ICOD3 Projects
Learn more about Illinois Center for Drug and Diagnostic Development projects, both pre-clinical and clinical.
DOVS-Mc100: Contrast Sensitivity Eye Chart Heading link
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What is the project?
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:
- CS against a uniform field (top)
- CS in “noise” (bottom)
How does it work?
- Read the top row
- Read the bottom row
- 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
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What does this mean?
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.
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Who does this help?
Patients with normal visual acuity but have subjective visual complaints.
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TRL 2
Research ideas and protocols developed. Hypothesis(es) generated.
DOVS-Aa100: Wound Healing Peptides Heading link
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What is the project?
Wound healing peptides
Histatins
- Histatins are a histidine rich family of endogenous antimicrobial peptides comprised of two genes and 13 proteins.
- Histatins are an important family of endogenous anti-microbial peptides with numerous biological actions including anti-microbial, immunomodulatory and pro-wound healing effects.
More details
- 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
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Acute corneal epithelial injuries
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.
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Who does this impact?
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).
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TRL 3
Hypothesis testing and initial proof-of-concept demonstrated in limited number in vitro and in vivo models.
DOVS-Dj100: (MSC) Exosomes Heading link
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MSC Secretome/Exosome modulate Macrophage phenotype:
- 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
MSC exosomes promote nerve sprouting in vitro:
Images above detail this work.
MSC Exosomes promote regeneration of corneal nerves after injury:
- Corneal epithelial injury (damages subbasal nerves)
- Treated topically with PBS or human bone marrow derived exosomes daily x 10 days
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What does this mean?
Modulation of inflammation and promotion of ocular surface components.
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Who does this impact?
- Patients with limbal stem cell deficiency
- Neurotrophic keratitis
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TRL 3
Hypothesis testing and initial proof-of-concept demonstrated in limited number in vitro and in vivo models.
DOVS-Dj200: Topical MEK Inhibitor Heading link
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Hypothesis
Congenital aniridia is a PAX6 haploinsufficiency Enhancing the expression of the normal PAX6 allele may in part compensate for the insufficient gene dosage.
In vitro testing
- 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
- Measured PAX6 protein (western) and mRNA expression after 48 hours
- 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 Inhibitor
- 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
- Phosphorylates ERK (p42/44)
- Multiple agents available – targeting melanoma, etc
- Cobimetinib (FDA approved)
- Mirdametinib (clinical trials)
- Refametinib(clinical trials)
- Trametinib (FDA approved)
In vivo results
- 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
- Screened ~ 50 compounds (3 different concentrations)
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What does this mean?
Inhibit proliferation and enhance cell differentiation
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Who does this impact?
- Patients with PAX6 related aniridic keratopathy
- Pterygia
- Ocular surface neoplasias
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TRL 3
Hypothesis testing and initial proof-of-concept demonstrated in limited number in vitro and in vivo models.
DOVS-Kz100: Diabetic Retinopathy Biomarker Heading link
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What is the project?
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.
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What does it mean?
This technology would be beneficial to diagnose various types of retinopathies, including diabetic retinopathy.
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Who does this impact?
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.
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TRL 3
Hypothesis testing and initial proof-of-concept demonstrated in limited number in vitro and in vivo models.
DOVS-Sh100: Anti-Heparin Sulfate Peptides G1 and G2 Heading link
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What is the project?
- Heparan sulfate is essential for the attachment of multiple viruses to enter host cells
- G1 and G2 peptides developed by Shukla lab are capable attaching to heparan sulfate and block viral entry into cells.
- Theoretically capable of restricting SARS-CoV-2 entry into airway cells also.
More details
Further documentation.
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What does this mean?
Novel treatment for multiple different viruses, including ocular HSV.
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Who does this impact?
Global incidence of HSV keratitis is roughly 1.5 million, including 40,000 cases of severe monocular visual impairment or blindness yearly.
DOVS-Sh200: DECON Heading link
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What is this project?
Drug Encapsulated Carbon: Novel platform for sustained ocular drug delivery
- Topically dosed ocular drugs have low bioavailability.
- Usually require 6-10 doses per day to be effective
- Carbon based ocular drug delivery system is novel and safe.
- Capable of reducing doses to once every alternate day
- Also capable of non-specific viral entry into host cells.
More details
Trifluridine (TFT), FDA approved topical treatment requires 6-9 doses/day, when dosed alternate days.
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What does this mean?
Delivery system to reduce frequency of eye drops needed for multiple different therapeutics.
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Who does this impact?
Global incidence of HSV keratitis is roughly 1.5 million, including 40,000 cases of severe monocular visual impairment or blindness yearly.
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TRL 3
Hypothesis testing and initial proof-of-concept demonstrated in limited number in vitro and in vivo models.
DOVS-Sh300: PBA Heading link
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What is the project?
Phenylbutyrate as a ER stress reducing antiviral agent
- Current antiviral drugs target a single aspect of the viral lifecycle.
- Can be toxic in the long run and instances of resistance reported
- CREB3 is a pro-viral factor, when inhibited can lead to loss of infection.
- Phenylbutyrate, an FDA approved drug for urea cycle disorders can suppress CREB3 activity, alleviate ER stress and inhibit HSV infection
- PBA synergizes with acyclovir, reducing effective concentration in half.
More details
Trifluridine (TFT), FDA approved topical treatment requires 6-9 doses/day, when dosed alternate days.
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What does this mean?
Phenylbutyrate can be used as an antiviral agent through reducing ER stress.
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Who does this impact?
Global incidence of HSV keratitis is roughly 1.5 million, including 40,000 cases of severe monocular visual impairment or blindness yearly.
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TRL 3
Hypothesis testing and initial proof-of-concept demonstrated in limited number in vitro and in vivo models.
DOVS-Ya100: KAI Heading link
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What is the project?
Development of a small peptide called KAI, which inhibits VEGFR2 trafficking to the cell surface thus inhibiting VEGF-induced responses such as vascular leakage and neovascularization.US patent (US-2019-0169241-A1) and international patents are filed. -
What does this mean?
Preventing vascular leakage and neovascularization in wet AMD and diabetic retinopathy which cause vision loss.
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Who does this impact?
Patients with wet AMD and diabetic retinopathy.
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TRL 3
Hypothesis testing and initial proof-of-concept demonstrated in limited number in vitro and in vivo models.
Clinical Projects Heading link
DOVS-Ja100: Antibody Based Eye Drops is a project focused on developing antibody-based eye drops that can be used for treatment of ocular surface diseases.
DOVS-Ja200: DNase Eye Drops is a project focused on developing DNase eye drops that can be used for treatment of ocular surface diseases.
Possible indications
Ocular surface diseases
Prevalence/target population
Dry eye syndrome affects between 4 to more than 20% of the population and becomes more common with age. A variety of patient and environmental factors can increase the risk of symptomatic and severe inflammatory manifestations of dry eye disease.1
Status
Both projects are TRL 6. Phase 1 clinical trials completed, data support proceeding to Phase 2 clinical trials, IND application prepared and submitted.