2013 Health & Genetics-Funding & Grants

2013
HEALTH and GENETICS 

COMMITTEE REQUEST 
for 
FUNDING and GRANT PROGRESS REPORT 
– Spring 2013
__________

GRANT PROGRESS REPORT REVIEW

01658: Urinary Protein and Gene Expression Characterization and Comparison
with Renal Biopsy Findings and Clinical Data in Dogs with Proteinuric Renal
Diseases

Report to Grant Sponsor from Investigator:
The primary goal of this project is to correlate urinary proteins and gene expression
products in the urine sediment with kidney biopsy findings and prognosis in dogs with chronic
kidney disease (CKD). The predominant portion of this project that has been completed to date is the analysis of urinary proteins and the evaluation of kidney biopsies. Three urinary proteins
have been measured in dogs with various kidney diseases (mostly protein-losing kidney
diseases). These were measured to assess their value in detecting severity of damage to the two major components of the functional unit of the kidney: the glomeruli and the tubules. We
determined that two of these urinary proteins provide a better indication of the severity of
glomerular damage than currently available tests and may therefore be useful to clinicians in
their diagnosis and monitoring of kidney disease. However, so far, none of the proteins evaluated provide a better indication of the severity of tubular damage than currently available tests. We are in the process of evaluating additional proteins that will hopefully provide more information regarding the tubulointerstitial compartment of the kidney, as this is currently a major limitation in the detection and monitoring of CKD in dogs.

We are also in the process of evaluating reference genes for quantitative PCR of gene
expression products in the urine sediment. We have successfully amplified 3 of these reference
genes in kidney tissue and are in the process of optimizing the reaction so that these genes can be tested as to their appropriateness as reference genes in urine sediment. Development of
additional primer/probe sets is underway.

Follow-up information regarding the patients in this study will be crucial in the
evaluation of the above biomarkers. We are in the process of developing a comprehensive survey that will serve the needs of this and future studies utilizing the samples from these patients. We are optimistic that we will obtain enthusiastic clinician and/or owner participation in these surveys.

GRANT PROGRESS REPORT REVIEW

01585: Phase I Study of Involved-Field Radiotherapy (IFRT) for Advanced Stage Canine Lymphoma

Grant Objectives:
1. To identify the maximum tolerated dose (MTD) of IFRT in canine patients with advanced-stage lymphoma.
2. To determine the rate of late adverse events other than dose-limiting toxicity (DLT) which are possible, probable, or definitely related to radiation therapy occurring within 6 months of IFRT.

Report to Grant Sponsor from Investigator:
The primary goal of this work is to perform involved-field radiotherapy (IFRT) on canine patients with advanced-staged lymphoma and test its feasibility, tolerability, and safety. This information is a necessary prerequisite to interrogating IFRT’s (in combination with chemotherapy) potential superiority to the current standard of care (chemotherapy alone). Patient accrual has improved and are within expectations with 8 patients enrolled at 12 months. Two patients have completed Dose Level 1 with acceptable toxicity and no infield failure as of this report (~1 month post IFRT). The third patient for Dose Level 1 will be completed by the end of January, 2013. This will close Dose Level 1 and open Dose Level 2. There are four patients within the queue to fill Dose Level 2.

Canine Health Foundation has reviewed and approved proposals for new OAK grants for 2013. Dr. Sharon Gillette and I have evaluated the new proposals and recommend to the Board the following grants listed below for funding. There were no grant proposals regarding deafness or hypothyroidism. The grants that we have recommended lean heavily towards oncology for the reason that the most innovative research is happening in that area.

The Board can veto any of the recommended grants. The funding amounts recommended can be increased or decreased by a vote of the Board.

01844: Treatment of Urinary Incontinence with Multipotent Muscle Cells:
A Regenerative Medicine Approach To a Common Canine Health Problem
Principal Investigator: Dr. Shelly Vaden, DVM PhD, North Carolina State University
$116,184.24, 1/1/2013 – 12/31/2014

Project Abstract:
Urinary incontinence affects more than 20% of spayed female dogs, with medium and large breeds more commonly affected. In the majority of the cases urinary incontinence is caused by dysfunction of the muscles controlling the urethral sphincter. This results in uncontrolled loss of urine and can lead to serious bladder and kidney infections, in addition to irritation and/or ulceration of the skin in contact with the urine. Treatment can include hormone therapy, drugs designed to strengthen the muscle tone of the urethral sphincter, collagen injections, or surgery. Recently, Dr. Vaden’s lab has reported that injection of muscle progenitor cells into damaged urethral sphincters can restore normal function in dogs. The purpose of this project is to extend those observations and examine the usefulness of cultured muscle cells for the restoration of function of the urethral sphincter in dogs with naturally occurring urinary incontinence. The effects of the procedure will be determined by owner reported continence scoring, as well as urodynamic testing that will provide an objective measurement for how well the bladder, sphincters, and urethra are storing and releasing urine.

Our Comments:
Urinary incontinence in spayed bitches is often a very frustrating condition for owners who frequently blame the veterinarian for the outcome. This study uses stem cells to repair the muscle tone of the urinary sphincter in order to stop the leaking of urine.

I recommend that we commit $1500.

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01806: A Novel Virus-Based Anti-Tumor Treatment for Canine Osteosarcoma

Principal Investigator: Dr. Bruce F Smith, VMD PhD, Auburn University
$118,848.00, 1/1/2013 – 12/31/2014

Project Abstract:
Osteosarcoma is an aggressive canine bone cancer, accounting for around 6% of all canine
cancers. Even with the standard-of-care therapy of amputation and chemotherapy, the prognosis is poor, with most dogs dying due to tumor spread (metastasis) within one year, and less than 20% surviving to 2 years following diagnosis. Therefore, improved strategies to treat metastatic disease are needed. Using a novel approach, Dr. Smith has engineered a virus to multiply in and kill tumor cells while sparing normal cells.

Preliminary studies have demonstrated that this virus-based anti-tumor treatment is safe when administered to canine osteosarcoma patients and is potentially efficacious in treating osteosarcoma. While this virus was hypothesized to kill osteosarcoma cells through its replication, Dr. Smith’s research team hypothesizes that the viral vector may also stimulate an anti-tumor immune response in addition to the expected anti-viral response. In this study, the efficacy and mechanism of action of the virus-based anti-tumor treatment will be evaluated.

Our Comments:
Osteosarcoma is an extremely painful and devastating disease. What is interesting about this study is that the engineered virus designed to attack osteosarcoma has already been developed and is ready to be tested on dogs with this diagnosis.

I recommend that we commit $2000.

_______________________________________

01843: Further Investigation of the Genes Controlling Canine Leukemia to Properly

Diagnose and Control the Disease
Principal Investigator: Dr. Matthew Breen, PhD, North Carolina State University
$131,265.00, 1/1/2013 – 12/31/2014

Project Abstract:
Leukemia represents a range of cancers, most often classified according to the type of blood cell affected and the clinical progression. Leukemia may be chronic, progressing slowly for many years with minimal symptoms, or acute, with sudden onset and rapid progression of symptoms, often resulting in euthanasia. The true incidence of leukemia in dogs is unknown, but consensus opinion is that many cases remain undiagnosed. In previous studies Dr. Breen found that canine leukemia presents with characteristic chromosomal and genetic changes shared with those known in human leukemia. In humans these chromosomal and genetic aberrations have been linked to disease progression and response to therapeutics, and in turn, this information drives clinical management of the patient. In this multicenter study, Dr. Breen’s group will use high-resolution genome-wide chromosomal evaluation to screen a large cohort of canine leukemia patients for the presence of recurrent chromosomal and genetic changes. This study will enhance our understanding of the pathogenesis of canine leukemia by identifying regions of the canine genome, and thus individual genes that may be critical for the control of these cancers. Additionally, this study will provide data that will impact our knowledge of the corresponding human disease.

Our comments:
This study is about further characterizing the genetic chromosomal alterations in leukemia patients. These alterations can be detected before there are clinical signs of disease or relapse. Sharon just loves this idea of early detection. This approach is also being studied in lymphoma. Also this is an outstanding group of investigators.

I recommend that we commit $1500.
_______________________________________


01826:
 A Novel Treatment for Brain Tumors Using a One Medicine Approach

Principal Investigator: Dr. Simon R. Platt, BVMS, University of Georgia
$119,065.00, 1/1/2013 – 12/31/2015

Project Abstract:
Drs. Platt (University of Georgia College of Veterinary Medicine) and Hadjipanayis (Emory
University School of Medicine) will take a One Medicine approach to treating canine glioma brain tumors. Brain tumors in humans and animals are often devastating and fatal diseases.
Many are not accessible to surgical removal which is the main treatment option. Likewise, chemotherapy has traditionally been ineffective because systemic delivery is prevented by the blood-brain barrier. In an effort to deliver chemotherapy drugs directly into brain tumors, a procedure called convection-enhanced delivery (CED) has been developed. This procedure utilizes small catheters, placed directly into tumors which allow direct drug delivery, limiting systemic drug concentrations, and therefore minimizing side effects. In this study dogs will undergo CED treatment with the monoclonal antibody cetuximab conjugated to magnetic iron- oxide nanoparticles (IONPs). Cetuximab is a monoclonal antibody specific to the epidermal growth factor receptor (EGFR) which is over-expressed in the majority of canine gliomas. Cetuximab is FDA-approved for use in several cancers in humans. When combined with IONPs, cetuximab can be visualized utilizing MRI. The dogs will be monitored clinically and with MRI over the next twelve months. The aim will be to detect a significant effect of the novel treatment on the progression free survival of the patients and the MRI volume of the tumors.

Our comments:
Brain tumors are so difficult to treat both radiation therapy and surgery can have grave side effects. Different approaches are needed. Sharon is curious about how the iron oxide particle will behave under MRI and if they will stay in place. She has seen similar studies and she believes that it is not as far out as it seems at first and it may not be that popular with the funding groups.

I recommend that we commit $2000.

© 2013 Michelle J. Raisor, Ph.D
Michelle J. Raisor, Ph.D
Health and Genetics Co-Chairman

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