, each one focused on improving brain function. The animal model we hope will be the best and most authentic model and will allow us to actually study the brain in NUBPL disease. We can perform imaging of the brain in order to study the impact of manipulating the NUBPL gene on the mouse cerebellum, balance and cognitive function. We then plan to study the effect of a drug panel on the structure and function of the brain in order to identify potential novel treatments that could be tried in children with NUBPL disease.

The cost of making the animal model and performing the experiments once the mouse is available is approximately $50,000
Phase 1—First Year
a. Development of Mouse Model for Research (1 year)— (total cost of $50,000 to be paid in two installments)
i. Mice share 99% of the human genetic makeup, and have proven to be a very useful model of the human disease based on experience in Dr. Kimonis’ lab for the past seven years.
ii. Currently there is no animal model; by making a mouse model of the common c.815-27T-C NUBPL or the specific Spooner c.311T>C (p.L104P) gene mutation, it will be possible to simulate and study the mechanisms that cause the human disease. It is already known that knocking out the gene is lethal in animals therefore a knock-in mouse with one of the patient’s mutation is planned.
iii. It is expected the mouse will show the typical clinical features such as the cerebellar atrophy. Currently there is almost no information on the brain pathology and function in this disease.

Phase 2—Second Year
I. Mouse Research (research costs—supplies, personnel, etc.)
a. Experiments to be conducted (breeding mice, behavior studies, study of cerebellum, study of the expression of the gene,)
b. Test different treatments (drugs) to improve the cells and the structure of the brain of the mice.

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