From the article"Neuroprotectants in Honghua: Glucose attenuates retinal ischemic damage" ; Romano et al.; Investigative Ophthalmology & Visual Science, January 1993, Vol. 34, No. 1, it is known that glucose is able to alleviate the effects of retinal ischemia, i. e. of an inadequate supply of blood or oxygen to the retina.

Retinal ischemia is a pathological condition whose cause is different from that of the conditions to be treated by the present invention, which conditions are attributable to degeneration of the photoreceptors and occur even when there is no disruption of the supply of oxygen to the retina.

A method of treating pathological conditions which are due to degeneration of the photoreceptors or other sensory cells, e. g. in the organ of Corti or in the vestibular organ itself, or--of treating acquired damage to sensory cells is known from DE 19718826 Al. To treat for example macular degeneration and retinitis pigmentosa amongst others, a proposal is made there for substances which act on the extra-cellular space surrounding the photoreceptors to be applied subretinally or intravitreally. These substances include not only guanosine triphospate (GTP) but also adenosine triphosphate (ATP), which is a source of energy.

However, for practical daily use by patients, ATP seems to be too difficult to store and handle. The shelf life of ATP or medications containing ATP is only limited under everyday conditions. Finally, medications of this kind are relatively expensive. The conditions to be treated comprise: - macular degeneration or dystrophy, - retinitis pigmentosa, - Usher's syndrome, - rod/cone degeneration or dystrophy, - cone/rod degeneration or dystrophy, - Stargardt's disease, - pattern dystrophy - fundus flavimaculatus - Sorsby's fundus dystrophy - punctus albinopunctatus - Refsum's disease - choroideremia, - Bardet-Biedl syndrome - Leber's congenital amaurosis.

Also, acquired degenerative conditions of sensory cells or of epithelial cells, glia cells or supporting cells adjacent to sensory cells in humans. may include the following: - night-blindness following treatment with vincristine or vinblastine, - effects of treatment with thioridazine, chloroquine, quinine or other ototoxic substances, - effects of treatment after retinal detachment, - effects of a retinal infection, - effects of a lack of physiological sensory stimulus, - effects of age-related sensory cell degeneration, - effects of non-physiological sound or noise-related stress, - effects of non-physiological stress caused by acceleration of the head.

The object of the invention is therefore to specify a use of a substance for treating the said conditions in which the substance used is one which is easier to handle and use than ATP and has a better shelf life than it.

This object is achieved by a use having the features detailed in claim 1 and claim 8.

Because a saccharide (monosaccharide, disaccharide or polysaccharide), and in particular intraocularly applied glucose, is used, the photoreceptor cells have made available to them in their immediate environment an energy source which is able to alleviate or cancel out any lack of energy to which the photoreceptors are subject. It is this lack of energy which is directly or indirectly responsible for the degeneration of photoreceptor cells. The saccharide may be the sole active substance or it may be used in a combination of active substances.

D-glucose is preferably applied.

The preparation can be applied in liquid form or as a solid, the latter in the form of implanted pellets for example. A glucose concentration used with liquid preparations is preferably in the range of 50 to 500 millimolar solution of D-glucose, so as to result in a subretinal concentration of 1 to 20 millimolar, where the glucose is contained in a suitable vehicle solution.

Application is preferably subretinal or intravitreal.

The intraocular application of glucose restores the energy balance of the photoreceptors, which is disrupted in degenerative conditions of the photoreceptors and particularly in retinitis pigmentosa and macular degeneration. The degeneration of the photoreceptors can be slowed down or stopped in this way. If degeneration has already occurred, it can be alleviated by the application of glucose.

Provision may also be made for lactose, fructose, saccharose or glycogen to be used. The intraocular application may be made by means of a deposit of active substance positioned on or in the eye.

In what follows, the probable cell-biological reason for the additional energy need by the photoreceptors will first be outlined and then the way in which the glucose acts in the region of the photoreceptors will be explained.

The photoreceptor cells of mammals,. i. e. including those of humans, respond when light is absorbed by the molecules of pigment in the outer segments, which triggers a series of biochemical reactions. These biochemical reactions are called phototransduction. If there is no further exposure to light these reactions stop after a certain time and the outer segments revert to their original state, the dark-adapted state, and are thus able to absorb light again.

Photoreceptors are able to operate over a very wide range of ambient light intensities because they are able to adapt to a given level of light intensity. The adaption of sensitivity to light is probably effected by way of a change in the calcium concentration in the cytoplasm of the outer segments. Also, the magnitude of the response to incident light is adjusted, via for example a controlled and adapted change in a gain which represents the signal per absorbed photon. At low light intensity levels the gain is high and when the light intensity is high the gain is low.

The retina of vertebrates is able to respond to very low light intensities such for example as exist at night when the moon is shining. What are used in this case are the very sensitive rod-shaped photoreceptors. When the ambient light intensity is high (in sunshine), cone- shaped photoreceptors are used. In a small range of medium light intensity, corresponding say to twilight, both rods and cones are used. Hence, in the natural world prior to the introduction of artificial lighting, vision at night was by way of the more sensitive rods whereas vision by day is provided by the cones while the rods are in the light-adapted state and are saturated as far as their sensitivity to light is concerned.

Many of the proteins whose genetic defects cause degeneration of the photoreceptors in humans are proteins which are present in the outer segments of the photoreceptors and which play a part in phototransduction. It can therefore be assumed that these proteins play some role in the gain in phototransduction or are affected by this gain.

Rods are far more susceptible to degeneration phenomena than cones. In many pathological conditions of the human retina, degeneration of the rods precedes any degeneration of the cones.

All or virtually all of the above biochemical reactions (phototransduction, adapting to light intensity levels) require energy. However, different reactions require different amounts of energy.

In the course of evolution, mechanisms have been developed to avoid the needless consumption of energy.

Hence, to avoid any needless consumption of energy during the 12 or so hours of daylight every day, a special mechanism is employed in the outer segments of the rods in many if not all the retinas of mammals to uncouple the first stages of phototransduction (the absorption of light by rhodopsin) from the later stages of phototransduction. It is presumed that this mechanism holds the gain of the outer segments of the rods at zero.

The final effect is that the rods"know"they will not be needed for about 12 hours and as a result they do not need to continuously consume energy-to no purpose during this time to stop the light-induced reactions. This unnecessary energy would be used by the rods in attempting to achieve a dark-adaption if the daylight failed, but except for eclipses of the sun this will not happen.

The outer segments of the photoreceptors have a cytoskeleton which is based on supporting microtubules (small, elongated, solid intracellular structures) to which certain protein molecules are attached within the membranes by filamentous connections. Due to the biochemical identity of many of these proteins which are situated in the cytoskeletal systems, at least some of them form the intracellular sites at which the control and regulation of the gain of the outer segments of the rod and cone photoreceptors take place and where the decoupling mechanism consequently operates for the outer segments of the rods.

The outer segments of all the rods and cones have a cytoskeletal system of this kind (the axoneme of the cilium) containing microtubules which is very similar in the two types of cell and plays a part in the control and regulation of the gain of the outer segments. However, in many retinas, such as in humans and amphibians for example, the outer segments of the rods have, at their multiple incisures, an additional cytoskeletal system which is separate from the cytoskeletal system of the cilium and which differs therefrom. This rod-specific cytoskeletal system at the multiple incisures of the outer segments of the rods in the human retina is probably the site of the mechanism specific to the rods for decoupling the phototransduction of the rods during daylight in order to avoid any under-supply of energy.

Many degenerative conditions of human photoreceptors are due to a defect in these cytoskeletal systems.

The degeneration of the rod-shaped photoreceptors which goes hand in hand with a failure of the cytoskeletal systems specific to the rods is due to an inability on the part of the rods to change to the state where they are insensitive to light (gain close to zero) or to remain in this state. Since the energy-saving state is not achieved, an excessive amount of energy is needed which is not available in an otherwise undisrupted system. The shortage of energy which this causes is, in the end, the direct cause of the damage which is done to the rod photoreceptors. In a similar way the cytoskeleton of the cilium plays a part in the regulation of gain in the rods and cones and as a result a genetic defect in this system may produce a faulty mechanism and likewise a greater need for energy.

Hence, the supply of energy to the retina of mammals and particularly of humans, or to be more exact to the photoreceptors of the human retina, prevents or alleviates the degeneration of the photoreceptors. In the final analysis, blindness caused by degenerative phenomena of this kind can be prevented or at least substantially delayed in this way.

Figures 1 and 2 are used to explain the invention in greater details.

Figure 1 shows that Microtubules serve as the framework for complex cytoskeletal systems in vertebrate photoreceptor outer segments.

The outer segments of cones (left) have longitudinal microtubules in the ciliary axoneme, which extend to the distal end of the outer segments.

The outer segments of rods (right) likewise have longitudinal microtubules in the ciliary axoneme, but these do not extend to the distal end of the outer segments. In addition, the outer segments of rods in amphibian, primate, and human retinas have longitudinal microtubules at each of their multiple incisures. These microtubules extend to the distal end of the outer segments.

Certain specific proteins within outer segments are located in close association with these microtubules, forming complex multicomponent cytoskeletal systems.

Figure 2 shows the Position of microtubules and associated cytoskeletal systems within photoreceptor outer segments, in cross section Phototransduction proceeds in a sequence of steps, as biochemical reactions between specific proteins that occur at specific locations within outer segments (left to right in Fig. 2).

1) The early steps of phototransduction (eg., photoactivation of rhodopsin) occur on the outer segment disk/lamellar membranes (at the left); 2) subsequent steps (eg., change in the level of cyclic GMP) occur in the cytoplasm surrounding the microtubules (arrows in the middle); and 3) the final steps (eg., opening or closing of the cyclic nucleotide gated channels) occur on the plasma membrane (at the right).

The photoreceptor outer segment cytoskeleton is important for normal photoreceptor function in the human retina, and that a disturbance involving this cytoskeleton can lead to human retinal degenerations.

Proteins implicated in human retinal degenerations (myosin VIIa, RPGR, RPGRIP, and RGS9) are components of the cytoskeletal systems in outersegments.

Proteins that in outer segments are colocalized with the microtubules and thus belong to these cytoskeletal systems, include: myosin VIIa, RPGR, RPGRIP, and RGS9.

Each of these four proteins is known to be essential for the normal function of human photoreceptors, because defects in the genes that encode them can lead to human retinal degenerations and blindness. These 4 proteins participate in phototransduction and/or adaptation via biochemical reactions with proteins at intermediate stages in phototransduction/adaptation.

Thus, the cytoskeletal systems associated with photoreceptor outer segment microtubules: a) comprise proteins whose gene defects are implicated in human retinal degenerations,. b) comprise proteins that participate in biochemical reactions at intermediate stages in the reactions of phototransduction/adaptation, and c) are situated within outer segments at an intermediate location, ideal for the control and regulation of the gain/amplification factors of phototransduction.

Therefore, these outer segment cytoskeletal systems are the subcellular site at which photoreceptors control and regulate the gain/amplification factors of phototransduction at different light levels. In other words, interactions between protein components of these OS cytoskeletal systems provide a mechanism for adjusting the gain and amplification of phototransduction and decoupling in rods during daylight in normal photoreceptors, so as to avoid the unneccessary expenditure of energy and prevent energy depletion.

As one finding, the reason that defects in the photoreceptor outer segment cytoskeleton lead to human retinal degenerations is that, as a result of such defects, the photoreceptors become depleted of energy.

A second finding is that many pathological degenerations of the photoreceptors in vertebrate retinas, especially those mentioned above, can be treated (ameliorated, slowed and/or prevented) by locally providing a supplementary source of energy, eg., via the intraocular delivery of D-glucose.

The use according to the invention of glucose for intraocular application provides a considerable degree of ease of handling in practice as compared with the known methods. Glucose is a known, biochemically stable and inexpensive medication which is not complicated to handle and which is also not at all sensitive with regard to storage and transportation. These advantages form an important criterion for the success of a treatment which is needed continuously and which is intended to be administered without any costly or complicated apparatus and without expensively trained medical personnel.

Compared with other known substances, glucose is also easy and reliable to use in implantable application and dose-delivery systems. The same advantages are obtained when a glucose-based preparation is used to treat hereditary or acquired sensory cell degeneration in the inner ear, in the organ of Corti or in the vestibular organ.

Finally, a major advantage of glucose lies in the fact that it is a substance of excellent physiological compatibility which is also present in the natural extra- cellular environment of photoreceptors and other sensory cells.