Our Pipeline
Pre-Clinical Projects
DOVS-Mc100: Contrast Sensitivity Eye Chart
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
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.
TRL 2
Research ideas and protocols developed. Hypothesis(es) generated.
DOVS-Aa100: Wound Healing Peptides
Wound healing peptides
- 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.
- 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
Shah D. et al, Mol Ther-Meth Clin D. 2020
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.
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).
TRL 3
Hypothesis testing and initial proof-of-concept demonstrated in limited number in vitro and in vivo models.
DOVS-Dj100: (MSC) Exosomes
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:
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
Modulation of inflammation and promotion of ocular surface components
- Patients with limbal stem cell deficiency
- Neurotrophic keratitis
TRL 3
Hypothesis testing and initial proof-of-concept demonstrated in limited number in vitro and in vivo models.
DOVS-Dj200: Topical MEK Inhibitor
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
Inhibit proliferation and enhance cell differentiation
- Patients with PAX6 related aniridic keratopathy
- Pterygia
- Ocular surface neoplasias
TRL 3
Hypothesis testing and initial proof-of-concept demonstrated in limited number in vitro and in vivo models.
DOVS-Kz100: Diabetic Retinopathy Biomarker
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. https://jamanetwork.com/journals/jama/fullarticle/186384
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
- 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.
G1/G2 Peptide Targets Heparan Sulfates
Tiwari V et al. J. Biol. Chem. 2011
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.
TRL 3
Hypothesis testing and initial proof-of-concept demonstrated in limited number in vitro and in vivo models.
DOVS-Sh200: DECON
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.
Yadavalli et al. Sci. Adv. 2019
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.
TRL 3
Hypothesis testing and initial proof-of-concept demonstrated in limited number in vitro and in vivo models.
DOVS-Sh300: PBA
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.
Yadavalli et al. Sci. Adv. 2020
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.
TRL 3
Hypothesis testing and initial proof-of-concept demonstrated in limited number in vitro and in vivo models.
Clinical Projects
DOVS-Ja100: Antibody Based Eye Drops
Antibody based eye drops that can be used for treatment of ocular surface diseases.
Ocular surface diseases
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
TRL 6
Phase 1 clinical trials completed, data support proceeding to Phase 2 clinical trials, IND application prepared and submitted.
DOVS-Ja200: DNase Eye Drops
DNase eye drops can be used for treatment of ocular surface diseases.
Ocular surface diseases
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
TRL 6
Phase 1 clinical trials completed, data support proceeding to Phase 2 clinical trials, IND application prepared and submitted.