Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
1995-03-27
2004-06-15
Kunz, Gary (Department: 1647)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S012200, C514S912000, C514S913000, C514S914000
Reexamination Certificate
active
06750196
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to methods of affecting retinal cell function.
BACKGROUND OF THE INVENTION
The invention relates to prophylactic or affirmative treatment of diseases and disorders of retina and associated tissues of the eye by administering polypeptides found in vertebrate species, which polypeptides are growth, differentiation and survival factors for several cell types. Normal function of retinal cells including survival, proliferation, differentiation, and maintenance is dependent upon the controlled expression of a variety of peptide growth factors. Some of these factors can be produced by neuronal cells and by other cells of the retina, which provide a signal to regulate retinal cell function.
Anatomy and Function of the Retina
The retina is that component of the visual system which senses light and transmits impulses via the optic nerve to the visual cortex where the signals are deciphered and interpreted as images. The retina is comprised of a series of layers and cell types as illustrated in FIG.
1
.
The basic function of the retina is to transduce the visual image into a pattern of electrical potential changes that can be processed by the visual centers in the brain. The changes in electrical potentials in the retinal cells are then relayed to the brain. The structure of the retina reflects these functions (FIG.
1
). The cells of the retina are arrayed in three layers: (1) the outer nuclear layer, which contains the photoreceptor cells; (2) the inner nuclear layer, which contains the cell nuclei of most of the retinal interneurons and glia; and (3) the ganglion cell layer, which contains the cell bodies, of the cells that relay the visual information to the brain via the optic nerve. In addition to these nuclear layers, there are three other distinct layers in the retina. The outermost layer is composed of the outer segments of the photoreceptor cells; this is where the actual process of light-to-electrical signal transduction take place. The outer plexiform layer lies between the outer and inner nuclear layers. It is made up of synapses between the terminals of the photoreceptors and the dendrites of the retinal interneurons of the inner nuclear layer. The inner plexiform layer lies between the inner nuclear layer and the ganglion cell layer. This layer is where the interneurons of the inner nuclear layer synapse with the retinal ganglion cell dendrites.
The retina is composed of five classes of neurons, and two classes of supporting cells (
Principles of Neural Science
, 3rd ed., Ed. by E. R. Kandel, J. H. Schwartz, and T. M. Jessell, Elsevier, New York, N.Y. 1991). Of the neuronal types, the receptor cells are the cells that transduce light into electrical signals. Receptor cells are of two subtypes: cones—which mediate form and color perception in daylight, and rods—which mediate form perception in dim light. Ganglion cells of the retina project axons into the brain via the optic nerve and are the output cells of the retina. The remaining neuronal types are interneurons that modulate retinal output: bipolar cells connect receptor cells to ganglion cells; horizontal cells mediate lateral interactions between receptors and bipolar cells; and amacrine cells mediate lateral interactions between bipolar cells and ganglion cells. The supporting cell types are the glial cells of the retina, Müller cells, and the pigment epithelium cells. The latter cell type plays an important role in the maintenance of receptor cells.
The basic flow of information through the retina is as follows (Refer to FIG.
1
): (1) light passes through the cells of the retina and is absorbed by the outer segments of the photoreceptor cells; (2) the photons are transduced into potential changes in the photoreceptor cells; (3) this change in potential is relayed to one type of retinal interneuron in the inner nuclear layer, the bipolar cell, via synapses in the outer plexiform layer; (4) the bipolar cells relay the electrical potential changes to the ganglion cells through their synapses in the inner plexiform layer; and (5) the ganglion cells convert the potential changes into action potentials that are sent along the optic nerve to the brain. This process results in a pattern of action potentials in the optic nerves that reflects the pattern of light and dark in the visual world. Some initial processing of the visual information takes place in the retina before it is relayed to the other visual areas in the brain.
Proper development and maintenance of the retina is necessary for sustaining normal vision. Degeneration of components of the retina can lead to partial or total blindness.
Peptide Growth Factors
The development and physiology of multicellular organisms requires multiple modes of intercellular communication. Such communication may be systemic, as in the case of hormones delivered via the bloodstream, or can be highly localized. In the latter case two modes are commonly recognized: synaptic signaling from neurons, and paracrine signaling from adjacent or nearby cells (
Molecular Biology of the Cell
, Alberts et al., 2nd ed. Garland Publishing, New York, N.Y. 1989). A function of such signaling is to coordinate cell survival, proliferation, differentiation, and/or metabolic activity. The molecules that serve as transmitted signals vary in their chemical composition; one group of molecules are proteins, the peptide growth factors. Peptide growth factors act upon cells by binding to cell surface receptors. These receptors are coupled to intracellular signal transduction pathways that give rise to the above described activities when activated by growth factor binding. The genesis and differentiation of the varied retinal cell types and the generation of distinct layers in the retina from progenitor cells of the optic cup are the result of developmental events that are mediated by intercellular communication involving peptide growth factors.
Peptide Growth Factors in the Retina
The roles of growth factors in the development and maintenance of the retina have been studied in cell culture, by molecular analysis of the expressed growth factors and their receptors, and in animal models of disease or injury.
As an example of in vitro studies, explants and partially-dissociated chick retinal pigmented epithelium (RPE) can trans-differentiate into neural retina in the presence of bFGF (Coulombre and Coulombre,
Dev. Biol
. 12:79, 1965). Proliferation of dissociated RPE cells is stimulated by aFGF, bFGF, EGF, PDGF, IGF, and insulin; and it is inhibited by TGFb (Sternfeld et al.,
Curr. Eye Res
. 8: 1029, 1989; Leschey et al.,
Invest. Ophthalmol. Vis. Sci
. 31: 839, 1990; Song and Lui,
J. Cell Physiol
. 143:196, 1990). Cultured RPE cells are induced by cytokines to release nitric oxide, which is cytotoxic—and the induction can be blocked by FGF (Goureau et al.,
Biochem. Biophys Res. Comm
. 186:854, 1992; op. cit., 198: 120, 1994). Further, retinal explants from the rd mouse are rescued from cell death by combined treatment with NGF and bFGF (Caffe et al.,
Curr. Eye Res
. 12:719, 1993).
The presence of growth factor receptors in retinal cells has been demonstrated by a variety of molecular analytical techniques, including immunostaining, in situ hybridization and tissue binding using radio-labeled ligands. Cells in the RPE express FGF receptors (Malecaze et al.,
J. Cell Physiol
. 154: .1105, 1993). Ganglion cells and Müller cells express receptors for BDNF, CNTF, FGF, trkA and trkB (Jelsma et al.,
J. Neurobiol
. 24:1207, 1993; Takahashi et al.,
Neurosci. Lett
. 151:174, 1993; Carmignoto et al.,
Exp. Neurol
. 111:302 191; reviewed in Steinberg,
Curr. Opin. Neurobiol
. 4:515, 1994). Müller cells also express PDGF receptors (Mudhar et al.,
Development
118: 539, 1993). Receptors for IGF are detected on photoreceptor cells (Waldbillig et al.,
Exp. Eye Res
. 47:587 1988; Ocrant et al.,
Exp. Eye Res
. 52:581, 1991), and depending on the species and developmental stage that are analyzed receptors for bFDF have been localized on several cell types, including retinal
Bermingham-McDonogh Olivia
Gwynne David I.
Mahanthappa Nagesh K.
Marchionni Mark A.
McCabe Kathryn L.
Acorda Therapeutics
Gucker Stephen
Kunz Gary
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