Gene Therapy for Osteoarthritis: Kinematic Analysis

Entry, Cases/Abstracts
Nichole Hughes, University of Florida

Steve Ghivizzani, MD; Patrick T. Colahan, DVM; Nichole Hughes
Department of Large Animal Clinical Sciences, University of Florida College of Veterinary Medicine, Gainesville FL
Department of Orthopedics and Rehabilitation, University of Florida College of Medicine,  Gainesville FL
Research supported by Merial

Osteoarthritis (OA) is one of the most prevalent diseases worldwide, causing chronic joint pain and progressive immobility due to the erosion of articular cartilage, subchondral bone sclerosis, and osteophyte formation. Though OA is widely unaffected by current treatments, experimentation has shown that local gene delivery of IL-1Ra (receptor antagonist) using scAAV (self-complimentary adeno-associated virus) vectors can have a significant effect in disease progression in animal models and allow sustained levels of IL-1Ra in the joint. This project uses kinematic analysis to evaluate the capacity of scAAV-mediated delivery of equine-IL-1Ra to block the development of experimental arthritis in the equine joint. To evaluate the therapeutic efficacy of scAAV-eqIL-1Ra, an osteochondral fragment (OCF) model is used to simulate the pathobiology of OA. After a recovery period, scAAV-eqIL-1Ra and placebo (saline) are delivered to the experimental and control groups, respectively. Motion analysis is conducted weekly on a high speed treadmill for 12 weeks. Quantifiable changes in kinematics are measured using Lameness Locator® software.

It is expected that local, intra-articular treatment with scAAV-eqIL-1Ra will provide protection from the development of the articular pathologies associated with OA.  Relative to placebo controls, treated animals should have reduced pain and improved mobility, thus resulting in a reduction in lameness as analyzed by the Lameness Locator. Thus far, only 5/20 horses have completed the project.  The kinematic analysis of these 5 horses shows that the placebo improves lameness at a rate 2.5 times faster than treatment with scAAV-eqIL-1Ra. However, it is too early to use these preliminary results to determine the overall efficacy of the therapy. Ultimately the final data from this part of the study will be compiled with MRI, radiography, arthroscopy, and data generated from recovered fluids and tissue biopsies to provide a comprehensive description of the effects of the gene based treatment. Based on these efficacy models in horses, we can gain insight on the use of gene transfer on a human scale as a therapy for osteoarthritis.

Transmyocardial therapeutic-delivery using real-time MRI guidance

Entry, Abstracts
Jeremy Maurer, Penn

Fig.1 (a) Needle catheter showing microcoils and extended nitinol injection needle. (b) Portions of the heart segmented on cine stack (TR/TE=3.4/1.54ms, voxel=1.3x1.3x5 mm3, FA 43o) are used to build 3d model of the left, right ventricle and infarcted region. (c) 3D model overlaid into real-time MR images is used to (d) navigate the catheter to pre- defined injection targets. Catheter model is built from MR images of active tracking coils. (e) Injection of iron-oxide laden therapeutic into myocardium (yellow arrow) monitored under real-time MRI. TR/TE=2.8/1.19 ms, voxel=1.9x1.9x5mm3, FA/tracking FA =50o/15o, 1.5-4 frames/s. (f, g) Pre- and post- injection MRI confirms injection of microbeads. TR /TE = 6.8/3.25ms, FA=30o, voxel =1.0×1.0×5.0mm3.Hegde S, Shea S, Pan L, Karmakar P, Barbot J, Kirchberg K, Vadakkumpadan F, Maurer J, Cook J, Trayanova N, Solaiyappan M, Johnston P, Kraitchman D. Transmyocardial Therapuetic-Delivery Using Real-Time MRI Guidance. SCMR 16th Annual Scientific Sessions, San Francisco, CA, January 31 - February 3, 2013. Poster.

Background: Catheter-based transmyocardial injection offers a minimally invasive method to deliver therapeutics to the heart. It is typically performed under X-ray fluoroscopic guidance, which suffers from poor demarcation of myocardial boundaries and an inability to assess myocardial viability. MRI-guided intramyocardial delivery of therapeutics at 3T offers the potential for more precise targeting of these therapies with superior tissue contrast.

Our group has been actively involved with microencapsulated stem cell therapy to improve cell retention and prevent stem cell rejection. However, most microencapsulated stem cell products are too large to be administered transmyocardially. We demonstrate here intramyocardial injection of a prototype single stem cell therapeutic into the myocardium of a normal swine using real-time MR guidance and a custom active injection catheter.

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Adoptathon Case Study

Sandy L. MacArthur, University of Florida
Abstracts, Winner

OUTCOME OF PETS ADOPTED DURING A WAIVED-FEE ADOPTION EVENT: MADDIE’S MATCHMAKER ADOPTATHON 

 S. L. MacArthur, J. K. Levy, P. A. Dingman, S. J. Tucker.
Maddie’s Shelter Medicine Program, College of Veterinary Medicine, University of Florida, Gainesville, FL USA.

 Campaigns to increase shelter pet adoptions by reducing or eliminating adoption fees are controversial due to concern they may increase risk of poor care or abandonment. The purpose of this study was to assess the outcome of pets adopted during a waived-fee adoption event in the San Francisco Bay Area in June 2011.

   A survey regarding the adoption experience was sent to all 1,928 pet adopters. Pet and owner characteristics and pet lifestyle were compared between adopters who still had their pets 6-12 months post-adoption and those who did not.

   A total of 57% of adopters completed the survey, reporting that 95% of cats and 93% of dogs were still in the home. Pets were lost from the home by return to the shelter (1.8% cats; 2.2% dogs), rehoming (1.6%; 2.4%), death (1.4%; 2.0%), or going missing (.12%; .44%). Most pets lived predominantly indoors (95%; 93%), slept on the family bed (62%; 44%), and had been to a veterinarian (74%; 87%). Strong or very strong attachment to the pet was reported by 94% of adopters. There were no significant differences between the two groups based on pet attachment level, post-adoption lifestyle or healthcare, or perception of the adoption event.

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Abstract: Granulomatous colitis in French Bulldogs

Winner, Cases and Abstracts category
Alison Manchester, Cornell University

GRANULOMATOUS COLITIS IN FRENCH BULLDOGS IS ASSOCIATED WITH INVASIVE E. COLI AND CLINICAL RESPONSE TO FLUOROQUINOLONE ANTIBIOTICS.

A Manchester1, S Hill2, B Sabatino3, R Armentano4, B Kessler1, M Miller1, B Dogan1, SP McDonough1, KW Simpson1. 1. College of Veterinary Medicine, Cornell University, Ithaca, NY. 2. Veterinary Specialty Hospital, San Diego, CA. 3. College of Veterinary Medicine, University of Tennessee, Knoxville, TN. 4. College of Veterinary Medicine, University of Florida, Gainesville, FL.

   French bulldogs have been reported to develop a form of inflammatory bowel disease that is histopathologically similar to granulomatous colitis of Boxer dogs (GCB). GCB is associated with mucosally invasive E. coli, whose eradication correlates with clinical remission. We sought to determine the clinical features, presence or absence of intramucosal bacteria and E. coli in colonic biopsies, and response to fluoroquinolone antibiotics in French bulldogs with GC.
 FISH staining to identify multifocal accumulations of intramucosal E. coli in colonic biopsies
   Five French bulldogs (4M, 1F; median age 10mo, range 5-12mo) with a histological diagnosis of GC were studied. Bacterial colonization was evaluated using eubacterial (EUB-338) and E. coli-specific FISH probes. E. coli were isolated and antimicrobial resistance was determined by broth microdilution MIC from available fresh biopsies. Response to fluoroquinolone antibiotics was determined by monitoring clinical signs.

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