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Principal Investigator: Soon Seog Jeong
Organization: HUMAN CELL CO
Fiscal Year: 2024
Award: $365,000
Funding agency: National Eye Institute
Project Summary
Dry eye disease (DED) is an increasingly frequency cause of visual dysfunction. It is characterized by loss
of homoeostasis of the ocular surface, resulting in tear film instability, hyperosmolarity, and inflammation of the
conjunctiva and cornea. Up to 30% of the population over age 50 suffers from DED in the US. The dense corneal
nerve plexus is critical to maintaining homeostatic function of the ocular surface. Current treatments such as tear
substitutes, immunosuppressive drugs, and steroids address inflammation and tear film instability, but do not
address degradation of the corneal nerve bed, which is a key pathophysiological driver of DED. Therefore,
improving nerve health will significantly improve vision function and quality of life.
Increasing experimental and clinical evidence has shown that NGF is an essential factor for the trophism,
sensitivity, and healing of the cornea and the conjunctiva. Wildtype NGF (NGF wt, OxervateTM, Cenegermim)
was approved by the FDA in 2018 as eye drops to treat neurotrophic keratitis, an ocular disease characterized
by impairment of corneal sensitivity, healing, and tear production. Topical use of Cenegermim was well tolerated
and improved symptoms and tear production in patients with moderate to severe DED. It is known that NGF
binding to TrkA receptors attenuates reactive astrocytosis and promotes neuron survival and proliferation. In
contrast, NGF binding to p75NTR receptors leads to inflammation and neuron apoptosis. p75NTR activity is up-
regulated under pathological conditions, potentially limiting the efficacy of NGF wt treatment for DED. Moreover,
inefficient manufacturing of Cenegermim using an E coli expression system compromises protein stability and
quality at a prohibitive cost for chronic treatment.
We have designed and are developing for human use HC201, a human NGF mutein which improves TrkA
binding and signaling while substantially abrogating p75NTR binding and signaling. In a rat model of glaucoma,
topical treatment with HC201 robustly protected retinal ganglion cells (RGC), while wildtype NGF was not
effective. Importantly, HC201 was also effective in a model of DED induced with scopolamine. Meanwhile, we
have developed a highly cost-effective and scalable process to produce recombinant NGF in mammalian cells
by optimizing the cleavage site to facilitate furin-mediated post-proteolytic modifications of pro-NGF into mature
NGF. In this Phase I SBIR application, we will determine the efficacy and mechanism of action in a translational
model of corneal nerve bed injury in mice. The specific aim is to determine whether topical treatment with
HC201 more effectively improves tear film production and corneal sensitivity compared to wildtype NGF.
The long-term goal is to develop HC201, alone or in combination with current tear substitutes or
immunosuppressive drugs, to preserve and restore corneal homeostasis and sensitivity in patients with moderate
to severe DED.
Terms: <Abscission><Acceleration><Acetylcholine Antagonists><Address><Adherence><Affect><Age><Animal Model><Animal Models and Related Studies><Astrocytes><Astrocytosis><Astrocytus><Astroglia><Attenuated><Autoregulation><Beds><Binding><Blinking><Cell Communication and Signaling><Cell Signaling><Cholinergic Antagonists><Cholinergic-Blocking Agents><Cholinolytics><Chronic><Clinical><Clinical Evaluation><Clinical Testing><Common Rat Strains><Cornea><Cranial Nerve V><Desiccation><Dessication><Devices><Dry Eye Syndromes><Dry eye disease><E coli><E. coli><Epithelium><Escherichia coli><Excision><Extirpation><Eye Drops><Eye diseases><Eyedrops><FDA approved><Fifth Cranial Nerve><Film><Frequencies><GP80-LNGFR><Glaucoma><Goals><Health><Homeostasis><Human><Hyoscine><Immunomodulation><Immunosuppressants><Immunosuppressive Agents><Immunosuppressive drug><Immunosuppressive treatment><Impairment><Inflammation><Injury><Intracellular Communication and Signaling><Keratoconjunctivitis Sicca><Lacrimal Glands><Lacrimal gland structure><Low-Affinity Nerve Growth Factor Receptor><Mammalian Cell><Mediating><Mice><Mice Mammals><Modeling><Modern Man><Modification><Molecular Interaction><Murine><Mus><NGF Receptor><NGFR Protein><NTRK1 Receptor><Nerve><Nerve Cells><Nerve Growth Factor Receptor><Nerve Growth Factor Receptor Type 1><Nerve Growth Factor Receptor p75><Nerve Growth Factors><Nerve Plexus><Nerve Unit><Nervus Trigeminus><Neural Cell><Neurocyte><Neuronotrophic Factors><Neurons><Neuropathy><Neurotrophic Keratitis><Neurotrophic Proteins><Neurotrophic Tyrosine Kinase Receptor Type 1><Neurotropin Receptor p75><Pathogenesis><Pathologic><Pathology><Patients><Permeability><Phase><Physiological Homeostasis><Population><Process><Production><Proliferating><Proteins><Public Health><QOL><Quality of life><Rat><Rats Mammals><Rattus><Receptor Protein><Recombinants><Removal><Retinal Ganglion Cells><SBIR><Scopolamine><Sight><Signal Transduction><Signal Transduction Systems><Signaling><Site><Small Business Innovation Research><Small Business Innovation Research Grant><Steroid Compound><Steroids><Surface><Surgical Removal><Symptoms><System><Topical Drug Administration><Topical application><Translations><Trigeminal Nerve><Trigeminal nerve structure><United States><Vision><Work><administer topically><ages><apoptosis of neuronal cells><apply topically><astrocytic glia><attenuate><attenuates><biological signal transduction><clinical relevance><clinical test><clinically relevant><conjunctiva><corneal><corneal epithelial><corneal epithelium><corneal healing><corneal regeneration><cost><cost effective><deliver topically><design><designing><determine efficacy><digital><dry eye><efficacy analysis><efficacy assessment><efficacy determination><efficacy evaluation><efficacy examination><efficacy validation><epithelial repair><evaluate efficacy><examine efficacy><eye blink><eye disorder><eye dryness><eyeblink><fabrication cost><glaucomatous><gp75 NGFR><healing><immune modulation><immune regulation><immune suppressive agent><immune suppressor><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunosuppressive substance><immunosuppressor><improve symptom><improved><injuries><innovate><innovation><innovative><manufacture><manufacturing cost><model of animal><neuro-sensory><neuron apoptosis><neuronal><neuronal apoptosis><neuronal cells programmed cell death><neuronal survival><neurons programmed cell death><neuropathic><neurosensory><ocular disease><ocular disorder><ocular surface><ocular surface disease><ocular surface disorder><ophthalmopathy><p140-trkA><p75 neurotrophin receptor><p75NTR><pharmacologic><preservation><prevent><preventing><programmed cell death of neuronal cells by apoptosis><programmed cell death of neurons by apoptosis><receptor><repair><repaired><research clinical testing><resection><retinal ganglion><screen time><side effect><success><symptom improvement><symptomatic improvement><television watching><therapy optimization><topical administration><topical delivery><topical drug application><topical treatment><topically administered><topically applied><topically delivered><topically treated><translation><translational model><treat topically><treatment optimization><trk1 Transforming Tryrosine Kinase><trkA Receptor><tv watching><validate efficacy><visual dysfunction><visual function>