University of Alicante

1. In the use of preventive strategies that attempt to counteract the underlying mechanisms of the disease, such as gene therapy.

2. In attempting to prevent cell death by administering anti-inflammatory and antiapoptotic compounds (e.g. a cocktail of antioxidants), as well as neurotrophic factors that delay cell death of the retina, thus slowing the progression of the disease.

The present invention refers to the use of the compound 3-(2-isothiocyanatethyl)-5-methoxy-1H-indol as a therapeutic strategy to avoid, prevent or mitigate retinal degeneration in diseases such as: retinitis pigmentosa, glaucoma, age-related macular degeneration and diabetic retinopathy, thanks to its potent antioxidant and cytoprotective effect.

The chemical formula of this compound is the following (see Figure 1):

In the preventive or therapeutic treatment of the degenerative diseases of the retina described above, the compound 3-(2-isothiocyanatethyl)-5-methoxy-1H-indol can be used, as well as its pharmaceutically acceptable salts from: organic acids, inorganic acids, metallic salts, ammonium salts, salts formed from organic bases, and salts with amino acids.

Preparation: this compound is easily prepared through different methods described in the scientific literature. Soluble complexes can be prepared with different excipients.

Administration: the pharmaceutical composition can be administered in daily doses orally, rectally, subcutaneously, intramuscularly, intravascularly, injectablely or intravenously. It may be administered locally as a solution (e.g., eye drops, intraocular injection, or intravitreal injection), or as an implant.

Different animal models of retinal degeneration have been studied, among them:

1. Cytoprotection against sodium nitroprusside induced toxicity in the cell line derived from 661W photoreceptors:

The compound of the present invention significantly increased neuronal survival. In fact, the viability of the 661W cell line increased up 20% respect to the control (see Figure 2).

2. Visual responses rescue in the animal model of retinosis pigmentaria rd10:

The murine strain rd10 is the most suitable model for testing therapies related to retinitis pigmentosa. Different doses of the compound administered intraperitoneally have been studied, from the beginning to an advanced stage of the degenerative process, and it has already proved that the compound exerts a protective effect, and therefore, it is an effective agent to treat retinitis pigmentosa.

3. Measurement of the amplitude of the electroretinogram (ERG):

There is a certain dose of the compound (10 mg/Kg) that achieves a statistically significant improvement in the functional response of the retina respect to control (see Figure 3).

4. Measurement of visual acuity and contrast sensitivity in the murine model rd10:

Visual acuity: it gives a measure of the functional activity of the retina. To do this, an optomotor test is performed. This test showed that in rd10 mice treated with the compound object of the present invention (a dose of 10 mg/Kg), visual acuity increased 35.6% respect to control (see Figure 4).

Contrast sensitivity: in animals treated with the compound (a dose of 10 mg/Kg), contrast sensitivity increased between 11% and 15% with respect to the control, depending on the spatial frequency of the stimulus (see Figure 5).

The compound which is the subject of this invention has demonstrated the following advantages over the medicines currently used to treat degenerative diseases of the retina (including melatonin and sulforaphane):

1) It possesses a combination of biological activities whose great therapeutic effect.

2) It is a powerful inducer of the signaling pathway Nrf2, effect that does not possess melatonin.

3) Rescued visual responses regarding rd10 mice treated with the vehicle (control).

4) Increased visual acuity up to 35.6%.

5) Increased contrast sensitivity from 11% to 15%.

The compound of the present invention differs from the current drugs because:

• It has a reducing effect on retinal degeneration associated with different degeneration models.

• It is a powerful inducer of the signalling pathway Nrf2, unlike melatonin.

• It is an effective antioxidant, unlike sulforaphane

The protective and reducing effects of retinal degeneration provided by the compound of the present invention have been successfully studied under the following laboratory conditions:

1. In vitro: it has been studied in the cell line 661W (derived from photoreceptors) subjected to damage by the oxidizing agent sodium nitroprusside. Cell viability has been studied and this compound has been shown to increase neuronal survival up 20%.

2. In vivo: it has been studied in the mice model rd10 (autosomal recessive inheritance pigmentary retinosis model). The neuroprotective capacity of the compound has been measured after administering 2 different doses, at the rate of 2 doses/day intraperitoneally, from the postnatal day P16 to P30. This compound has been shown to improve the functional response of the retina, and increases both visual acuity (up to 35.6%) and contrast sensitivity (from 11% to 15%).

The present invention is framed in the pharmaceutical sector, specifically, in the preventive or therapeutic treatment of the degenerative diseases of the retina, that cause destruction of cellular structures, such as:

• Retinitis pigmentosa.

• Glaucoma.

• Diabetic retinopathy.

• Age-related macular degeneration.

We are looking for companies interested in acquiring this compound for commercial exploitation through:

• Patent licensing agreement.

• Development of new applications.

• Agreements regarding technology and knowledge transfer.

Company profile searched:

→ Pharmaceutical companies interested in prevention or treatment of degenerative diseases of the retina, among them:

• Retinitis pigmentosa.

• Glaucoma.

• Diabetic retinopathy.

• Age-related macular degeneration.

This invention is protected through patent application:

• Title: "Uso del 3-(2-isotiocianatoetil)-5-metoxi-1H-indol para el tratamiento de las enfermedades degenerativas de la retina".

• Application number: P201830704.

• Application date: 13th July, 2018.