ICOD3 Projects

Contrast sensitivity (CS) measures how well an individual can detect differences in light. CS is reduced in several ocular diseases, even in cases where visual acuity is normal. In certain patient populations (e.g. glaucoma), CS predicts the ability to perform tasks of daily living better than visual acuity. Despite the importance of CS, it is not routinely measured in the clinic, in part due to a lack of convenient, inexpensive, clinically-applicable instrumentation.

A novel eye chart for measuring CS is under development (shown below). Two measures of CS are obtained with this new eye chart:

1. CS against a uniform field (top)
2. CS in “noise” (bottom)

How does it work?

1. Read the top row
2. Read the bottom row
3. Compute the ratio of the number of letters read correctly for each row

This novel chart may have important advantages including:

• Less affected by optical abnormalities/cataract
• Insight into the cause of CS loss can be obtained
• Minimal dependence on room illumination
• Small, portable, and inexpensive

Measuring CS can provide insight into visual function in patients who present with subjective visual complaints, but have normal visual acuity. Measurement and comparison of CS in the presence and absence of noise may be useful to help predict potential gain in visual function due to cataract extraction in patients who have clinically-significant cataract and glaucoma, or clinically-significant cataract and diabetic retinopathy.

Patients with normal visual acuity but have subjective visual complaints.

Research ideas and protocols developed. Hypothesis(es) generated.

• A series of truncation experiments were used to determine the critical pentapeptide (SHRGY) domain which is necessary and sufficient for promotion of healing corneal wounds.
• SHRGY can be delivered in a topical drop to enhance wound healing

Acute corneal epithelial wounds (corneal abrasions, foreign bodies, contact lens related injuries) are extremely common. Corneal abrasions can lead to complications such as corneal ulcers, vision loss, and chronic wounds. Very limited interventions are currently available for these wounds. Additionally, patients undergoing photorefractive keratectomy and other ocular procedures are associated with corneal epithelial wounds. This technology would allow patients to recover faster, return to work sooner and with a lower risk of complications.

Acute corneal epithelial wounds (corneal abrasions, foreign bodies, contact lens related injuries) are extremely common (more than 1 million per year) and account for 271,750 emergency department visits per year. Additionally, over 800,000 people per year undergo refractive eye surgery procedures, the majority of which are either Laser-Assisted In Situ Keratomileusis (LASIK) or photo refractive keratectomy (PRK).

Hypothesis testing and initial proof-of-concept demonstrated in limited number in vitro and in vivo models.

• Macrophages (from PBMC) exposed to MSC secretome or exosomes
• Adopt an “inflammation resolving”, less-angiogenic “M2” phenotype
• MSC secreted PEDF (pigment epithelium derived factor) one of the mediators
• MSC exosomes similarly modulate human macrophage phenotype

• Corneal epithelial injury (damages subbasal nerves)
• Treated topically with PBS or human bone marrow derived exosomes daily x 10 days

Modulation of inflammation and promotion of ocular surface components.

• Patients with limbal stem cell deficiency
• Neurotrophic keratitis

Hypothesis testing and initial proof-of-concept demonstrated in limited number in vitro and in vivo models.

Congenital aniridia is a PAX6 haploinsufficiency Enhancing the expression of the normal PAX6 allele may in part compensate for the insufficient gene dosage.

• Screened ~ 50 compounds (3 different concentrations)
  • Measured PAX6 protein (western) and mRNA expression after 48 hours
    • Human corneal epithelial cell line (HCLE), primary human corneal epithelial cells
    • Patient corneal mesenchymal cells (discarded surgical specimen – IRB approval)
    • PAX6+/- mouse corneal mesenchymal cells
• Drugs/compounds found to increase PAX6 in vitro
  • Metformin 1.5-1.8 x
  • Dihydrotestosterone 1.4x
  • Rosiglitazone 1.4x
  • Simvastatin 1.5x
  • MEK Inhibitors 2 – 2.5x
• Notable drugs that decrease PAX6
  • Retinoic acid
  • Lithium
  • Valproic acid

• MEK (MAPK Kinase) 1/2
  • Phosphorylates ERK (p42/44)
    • EGFR-ERK previously shown to downregulate PAX6
  • Enhanced PAX6 ? in part due to
    • Inhibiting proliferation à Promoting differentiation
• Multiple agents available – targeting melanoma, etc
  • Cobimetinib (FDA approved)
  • Mirdametinib (clinical trials)
  • Refametinib(clinical trials)
  • Trametinib (FDA approved)

• Pax6Sey-Neu/+ model from Jim Lauderdale (with support from VFT)
• Applied Mirdametinib PO once day or topically once a day starting on PND5 to day 30.
• Significant improvement in corneal phenotype
  • Thinner corneal stroma
  • Thicker epithelium
  • Less corneal scarring
• Treatment effect persistent at day 60 and 90
• Replicated in 4 independent sets of experiments

Inhibit proliferation and enhance cell differentiation

• Patients with PAX6 related aniridic keratopathy
• Pterygia
• Ocular surface neoplasias

Hypothesis testing and initial proof-of-concept demonstrated in limited number in vitro and in vivo models.

roGFP sensors are variants of GFP that are sensitive to changes in redox. roGFP sensors are reversible and thereby enable observation of not only an increase, but also a subsequent decrease in oxidative stress in live cells and in real time.

This technology would be beneficial to diagnose various types of retinopathies, including diabetic retinopathy.

According to the CDC, diabetes is the leading cause of new cases of blindness in adults. One in three people with diabetes have diabetic retinopathy. A recent study conducted at the CDC found that 4.2 million adults have diabetic retinopathy and 655,000 have vision threatening diabetic retinopathy.

Read more.

Hypothesis testing and initial proof-of-concept demonstrated in limited number in vitro and in vivo models.

Further documentation.

Novel treatment for multiple different viruses, including ocular HSV.

Global incidence of HSV keratitis is roughly 1.5 million, including 40,000 cases of severe monocular visual impairment or blindness yearly.

Farooq AV, Shukla D. Herpes simplex epithelial and stromal keratitis: an epidemiologic update. Surv Ophthalmol. 2012 Sep;57(5):448-62. doi: 10.1016/j.survophthal.2012.01.005. Epub 2012 Apr 28. PMID: 22542912; PMCID: PMC3652623.

Trifluridine (TFT), FDA approved topical treatment requires 6-9 doses/day, when dosed alternate days.

Delivery system to reduce frequency of eye drops needed for multiple different therapeutics.

Global incidence of HSV keratitis is roughly 1.5 million, including 40,000 cases of severe monocular visual impairment or blindness yearly.

Farooq AV, Shukla D. Herpes simplex epithelial and stromal keratitis: an epidemiologic update. Surv Ophthalmol. 2012 Sep;57(5):448-62. doi: 10.1016/j.survophthal.2012.01.005. Epub 2012 Apr 28. PMID: 22542912; PMCID: PMC3652623.

Hypothesis testing and initial proof-of-concept demonstrated in limited number in vitro and in vivo models.

Trifluridine (TFT), FDA approved topical treatment requires 6-9 doses/day, when dosed alternate days.

Phenylbutyrate can be used as an antiviral agent through reducing ER stress.

Global incidence of HSV keratitis is roughly 1.5 million, including 40,000 cases of severe monocular visual impairment or blindness yearly.

Farooq AV, Shukla D. Herpes simplex epithelial and stromal keratitis: an epidemiologic update. Surv Ophthalmol. 2012 Sep;57(5):448-62. doi: 10.1016/j.survophthal.2012.01.005. Epub 2012 Apr 28. PMID: 22542912; PMCID: PMC3652623.

Hypothesis testing and initial proof-of-concept demonstrated in limited number in vitro and in vivo models.

Preventing vascular leakage and neovascularization in wet AMD and diabetic retinopathy which cause vision loss.

Patients with wet AMD and diabetic retinopathy.

Hypothesis testing and initial proof-of-concept demonstrated in limited number in vitro and in vivo models.