Research

We have multiple ongoing research projects investigating corneal wound healing, non-human primate models of retinal disease, tear film disorders, and the genetics of ocular diseases.

Active Federal Grants

Mechanotransduction in corneal disorders
We have determined that transcriptional co-activators and mechanotransducers, YAP/TAZ, influence corneal epithelial contact guidance, myofibroblast transformation, and that TAZ (encoded by WWTR1 in humans and Wwtr1 in mice) is crucial for a healthy corneal endothelium. Corneal disease is a leading cause of blindness worldwide; corneal transplantation is often required to restore vision particularly for the common condition, Fuchs endothelial corneal dystrophy (FECD). Hallmarks of FECD include premature corneal endothelial cell (CEC) degeneration and the formation of excrescences of extracellular matrix (ECM), termed guttae, on Descemet’s membrane (DM). Biophysical cues intrinsic to ECMs are widely recognized as ubiquitous and potent modulators of myriad cell behaviors, including their response to stress. Despite this, there remains a major knowledge gap in regard to the mechanical properties of DM in health and disease and the associated mechanotransduction events in CECs. Furthermore, a large body of evidence points to oxidative stress playing a major role in FECD. Together, we hypothesize that TAZ plays a critical role in the onset and progression of FECD via changes in cell signaling, matrix remodeling, and cellular stress responses. Exciting preliminary data document that TAZ knockout (Wwtr1-/-) mice have reduced CEC density, increased cellular polymegathism, and an abnormal DM with guttae in comparison to wildtype (WT) littermates. Furthermore, CEC injury to TAZ deficient mice results in bullous keratopathy and diminished CEC regeneration similar to what is observed in severe, chronic FECD. These data suggest that TAZ deficient mice may represent an important late-onset model for FECD to define the role of mechanotransduction in its etiopathogenesis and to test new therapies to delay disease onset and/or progression. In this proposal, we utilize this model to test the efficacy of netarsudil, a rho-kinase and norepinephrine transport inhibitor, recently approved for glaucoma in the US. Preliminary data suggests that netarsudil increases CEC regeneration in TAZ deficient mice. The literature supports the use of rho-kinase inhibitors in CEC regeneration but netarsudil has never been studied in this context to our knowledge. The central goals of this proposal are to 1) determine the role of TAZ in CEC regeneration and 2) investigate the efficacy of netarsudil for CEC regeneration using murine models more predictive of human FECD.
Modulation of Hsp90 signaling to limit corneal fibrosis and improve ocular drug penetration
Keratoablative surgeries, including photorefractive keratectomy (PRK), phototherapeutic keratectomy (PTK), and laser assisted in situ keratomileusis (LASIK), are commonly performed procedures to correct refractive error and treat anterior stromal corneal diseases. The success of these surgeries requires a well-coordinated corneal wound healing response to limit post-operative corneal fibrosis. Heat shock protein 90 (Hsp90) is a key molecular chaperone responsible for the correct folding of many cellular proteins. In addition, Hsp90 has been shown to regulate two signaling pathways important to wound healing, transforming growth factor β (TGF-β) and the Hippo (mainly YAP and TAZ) pathways, by (1) stabilizing the activated TGF-β receptor complex and (2) targeting YAP and TAZ for degradation by the proteasome. Our lab and others have demonstrated the importance of both cytoactive factors and biophysical cues on determining the responses of corneal stromal cells. For example, corneal fibroblasts stimulated with TGF-β and grown on stiff substrates, mimicking a corneal wound bed, will upregulate αSMA expression and transdifferentiate to myofibroblasts. Clinically, excessive numbers or sustained persistence of myofibroblasts can be associated with development of corneal fibrosis and haze. YAP and TAZ, two important mechanotransducers, “sense” the matrix stiffness surrounding the cell. When grown on stiffer substrates, YAP and TAZ will localize the nucleus, resulting in the expression of multiple downstream molecules, including TGF-β. We propose to inhibit Hsp90 to modulate both the TGF-β and TAZ signaling pathways to limit αSMA expression and corneal fibrosis/haze. Experiments with knockout mice and with chemical inhibitors of these pathways are designed to help dissect the interaction between TGF-β and TAZ in the context of corneal wound healing. In addition, we have investigated the role Hsp90 inhibition in corneal epithelial cells. We demonstrate that treatment of stratified corneal epithelial cells with an Hsp90 inhibitor can result in the disruption of paracellular tight junctions, characterized by reduced trans- epithelial electrical resistance and loss of ZO-1 localization at the epithelial cell borders. We propose to define the toxicity, time course and effect on permeability of an Hsp90 inhibitor on corneal epithelial cells, both in vitro and in vivo. Results from these experiments could lead to the development of a novel method for increasing drug permeability, helping to overcome one the of the largest barrier to topical drug delivery, the corneal epithelial tight junction. This proposal is focused on two independent outcomes, (1) limiting corneal fibrosis/haze during wound healing and (2) increase corneal permeability to promote topical drug penetration, that are harmonized through the inhibition of Hsp90. Overall, findings from this proposal could prove to be clinically significant and lead to the development of novel therapeutic approaches to the benefit of patients.
Novel model systems for the study of cone disorders and other heritable retinal diseases
Abstract

Retinal degeneration diseases are a common cause of untreatable blindness worldwide, affecting the lives of millions. The only FDA-approved treatment for these disorders is gene therapy for specific RPE65 mutations that cause Leber’s congenital amaurosis and retinitis pigmentosa. One major limitation to the development of effective therapies is the use of model systems that poorly replicate the human condition. Particularly for cone disorders, studies that use model systems with a rod-dominant retina and no true macula have substantive limitations. We propose to develop a series of novel and spontaneous animal models of human inherited retinal diseases. In preliminary analyses, we have identified a new spontaneous model directly relevant to human retinal disease. Genetic testing identified four individuals homozygous for a naturally occurring damaging mutation in the PDE6C gene, which has previously been associated with cone dystrophy in humans. Scotopic and photopic full-field electroretinograms performed on animals homozygous for the PDE6C mutation demonstrated a relatively normal rod response but no cone response whatsoever. A subtle but characteristic retinopathy was identified using fundus photography, blue autofluorescence, and fluorescein angiography with concurrent foveal thinning using spectral-domain optical coherence tomography. Our genetic survey also identified individuals with mutations in 7 other human retinal disease genes that are predicted to severely damage gene or protein function, pointing to possible additional new models. To develop the new model of PDE6C cone dystrophy, and make this and other new models available to the vision research community, we propose four Specific Aims: 1) to identify and genetically characterize new animal models of human retinal disease via DNA sequencing, 2) to perform complete ophthalmic phenotyping of the new models of retinal disease, 3) to breed a colony of animals with PDE6C cone dystrophy and 4) to compare cell-based and gene replacement therapies in these subjects with PDE6C cone dystrophy mutations. Successful completion of this work will produce a well-characterized new animal model of inherited cone dystrophy with significantly greater similarity to human disease than existing models, thus providing substantially better translation to subsequent human trials. In addition, affected animals will be made available to the wider vision research community, and other new models with similar potential will be identified.

Project Narrative

Retinal degeneration is a major cause of visual impairment and blindness in humans, but there are few effective treatments available to the many patients in need. The goal of this project is to advance the pace and efficiency of research regarding treatments for retinal degeneration disease by developing novel spontaneous (not induced) models of human retinal disease. By developing new and better model systems, and making those models available to the wider vision research community, this project will speed the development and efficacy testing of innovative therapies, including cell and gene therapy, that will reduce the morbidity caused by retinal degeneration diseases in humans.
Development of new models of AMD
Complement factor H (CFH), a key regulator of the complement system, plays an integral role in the pathogenesis of age-related macular degeneration (AMD), the most common cause of blindness in developed countries. CFH knockout (KO) mice and other rodent models have provided many insights into the pathogenesis of AMD. However, these models are of limited value, especially for translational studies, given the significant differences in retinal anatomy and biology between humans and rodents (e.g., the latter lack maculae). Non-human primates (NHP) are superior models of human diseases, especially retinal diseases, because of the close physiological and anatomical similarities between NHP and humans (e.g., NHP are the only animals with maculae). However, despite recent technology advances, it remains technically and ethically challenging to generate gene-engineered NHP-based disease models. Our results from preliminary studies suggest the existence of naturally occurring CFH-deficient monkeys. Therefore, a combination of detailed assays of complement function, genomic sequencing, and analyses of non-invasive retinal imaging and functional parameters should allow us to identify and develop CFH-deficient monkeys as new models for AMD. This project will combine the respective expertise of three collaborative teams, including the Lin Lab at Cleveland Clinic (complement biology), the Chen Lab at Baylor College of Medicine (non-human primate genetics), and the Thomasy Lab at UC Davis (non-invasive NHP retinal imaging and function analyses) to achieve our short-term goal of identifying breeding monkeys harboring deficiencies in CFH (or other complement components). Ultimately, we aim to develop novel NHP AMD models that will enable the development of novel therapeutics (e.g. regenerative medicine and gene therapy) for this devastating blinding disease.
Sustained Ocular Drug Delivery System for Anti-VEGF Agents
Recently employed intravitreal anti-vascular endothelial growth factor (anti-VEGF) therapy is a promising treatment for the wet form of age-related macular degeneration with choroidal neovascularization (CNV) and diabetic retinopathy. In fact, the anti-VEGF therapy has become a gold standard for these diseases. While the therapeutic effects are positive, a major drawback is that this treatment must be repeated every four to six weeks. The repetitive treatment burden on the patients, family members, and clinicians is substantial. Recently, we have developed a biodegradable microspheres, thermo-responsive hydrogel ocular drug delivery system (DDS). Biodegradable microspheres are produced using our modified double emulsion technique providing a better microenvironment for pharmacological agents. The biodegradable thermo-responsive hydrogel is a safe, effective, and injectable biomaterial that is used to confine the microspheres to a specific delivery site. We have previously demonstrated a controlled sustained release of anti-VEGF for a period of 6 months with excellent safety profiles. The overall goal of this proposal is to quantitatively evaluate the safety and efficacy of our proposed DDS in a non-human primate model and compare to the conventional therapy. Our hypothesis is that a sustained controlled anti-VEGF release over a prolong period of ~6 months, will be as effective, if not more effective, as the conventional therapy.
The Specific Aim 1 is to determine ocular pharmacokinetics (PK) of aflibercept released from DDS in a non-human primate (NHP) model.
The Specific Aim 2 to determine biocompatibility of DDS in a NHP model.
The Specific Aim 3 is to quantitatively compare the efficacy and bioactivity of the proposed DDS to the conventional therapy in its ability to suppress angiogenic responses in CNV model.
The Specific Aim 4 is to measure long-term potential side effects, if any, of the proposed DDS and exposure of anti-VEGF in a rodent model.
The Specific Aim 5 is to quantitatively evaluate the drug release kinetics and bioactivity of the dual-drug release DDS. Widespread clinical use of anti-VEGF necessitates a practical and effective delivery method to the posterior segment of the eye. We believe that our drug delivery system will fill this critical clinical need. The knowledge gained in this proposal will bring this technology one step closer to translation into the clinical practice and will have a significant impact on the current healthcare system.
Large Animal Core
The Large Animal Core (LAC) provides a wide spectrum of support to vision scientists who are investigating fundamental processes and therapeutic strategies in large animal models. The Core comprises an AAALAC- accredited, fully equipped microsurgical suite and three advanced imaging suites. The LAC provides ocular imaging instrumentation, including multiple SD-OCTs, multiple electroretinography units, confocal biomicroscopy, digital slit lamps, tonometers, pachymeters, external digital SLR cameras, fundus cameras, and a Pentacam imaging system. The LAC will also provide expert technical support to help investigators understand the Core technologies and their capabilities, develop appropriate study designs, perform procedures and/or collect data. The LAC will stimulate collaboration among vision scientists by providing support for innovative multidisciplinary research, and it will support early-career vision scientists as they set up their laboratories and collect data essential for future NEI grant applications.

Our Clinical Trials

Corneal cross-linking (CXL) as a treatment for canine infectious keratitis
Background and purpose: Infectious keratitis is an eye condition that can occur in all breeds of dogs. During this disease, the cornea becomes damaged and undergoes a melting process due to an enzymatic imbalance of the cornea and the tear film. The health of the cornea can rapidly deteriorate in the presence of bacterial infection, causing pain and leading to severe scarring and vision impairment if the eyes heal. If the ulcer does not heal, the globe can rupture and result in permanent blindness. Current treatment standards for infectious keratitis in dogs consist of frequent application of eye drops and are aimed at killing the microorganisms with antibiotics and arresting tissue melting. Ultraviolet-A (UV-A) cross-linking of the corneal stroma with riboflavin as a photosensitizing agent (CXL) has been in use for more than 15 years for the treatment of corneal disorders in human medicine. The efficacy of CXL in infectious keratitis has also been established in studies in veterinary and human patients.

What happens in this study: Ophthalmic examination, including digital slit-lamp biomicroscopy, Schirmer tear test, staining of the eye with fluorescein, and digital photography. Noninvasive advanced corneal imaging, including a Fourier-domain optical coherence tomography (FD-OCT) a non-contact imaging technique that gives a high-resolution, cross-section of the corneal layers to monitor the healing of the corneal ulcer. Evaluation of the stability of the cornea and of the size and depth of the corneal ulcer. Cytology testing and bacterial culture and sensitivity testing of the corneal ulcer. The follow-up examinations will be performed on days 1, 2, or 3, and days 7, 14, and 28.

Enrolled patients will be randomly allocated into two groups: a group of 10 dogs will receive CXL with Riboflavin treatment protocol and a control group of 10 dogs will receive intensive medical treatment only, following the current gold standards in the treatment of infectious keratitis. Some dogs may be administered sedation during participation in the study.

Pet owner responsibilities: Owners will be asked to comply with an intensive topical treatment schedule and bring their dogs for follow-up appointments performed on days 1, 2 or 3, and days 7, 14, and 28 at the UC Davis Veterinary Hospital. Food cannot be given in the morning in preparation for potential sedation. The study will also cover the costs of any complications from the sedation, blood sampling, or imaging up to $1000 if performed at UC Davis.

Participation requirements: We are looking for dogs with a clinical diagnosis of a unilateral malacic/melting ulcer (infectious keratitis), defined as: loss of the outer epithelium, stromal loss and/or stromal neutrophil infiltrates, neutrophilic inflammation or a large number of bacteria confirmed on cytology. Compensation: There will be no cost to you for your participation in this study. Your dog will receive a very thorough eye examination together with follow-up appointments and intensive medical treatment at no charge. We will cover all costs, including sedation, hospitalization, and CXL procedure (if the patient is randomly allocated to that group), as well as topical and oral medications. All patients will receive blood work (a serum biochemistry panel) to ensure there are no contraindications to receiving oral anti-inflammatory medications. The study will also cover the costs of any complications from the sedation, blood sampling, or imaging up to $1000 if performed at UC Davis.

Benefits and risks of participating: Each patient enrolled in our study (both in CXL and control group) will receive intensive medical treatment, following the current gold standards in the treatment of infectious keratitis. In addition to this, results from the current study will allow us to provide an unbiased answer to whether CXL is a valid alternative therapy to medical treatment for bacterial corneal ulcers in dogs, then we may be able to develop new, potentially more effective, treatment protocols for this disease.
Sudden Acquired Retinal Degeneration Syndrome (SARDS): Understanding the Disease
Title: Proteomics and genomics of canine sudden acquired retinal degeneration syndrome

Purpose of Study: Sudden acquired retinal degeneration syndrome (SARDS) is a common cause of permanent blindness in dogs. Dogs usually present with rapid onset of blindness with no obvious abnormalities in the retina; however, the underlying cause for SARDS is unknown and no treatment exists. We are interested in characterizing this disease better with hopes of identifying protein biomarkers and/or the genetic components of this disease.

Contact: Monica Motta at mjmotta@ucdavis.edu or 530-752-6967

Participation Requirements:
Dogs diagnosed with Sudden Acquired Retinal Degeneration Syndrome (SARDS)
Dogs with healthy retinas

Initial Evaluation for Participation: None.

Procedures:
Routine ophthalmic examination
Dilation of the eyes to examine the back of the eyes
Staining of the eye with fluorescein to assess for corneal ulcers
Digital photography of the eye (fundus photography)
Blood collection for DNA analysis and serum storage
Electroretinogram (ERG) to measure retinal function

Benefits: Costs of any complications from the ophthalmic examination, diagnostic testing, ERG, sedation, or blood sampling will be covered by the study up to $200.

Results from this study will hopefully lead to a better ability to predict the onset and progression of this disease. If a gene that causes this disease is found, then we may be able to develop a genetic test to know which dogs have or do not have this disease.

Owner Responsibilities: You will be responsible for the cost of the ophthalmic exam and all diagnostic tests performed.

For most dogs, we expect that participation in this clinical trial will last for one visit for the ophthalmic exam, diagnostic testing and blood collection. However, we may ask you to come back for repeated blood sampling. We will also ask you to fill out a questionnaire regarding your dog’s history.
Corneal Endothelial Dystrophy: Understanding the Disease in Boston Terriers, German Shorthaired Pointers, and German Wirehaired Pointers
Title: Phenotype and Genotype of Corneal Endothelial Dystrophy in Boston Terriers, German Shorthaired Pointers, and German Wirehaired Pointers

Purpose of Study: Corneal endothelial dystrophy (CED) is a devastating disease in dogs that can result in blindness and severe ocular pain from secondary complications. The endothelial cells comprise the most inner aspect of the cornea and are responsible for maintaining a proper fluid balance. This function is critical to ensuring that the cornea remains transparent for vision. In many animals, including dogs, corneal endothelial cells have a very limited capacity to regenerate following injury. In canine patients with CED, the endothelial cells degenerate until the cells still remaining can no longer function properly. This results in swelling of the cornea (edema) which results in decreased vision as well as formation of small fluid-filled blisters (bullae) on the cornea which can rupture and cause ocular discomfort. There are palliative treatments such as hypertonic saline to decrease corneal bullae formation but the only definitive treatment for this condition is a corneal transplant (penetrating keratoplasty). Unfortunately, corneal transplants are rarely performed in canine patients with CED due to the expense of the surgery and follow-up care, relatively high risk of complications, and lack of appropriate donor tissue.

Several dog breeds, including Boston Terriers, German Shorthaired Pointers and German Wirehaired Pointers, are seen more commonly for CED in comparison to other breeds. This observation suggests that this disease may have a genetic component. A similar condition called Fuch’s endothelial corneal dystrophy (FECD) exists in humans and several genes associated with FECD have been identified. We propose to identify the region of the dog genome associated with CED in Boston Terriers, German Shorthaired Pointers and German Wirehaired Pointers. In order to do this, we will perform thorough eye examinations and use non-invasive advanced imaging techniques to examine Boston Terriers, German Shorthaired Pointers and German Wirehaired Pointers with CED and age-matched control dogs. We will collect blood from these dogs to obtain DNA. The entire canine genome will be evaluated for an association with CED. This work will be used to identify the gene(s) responsible for this condition in Boston Terriers, German Shorthaired Pointers and German Wirehaired Pointers. The ultimate goal will be to develop a genetic test for CED in Boston Terriers, German Shorthaired Pointers and German Wirehaired Pointers and possibly other breeds, such as Chihuahuas and Dachshunds, with an increased risk of CED.

Contact: Monica Motta at mjmotta@ucdavis.edu or 530-752-6967

Participation Requirements:
Boston Terriers, German Shorthaired Pointers and German Wirehaired Pointers with Corneal Endothelial Dystrophy
Healthy Boston Terriers, German Shorthaired Pointers and German Wirehaired Pointers (>7 years of age)

Initial Evaluation for Participation: Dogs must receive a diagnosis by a veterinary ophthalmologist for corneal endothelial dystrophy.

Procedures:
Blood collection for DNA analysis
Ophthalmic examination, including digital slit lamp biomicroscopy, Schirmer tear test followed by dilation and staining of the eye wtih fluroescein and digital photography
Noninvasive advanced corneal imaging with ultrasonic pachymetry, confocal biomicroscopy and spectral domain-optical coherence tomography (all of which will require sedation)

Benefits: Benefits include an ophthalmic examination at no cost with thorough characterization of disease to aid in monitoring for progression.

Owner Responsibilities: No ophthalmic medications can be administered 48 h prior to examination. Food cannot be given in the morning in preparation for sedation.
Dry Eye Syndrome (Keratoconjunctivitis sicca): Understanding the Genetics in West Highland White Terriers
Title: The Genetics of Keratoconjunctivitis Sicca in West Highland White Terriers

Purpose of Study: Keratoconjunctivitis sicca (KCS) or dry eye is a devastating disease that causes ocular pain and potentially blindness. It is seen more frequently in West Highland White Terriers in comparison to many other breeds. We are interested identifying the genetic components of this disease as well as characterizing this disease better with examination and testing of the tear film and ocular surface and in select patients using advanced imaging techniques.

Contact: Monica Motta at mjmotta@ucdavis.edu or 530-752-6967

Participation Requirements:
West Highland White Terriers with Dry Eye Syndrome (affected); or,
West Highland White Terriers >7 years of age with no ocular abnormalities (control)

Initial Evaluation for Participation: Affected patients must receive a diagnosis by a veterinary ophthalmologist for dry eye. Dogs without ocular disease (controls) require no prior initial examination.

Procedures:
Routine ophthalmic examination and tear film tests
Blood collection for DNA analysis
Tears will be collected from the conjunctival sac using a blunt-tip needle attached to a syringe from both eyes. Tear collection will be performed at a separate time from the initial ophthalmic examination and tests.
Conjunctival biopsy: Two (2) minutes after regional anesthesia is applied, a small (approximately 5 mm x 2 mm) piece of conjunctiva will be removed from inside the lower eyelid.
Select patients only:
Advanced imaging: Spectral domain optical coherence tomography (non-contact imaging) and confocal biomicroscopy (imaging in which a gel on the instrument contacts the cornea) will also be performed to carefully image the cornea along with digital slit lamp photography.
Sedation for advanced imaging: In order to keep dogs relaxed and comfortable but awake for the advanced imaging, your dog will be given a mild sedative. The sedation chosen for your pet will depend on your dog’s age and health status.

Benefits: There will be no cost to you for your participation in this study and your dog will receive a very thorough eye examination at no charge. If a corneal ulcer occurs at the time of evaluation, the cost of medications, recheck examinations, and procedures (e.g., cotton-tipped applicator or Diamond burr debridement, grid keratotomy) will be performed at no cost to you if they are performed at UC Davis. If a surgical procedure is required, you will receive $200 of compensation towards the procedure if it is performed at UC Davis. If your dog has KCS, you will be compensated for taking part in this study with 2 months worth of immunosuppressive medication (e.g., cyclosporine/tacrolimulus) ointment or drops. The study will also cover the costs of any complications from the sedation, blood sampling or imaging up to $200.

Results from this study will allow us to better predict the onset and progression of this disease. If a gene that causes this disease is found, then we may be able to develop a genetic test to know which dogs have or do not have this disease.

Owner Responsibilities: Although there is no cost to participate in the study, you will need to cover any costs due to complications from sedation, blood sampling, or examination (including corneal ulceration) beyond $200. Additionally, please do not administer any medications to treat your dog’s dry eye for one week prior to the appointment other than the lubricant provided to you. If your dog is participating in the advanced imaging, please do not feed your dog the morning of the appointment (water is fine), as the sedation administered can cause vomiting.
Understanding retinal degeneration in greyhounds
Background and purpose: This trial is being conducted to better characterize retinal degeneration syndrome in greyhounds with hopes of identifying the genetic components of this disease.

What happens in this study: If your dog is determined to be eligible and you choose to enroll him/her, then the following will be performed (some of the imaging may be performed under sedation if needed):
A routine ophthalmic examination
Dilation of the eyes to examine the backs of the eyes
Staining of the eye with fluorescein to look for corneal ulcers
Advanced diagnostic ocular imaging including spectral domain optical coherence tomography (non-contact imaging) and fundus photography
Blood collection for DNA analysis
Electroretinogram (ERG) to measure retinal function
Alternatively, participation from home might be available through the use of an oral swab to provide a sample of DNA after providing clinical records.

Participation Requirements: We are looking for Greyhounds diagnosed with retinal degeneration and their relatives. We are also looking for American Kennel Club registered Greyhounds, both males or females. Those will be candidates to participate in the study from home, using an oral swab that we will mail to the owner to provide a sample of DNA.

Benefits and risks of participating: Your pet will benefit from the thorough ocular examination included in this trial. Results from this study will hopefully help us identify a gene associated with this disease in greyhounds.

Compensation: The study will cover all costs associated with the study and may pay up to $200 for medical treatment of adverse events incurred because of participation in this trial. If you elect to participate from home, we will ship you the oral swabs and send you a return label for free.

Pet owner responsibilities: If you choose to enroll your dog in the trial, you may be responsible for committing to at least one appointment, fasting your dog for procedures that may require sedation, keeping all scheduled appointments, monitoring the well-being of your dog at home, and reporting any changes or side effects. For owners participating from home, providing clinical records will be required.

Other Ophthalmology Clinical Trials

Equine Recurrent Uveitis: Understanding the Genetics in Appaloosa Horses
Title: Genomic investigation of Equine Recurrent Uveitis in Appaloosa horses

Purpose: Equine recurrent uveitis (ERU) is the leading cause of blindness in horses, marked by repeated episodes of inflammation of the uveal tract of the eye. Appaloosa horses, known best for their white coat spotting patterns (termed leopard complex or LP), are eight times more likely than any other breed to develop this disease and four times more likely to go blind, suggesting genetics plays a major contributing role. However, little is known about the specific genetic factors involved. The objective of this study is to determine the genetic factors contributing to ERU in Appaloosa horses.

Contact: Drs. Mary Lassaline (lasutter@ucdavis.e du or 530-752-0290) or Rebecca Bellone (rbellone@ucdavis.edu or 530-752-9299)

Participation Requirements: Appaloosas with known pedigrees

Initial Evaluation for Participation: None.

Procedures:
Examination of the horse’s eyes by a veterinary ophthalmologist
Photography of the horse to document coat color and any abnormalities found in the eyes
Collection of hair samples from the horse’s mane and/or a blood sample to analyze the DNA
Discussion of the horse’s medical history
Follow up phone calls or emails may be necessary if any questions about the horse’s medical history arise after the examination.
If any horse objects to having their eyes examined, to having mane hair pulled, or blood drawn, these procedures would not be performed.

Benefits: The results of this work may help to lower the incidence of this ocular disease in Appaloosas and other affected breeds, help breeders to make informed mating decisions, and be utilized by veterinarians to predict risk of developing disease for earlier diagnosis and treatment.

Owner Responsibilities: We expect that participation in this clinical trial will last for about 15 minutes but may take as long as one hour. If you allow your horse to participate in this study, you will be responsible for covering any injury sustained while participating and further diagnostics or therapy associated with the diagnosis of ERU if a presumptive diagnosis of ERU is made for your horse.
Bilateral Corneal Stromal Loss: Understanding the Genetics in Friesian Horses
Title: Genetic investigation of bilateral corneal stromal loss in Friesian horses

Purpose: Bilateral corneal stromal loss (BCSL) is a potentially progressive ocular disease that can be associated with pain, vision loss and even loss of the eye. The objective of this study is to determine the role genetics plays in BCSL in Friesian horses. This study is designed to determine the incidence of BCSL in the breed, to determine the mode of inheritance if a single gene is involved, and identify candidate genes for further investigation.

Contact: Drs. Mary Lassaline (lasutter@ucdavis.edu or 530-752-0290) or Rebecca Bellone (rbellone@ucdavis.edu or 530-752-9299)

Participation Requirements: Friesian horses with and without a diagnosis of bilateral corneal stromal loss (BCSL)

Initial Evaluation for Participation: Any Friesian horse is invited to participate. Please contact Drs. Mary Lassaline (lasutter@ucdavis.edu or 530-752-0290) or Rebecca Bellone (rbellone@ucdavis.edu or 530-752-9299) for more information.

Procedures:
Participation in this study would involve up to one hour of time per horse included in the study. This time may involve examination of the horse’s eyes by a veterinary ophthalmologist, photography of the horse to document coat color and any abnormalities found in the eyes, collection of hair samples from the horse’s mane, and discussion of the horse’s medical history.
For some horses, hair samples may be collected from the mane to examine DNA for genes that may be involved in the development of BCSL.
If any horse objects to having their eyes examined, or to having mane hair pulled, these procedures would not be performed.

Benefits: All costs associated with the study will be paid by the sponsor/department. However, if a presumptive diagnosis of BCSL is made for your horse, any further diagnostics or therapy associated with the diagnosis of BCSL will be your responsibility. Copies of any biopsy reports from horses that have been affected with BCSL may be requested.

We cannot promise any benefits to your horse or other animals from your taking part in this clinical trial; however, possible benefits include lowering the incidence of this ocular disease in Friesians and other affected breeds, helping breeders to make informed mating decisions, and better prediction of the risk of developing disease for earlier diagnosis and treatment.

Owner Responsibilities: If you allow your horse to participate in this study, you will not be responsible for anything other than allowing us access to examine your horse and pull hairs from the mane.
Ocular Squamous Cell Carcinoma: Understanding the Genetics in Haflinger, Beligan, Percheron, Appaloosa, and Arabian Horses
Title: Genetic Investigation of Ocular Squamous Cell Carcinoma in Haflinger, Belgian, Percheron, Appaloosa, and Arabian Horses

Purpose: Squamous cell carcinoma (SCC) is one of the most common forms of cancer to affect the eye in horses, frequently occurring at the limbus, where the clear cornea meets the white of the eye, or on the nictitating membrane, also known as the third eyelid. This type of eye cancer affects Haflingers, Belgians, Percherons, Appaloosas, and Arabians among others and the objective of this study is to determine the role genetics plays in ocular squamous cell carcinoma in these breeds. This study is designed to determine the incidence of SCC in the listed breeds, to determine the modes of inheritance and identify DNA variants that put horses at risk for this cancer.

Contact: Drs. Mary Lassaline (lasutter@ucdavis.edu or 530-752-0290), Rebecca Bellone (rbellone@ucdavis.edu or 530-752-9299), or Kelly Knickelbein (kknickelbein@ucdavis.edu or 530-718-8359)

Participation Requirements: Haflinger, Belgian, Percheron, Appaloosa, and Arabian Horses with confirmed ocular SCC (confirmed by pathology), or horses that have not been diagnosed with ocular SCC that are at least 13 years old. Horses that are suspicious for ocular SCC are invited to participate, but confirmation would be required prior to inclusion in the study.

Initial Evaluation for Participation: Any horse with confirmed ocular SCC does not need to be evaluated in person to participate. Participation for horses with confirmed ocular SCC involves providing (1) a copy of a pathology report confirming ocular SCC, (2) the horse’s registered name for pedigree analysis, and (3) a blood or hair sample. Horses that have not had ocular SCC and are at least 13 years old will need to be examined by a boarded veterinary ophthalmologist to confirm that they do not have ocular SCC. This may be done at UC-Davis VMTH or elsewhere.

Procedures:
Participation in this clinical trial, which could last between 15 minutes to one hour, will include discussion of the horse’s medical history, documentation on known pedigree information, examination of the horse’s eyes by a veterinary ophthalmologist, photography of the horse to document coat color and any abnormalities found in the eyes, and collection of hair samples from the horse’s mane.
Examination of a horse’s eyes is similar to examination of a person’s eyes, with lights and magnifying lenses shone into the eyes to see if they are normal, or if any signs suspicious for ocular SCC are present.
For some horses, a blood sample may be collected from the jugular vein, and hair samples may be collected from the mane. This is similar to pulling the mane for show but only pulling a very small sample of about 50 hairs. This blood and hair would be used to isolate DNA for genetic studies to help understand which genes may be involved in the development of ocular SCC.
Follow up phone calls or emails may be necessary if any questions about the horse’s medical history arise after the examination.
If any horse objects to having their eyes examined or to having blood taken or mane hair pulled, these procedures would not be performed.

Benefits: If you are selected to participate in the study, the study will cover the costs associated with eye examination, blood collection, and mane pulling; however, if a presumptive diagnosis of SCC is made for your horse, any further diagnostics or therapy associated with the diagnosis of SCC will be your responsibility.

We cannot promise any benefits to your horse or other animals from your taking part in this clinical trial; however, possible benefits include lowering the incidence of this common eye cancer in Haflinger, Belgian, Percheron, Appaloosa, and Arabian Horses, helping breeders to make informed mating decisions, and better prediction of the risk of developing disease for earlier diagnosis and treatment.

Owner Responsibilities: Financially, you will be responsible for covering any costs associated with injuries sustained while participating in this trial and any costs associated with follow up of your animal at VMTH for assessment.
Nasolacrimal Apparatus Blockage: A multidisciplinary, minimally invasive treatment
Title: Canine Nasolacrimal Apparatus Stenting for Treatment of Obstruction

Purpose of Study: Tears from the ocular surface are drained from the eye through several important structures collectively known as the nasolacrimal apparatus (NLA). This frequently becomes blocked and sometimes infected leading to discomfort, tear staining, eye discharge, and skin inflammation, all of which are associated with a decreased quality of life. Clinically, NLA obstructions can be very frustrating to treat and can often lead to permanent obstruction.

We have established a team at the UC Davis Veterinary Medical Teaching Hospital consisting of specialists with expertise in Ophthalmology, Internal Medicine, Endoscopy, Diagnostic Imaging, and Interventional Radiology and have utilized fluoroscopy to successfully treat NLA obstruction in dogs. We have utilized fluoroscopy, CT, and endoscopy and capitalized on improvements in instrumentation and minimally invasive techniques developed for catheterization of other challenging locations such as the ureters to successfully treat NLA obstruction.

Based upon the success of this initial pilot study, we have initiated a clinical trial to recruit and treat more cases and to evaluate more objective outcome measures.

Contact: Please call 530-752-3937 to schedule your initial visit to the UC Davis Veterinary Ophthalmology Service.

Participation Requirements: Dogs demonstrating signs of nasolacrimal apparatus (NLA) blockage

Initial Evaluation for Participation: None

Procedures: After an initial examination at the UCD VMTH to ensure the patient meets study entry criteria, you will provide informed consent and complete a questionnaire concerning their dog’s signs. Patients will then undergo initial testing including CT scanning of the NLA, and NLA stenting using endoscopy and fluoroscopy. The stent will be left in position for at least 6 weeks. After stent removal, similar testing including CT scanning will again be performed, and you will repeat the same questionnaire. Diagnostic test results from before and after stenting will be compared. Some financial subsidization of case management costs is available through the clinical trial.

Benefits: The study will subsidize costs associated with the second CT scan. Based upon results from the 6 patients in the pilot study, it is possible but not assured that your pet will have reduction or resolution of signs associated with NLA obstruction. Information acquired during this study will allow us to advance the treatment for NLA blockage for veterinary patients worldwide.

Owner Responsibilities: You will be responsible for all costs except those associated with the repeat CT scan following stent removal. Additionally, you will need to bring your dog to the VMTH for all scheduled appointments including a follow-up visit at least 6-8 weeks after the procedure. Lastly, you will be required to complete questionnaires prior to and after the NLA stenting procedure.