Mimetogen develops small molecule drugs that mimic the effects of neurotrophins, proteins that are critical for the survival and differentiation of neurons and also help maintain the health and growth of many cells and tissues found in the eye. Nerve growth factor (NGF) is one member of the neurotrophin family. NGF activates the tropomyosin-related kinase (TrkA) receptor and the p75NTR receptor, a member of the tumor necrosis factor superfamily.1
Targeting these well-validated cell surface Trk receptors is a novel approach in the development of drugs to treat ophthalmic indications of both the anterior (dry eye) and posterior segments (glaucoma, retinitis pigmentosa, age-related macular degeneration) of the eye. Our lead compound, MIM-D3, is a proteolytically stable, cyclic peptidomimetic partial TrkA receptor agonist, which demonstrates similar activities to NGF.2
- Patapoutian, A. and Reichardt, L. (2001) Curr Opin Neurobiol 11, 272-280.
- Maliartchouk, S., et. al. (2000) Mol Pharmacology 57, 385-391.
There is an important unmet medical need in dry eye. A therapy is needed that not only modulates one of the signs or symptoms, but an approach that addresses the underlying multifactorial causes of the disease.Neurotrophins offer the potential of such a multifactorial approach. NGF and the TrkA receptor are expressed in the cornea, conjunctiva and on the sensory nerves that function together as an integral part of the lacrimal functional unit (LFU).
The LFU regulates both tear quantity and quality in order to maintain a healthy tear film1. The tear film is composed of an oily, lipid layer (produced from the meibomian glands), water or aqueous layer (produced from the lacrimal gland), and a mucus layer (produced from the conjunctival cells). Together, these layers lubricate and protect the ocular surface from the environment (allergens, pathogens and debris), and provide a smooth optical surface that is critical for unimpaired vision. Production of a normal tear film by the LFU depends on a neuronal feedback reflex loop involving sensory neural stimulation from the ocular surface of the eye to the brain and from the brain via motor nerves to the lacrimal glands and conjunctival cells, which in response produce an appropriate tear film.
In dry eye, irritation causes impairment of various functions of the LFU causing altered and decreased tear production2. Dry eye disease has been defined by the Dry Eye Workshop (DEWS) as “A multifactorial disease of the tears and ocular surface that results in symptoms of discomfort, visual disturbance and tear film instability with potential damage to the ocular surface. It is accompanied by increased osmolarity of the tear film and inflammation of the ocular surface.”1 This chronic condition can create a vicious cycle with a decrease in the neuronal feedback loop leading to a further reduction in tear production and the inability of the ocular surface to respond to environmental challenges.
The innovation: TrkA agonists have the potential to alter dry eye at several key points.
In order to break this vicious cycle, a product with a multifactorial mechanism of action is needed to better address this disease. TrkA receptor agonists have been shown to have the potential to alter the dry eye cycle at several key points:
- NGF stimulates conjunctival mucin secretion thereby may stabilize the tear film3,4
- NGF improves corneal healing and may reduce ocular surface damage5,6
- NGF supports the survival and differentiation of neurons and may improve the sensory response and the LFU7,8
- Topically applied NGF has been shown to have therapeutic effects in patients with neurotrophic keratitis and corneal ulcers9,10
NGF itself, however, has a poor safety profile and as a drug and poses significant pharmaceutical challenges for topical ophthalmic formulation. Mimetogen has developed a small molecule selective TrkA receptor agonist, MIM-D3, which retains the more attractive therapeutic features of NGF while offering significant pharmaceutical advantages.
MIM-D3 is a novel small molecule neurotrophin mimetic the use of which has been shown in pre-clinical models to improve ocular surface properties.11
In preclinical research studies, MIM-D3 has been shown to stimulate the production of protein glycoconjugates (mucins) in conjunctival cells from animal tear fluids.11 In addition, in an animal model of dry eye, topical instillation of MIM-D3 increased the concentration of mucin in tear fluids and significantly decreased ocular surface damage.11 MIM-D3 may have additional benefits than currently available dry eye therapies including the potential to improve neural function, which may improve corneal sensitivity and integrity. These multiple activities suggest a strong rationale for the use of MIM-D3 as a novel therapeutic for dry eye because of its multifactorial mechanism of action.
- Subcommittee of the International Dry Eye Workshop (2007) Ocul Surf 5, 75-92.
- Stern, M. E., et al. (2004) Exp Eye Res 78, 409-416.
- Rios, J., et. al. (2007) Invest Ophthalmol Vis Sci 48, 1543-1551.
- Lambiase, A., et. al. (2009) Invest Ophthalmol Vis Sci 50, 4622-4630.
- Lambiase, A., et. al. (2000) Invest Ophthalmol Vis Sci 41, 1063-1069.
- Coassin, M., et. al. (2005) Graefes Arch Clin Exp Ophthalmol 243, 151-155.
- Joo, M.J., et. al. (2004) Arch Ophthalmol 122, 1338-1341.
- Esquenazi, S., et. al. (2005) Invest Ophthalmol Vis Sci 46, 3121-3127.
- Bonini, S., et. al. (2000) Ophthalmology 107, 1347-1351.
- Lambiase, A., et. al. (1998) N Engl J Med 338, 1174-1180.
- Jain, P., et. al. (2011) Exp Eye Res, 93, 503-512.
The processes of neurodegeneration are implicated in several diseases of the retina. These include glaucoma, age related macular degeneration and some inherited retinal disorders.
Glaucoma is the second leading cause of blindness in the world (after cataracts). The majority of individuals will have open angle glaucoma. This is a disorder characterized by optic nerve damage and progressive visual field loss associated to high intraocular pressure (IOP). High IOP is a risk factor for glaucoma, which pharmacological therapy can normalize. Yet, in spite of successful IOP reduction, the disease remains chronic and many patients go on losing fibers (optic nerve axons) and cell bodies (retinal ganglion cells) and continue to lose vision. Thus, glaucoma can be viewed as a neurodegenerative disease, which is amenable to protection.
Age-related macular degeneration (AMD) and retinitis pigmentosa (RP) are two blinding eye diseases that share the phenotype of having photoreceptor neurons degenerate. This is often accompanied by the degeneration of the retinal pigmented epithelial layer (RPE), whose function is to detoxify the highly oxidative environment and to support the health of the photoreceptors by secreting growth factors. At present, neuroprotection appears to be among the most promising approach for both RP and dry AMD.
Disturbances to the neurotrophin-Trk receptor axis and thus loss of neurotrophic support to the neurons, is among the many factors that contribute to neuronal cell death in the retina. Mimetogen’s research has focused on achieving neuroprotection through neurotrophic activation, by developing selective and potent TrkA and/or TrkC agonists that prevent neuronal death.1 These compounds have been tested in vivo in preclinical animal models of glaucoma2,3 and in vitro models of oxidative stress induced apoptosis of RPE cells.4 The bioactivity of our peptidomimetic agonists suggests a strong rationale for the use of Trk receptor agonists as novel therapeutics for retinal degenerative diseases.
- Zaccaro, M.C., et. al. (2005) Chem Biol, 12, 1015-1028.
- Shi, Z., et. al. (2007) Dev Neurobiol 67, 884-94.
- Lebrun-Julien, F., et. al. (2009) Mol Cell Neurosci 40, 410-420.
- Mukherjee, P.K., et. al. (2009) Invest Ophthalmol Vis Sci 50, E-abstract 2163 .