KR20240086741A - Composition for preventing or treating inherited retinal diseases comprising adenovirus recombinant vector including a PDE6B gene - Google Patents

Abstract

The present invention relates to a composition for preventing or treating hereditary retinal diseases containing an adenovirus recombinant vector containing the PDE6B gene as an active ingredient. The present inventors discovered the PDE6B gene as a candidate gene for the treatment of hereditary retinal diseases, and through this A highly efficient AAV-based gene therapy platform was developed and the process was optimized. In addition, the biocompatibility and cell rescue effect of the highly efficient AAV-based gene therapy were confirmed for in vitro conditions, and the preclinical in vivo stability and treatment efficiency in in vivo disease models of the highly efficient AAV-based gene therapy were confirmed. Accordingly, the present invention can be expanded to various indications for hereditary eye diseases, and can also be applied to other rare and incurable genetic diseases, so it is expected to be fully utilized, and it is possible to secure the original technology for gene therapy, especially in Korea. It is expected that

Description

Composition for preventing or treating inherited retinal diseases comprising adenovirus recombinant vector including a PDE6B gene}

The present invention relates to a composition for preventing or treating hereditary retinal diseases comprising an adenovirus recombinant vector containing the PDE6B gene as an active ingredient.

Hereditary retinal diseases are rare diseases caused by mutations in various genes related to the development, structure, and function of the retina. In most cases, they cause progressive retinal degeneration, leading to blindness in severe cases. To date, there is no cure for most hereditary retinal diseases. The retina is composed of 10 highly differentiated layers, and various membrane proteins and optic pigments that accept light stimulation are involved, and as the genes related to them are diverse, various genes (about 270 so far) cause diseases. Among inherited retinal diseases, retinitis pigmentosa is the most common. The prevalence is approximately 1 in 3,000-4,000, which is quite high among hereditary diseases, and the number of patients in Korea is estimated to be more than 10,000.

Voretigene neparvovec (Luxturna®) was the first gene therapy to receive FDA approval in late 2018. This drug is made by inserting the RPE65 gene, one of the genes that cause Leber congenital amaurosis, into a recombinant adeno-associated virus (rAAV), and the gene mutation of RPE65 causes both alleles ( When the drug was injected under the retina in patients with defects in all allele) functions, visual indicators increased and treatment results for the disease were reported. However, there is still no treatment for the remaining genes except RPE65.

As a result of analyzing the causative genes of Korean patients to date, mutations in the RPE65 gene, which is the target of the developed gene therapy Luxturna®, were rarely found, and there was a difference between the causative genes of known hereditary retinal diseases in the West and the causative genes reported in the East. There is. There is a need to develop gene treatments for major causes in Korea, but such gene treatments have not yet been developed. Meanwhile, in Asia, including Korea and Japan, the proportion of the EYS gene is relatively high, and in Korea and many other countries, the proportion of the PDE6B gene is high; however, few gene treatments for PDE6B have been developed or clinical trials are being conducted.

Korean Patent Publication No. 10-2020-0036912 (published on 2020.04.07)

The present invention relates to a CMV promoter gene or a CAG promoter gene; The object is to provide an adenovirus recombinant vector containing the PDE6B gene and a marker gene in that order, and an adenovirus strain transfected with the adenovirus recombinant vector.

In addition, the present invention seeks to provide a pharmaceutical composition for preventing or treating hereditary retinal diseases containing the adenovirus recombinant vector as an active ingredient.

In order to solve the above problem, the present invention provides a CMV promoter gene or a CAG promoter gene; An adenovirus recombinant vector containing the PDE6B gene and marker gene in order is provided.

Additionally, the present invention provides an adenovirus strain transfected with the adenovirus recombinant vector.

Additionally, the present invention provides a pharmaceutical composition for preventing or treating hereditary retinal diseases comprising the adenovirus recombinant vector as an active ingredient.

The present invention relates to a composition for preventing or treating hereditary retinal diseases containing an adenovirus recombinant vector containing the PDE6B gene as an active ingredient. The present inventors discovered the PDE6B gene as a candidate gene for the treatment of hereditary retinal diseases, and through this A highly efficient AAV-based gene therapy platform was developed and the process was optimized. In addition, the biocompatibility and cell rescue effect of the highly efficient AAV-based gene therapy were confirmed for in vitro conditions, and the preclinical in vivo stability and treatment efficiency in in vivo disease models of the highly efficient AAV-based gene therapy were confirmed. Accordingly, the present invention can be expanded to various indications for hereditary eye diseases, and can also be applied to other rare and incurable genetic diseases, so it is expected to be fully utilized, and it is possible to secure the original technology for gene therapy, especially in Korea. It is expected that

Figure 1 shows the results of previous experiments measuring the titer of AAV using real-time PCR and the results of confirming AAV-GFP (GAG, GAG[cutten], CMV promoter) virus fluorescence.
Figure 2 is a schematic diagram of the AAV packaging process and the results of experiments on transduction efficiency and viability in retinal pigment epithelial (RPE) at different rAAV-CMV-GFP concentrations.
Figure 3 shows NM_00283.4 and NP_000274.3, the longest among several transcripts of PDE6B scheduled to be inserted into rAAV.
Figure 4 shows the titer measurement results of AAV using real-time PCR.
Figure 5 shows the results of viability and transduction analysis according to the AAV-PDE6B promoter (CMV, CAG, CAG-Cutten).
Figure 6 shows the results of live cell image analysis 24 hours after AAV-CMV-PDE6B treatment.
Figure 7 shows the results of live cell image analysis 24 hours after AAV-CAG-Cutten treatment.
Figure 8 shows the results of live cell image analysis 24 hours after AAV-CAG-PDE6B treatment.
Figure 9 shows the results of analysis of transduction efficiency and RPE cell viability for each rAVV promoter.
Figure 10 shows the electroretinography (ERG) test results of PDE6B knock-out rats. In the ERG test, unlike the wild type in the first line, loss of ERG waveform was observed in the PDE6B knock-out homozygote rat in the third line.
Figure 11 shows the results of immunohistochemistry staining using an anti-GFP antibody after administration of AAV-GFP (pilot study, Red: GFP, blue: DAPI, Green: lectin).
Figure 12 shows the results of analysis of changes in PDE6B expression in the retina upon intravitreal administration of AAV-PDE6B (pilot study, Red: PED6b, Blue: DAPI).
Figure 13 is a schematic diagram of an experiment in PDE6B knock-out rats on the short-term effect of rAAV-PDE6B.
Figure 14 shows fundus photographs and optical coherence tomography (OCT) images according to PDE6B protein expression in the retina of PDE6B KO rats (A) and normal rats (B).
Figure 15 shows the results of retinal confirmation through immunohistochemistry (IHC) staining for PDE6B by extracting a rat eye injected with AAV-PDE6B.
Figure 16 shows the results of retinal confirmation through immunofluorescence (IF) staining for PDE6B by extracting a rat eye injected with AAV-PDE6B.
Figure 17 is a schematic diagram of the AAV-CMV-PDE6B-GFP recombinant vector.
Figure 18 is a schematic diagram of the AAV-CAG-PDE6B-GFP recombinant vector.
Figure 19 is a schematic diagram of the AAV-CAG-PDE6B-GFP (Cutten) recombinant vector.

The present invention relates to a CMV promoter gene or a CAG promoter gene; An adenovirus recombinant vector containing the PDE6B gene and marker gene in order is provided.

Preferably, the CMV promoter gene may consist of the base sequence represented by SEQ ID NO: 1, but is not limited thereto.

Preferably, the CAG promoter gene may consist of the base sequence represented by SEQ ID NO: 2, but is not limited thereto.

Preferably, the marker gene is luciferase, enhanced green fluorescent protein (EGFP), green fluorescent protein (GFP), yellow fluorescent protein (YFP), It may be red fluorescent protein (RFP) or cyan fluorescent protein (CFP), but is not limited thereto.

More preferably, the adenovirus recombinant vector is AAV-CMV-PDE6B-GFP consisting of the base sequence shown in SEQ ID NO: 3 (FIG. 17), AAV-CAG-PDE6B-GFP consisting of the base sequence shown in SEQ ID NO: 4 (FIG. 18) or AAV-CAG-PDE6B-GFP (Cutten) (FIG. 19) consisting of the base sequence shown in SEQ ID NO: 5, but is not limited thereto.

In the present invention, AAV-CAG-PDE6B-GFP (Cutten) refers to a recombinant vector in which a portion of the region between the end of the CAG promoter and the PDE6B gene has been removed from the AAV-CAG-PDE6B-GFP recombinant vector.

In the present invention, "PDE6B" is Rod cGMP-specific 3',5'-cyclic phosphodiesterase subunit beta, NCBI accession no. . It may be NM_00283.4/NP_000274.3, but is not limited thereto.

In the present invention, the term "recombinant vector" refers to a vector capable of expressing a target protein or target RNA in a suitable host cell, and refers to a genetic construct containing essential regulatory elements operably linked to express the gene insert.

The vector used in the present invention is a vector containing linear DNA expressed in human or animal cells, a plasmid vector, or a viral expression vector, or a recombinant retrovirus vector, a recombinant adenovirus vector, or a recombinant adeno-related virus. It may be a recombinant expression vector including an adeno-associated virus (AAV) vector, a recombinant herpes simplex virus vector, or a recombinant lentivirus vector. More preferably, the recombinant vector is an adeno-related vector. It may be a virus (adeno-associated virus; AAV), but is not limited thereto.

Additionally, the present invention provides an adenovirus strain transfected with the adenovirus recombinant vector.

Preferably, the adenovirus may be an adeno-associated virus (AAV), but is not limited thereto.

Additionally, the present invention provides a pharmaceutical composition for preventing or treating hereditary retinal diseases comprising the adenovirus recombinant vector as an active ingredient.

Preferably, the hereditary retinal disease may be retinitis pigmentosa, Leber's congenital amaurosis, or cryptorchidism, but is not limited thereto.

The pharmaceutical composition of the present invention can be prepared using pharmaceutically suitable and physiologically acceptable auxiliaries in addition to the active ingredients, and the auxiliaries include excipients, disintegrants, sweeteners, binders, coating agents, swelling agents, lubricants, and glidants. Alternatively, solubilizers such as flavoring agents may be used. For administration, the pharmaceutical composition of the present invention can be preferably formulated as a pharmaceutical composition containing one or more pharmaceutically acceptable carriers in addition to the active ingredient. Acceptable pharmaceutical carriers for compositions formulated as liquid solutions include those that are sterile and biocompatible, such as saline solution, sterile water, Ringer's solution, buffered saline solution, albumin injection solution, dextrose solution, maltodextrin solution, glycerol, ethanol, and One or more of these ingredients can be mixed and used, and other common additives such as antioxidants, buffers, and bacteriostatic agents can be added as needed. In addition, diluents, dispersants, surfactants, binders, and lubricants can be additionally added to formulate injectable formulations such as aqueous solutions, suspensions, emulsions, etc., pills, capsules, granules, or tablets.

The pharmaceutical preparation form of the pharmaceutical composition of the present invention may be granules, powders, coated tablets, tablets, capsules, suppositories, syrups, juices, suspensions, emulsions, drops or injectable solutions, and sustained-release preparations of the active compound. You can. The pharmaceutical composition of the present invention can be administered in any conventional manner via intravenous, intraarterial, intraperitoneal, intramuscular, intraarterial, intraperitoneal, intrasternal, transdermal, intranasal, inhalation, topical, rectal, oral, intraocular or intradermal routes. It can be administered. The effective amount of the active ingredient of the pharmaceutical composition of the present invention refers to the amount required for the prevention or treatment of disease. Therefore, the type of disease, the severity of the disease, the type and content of the active ingredient and other ingredients contained in the composition, the type of dosage form and the patient's age, weight, general health condition, gender and diet, administration time, administration route and composition. It can be adjusted depending on a variety of factors, including secretion rate, duration of treatment, and concurrent medications.

Below, the present invention will be described in detail according to examples that do not limit the present invention. Of course, the following examples of the present invention are only intended to embody the present invention and do not limit or limit the scope of the present invention. Accordingly, what can be easily inferred by an expert in the technical field to which the present invention belongs from the detailed description and examples of the present invention is interpreted to fall within the scope of the rights of the present invention.

< Example 1> Discovery of candidate genes for the treatment of hereditary retinal diseases and their Through suffering Efficient AAV-based gene therapy platform development and process optimization

1. Hereditary retinal disease centered on genetic mutations Clinical data about the patient Establishing a base and discovering and analyzing candidate genes through this

The present inventors are representative researchers of the Korean Eye Gene Consortium (KEGC), and are currently building and expanding the Korean Hereditary Retinal Disease Database in collaboration with researchers at several hospitals. Currently, 24 Korean researchers and 15 medical institutions are participating and are continuing to recruit. As of May 2021, a total of 681 Korean patients with hereditary eye diseases have been registered, and most of them, more than 95%, are patients with hereditary retinal diseases, the most common disease. These were retinitis pigmentosa, Leber congenital amaurosis, and cryptorchidism. In rare diseases, it is common for clinical trials to not proceed due to difficulties recruiting target patients, so securing a database of actual patients in which the causative genes for inherited retinal diseases have been identified is an important key in developing gene therapy. Accordingly, it is expected that the system built by the present inventors will be able to easily secure patients for actual clinical trials, and to discover efficient therapeutic genes by further expanding the Korean hereditary retinal disease database to develop a highly efficient AAV-based gene therapy platform. can do.

2. High efficiency AAV Insertion of therapeutic gene into gene carrier and Cloning Gene therapy development and process optimization through

To produce highly efficient AAV gene therapy, the following production protocol was developed and process optimization was established.

(1) Production of 3 types of AAV-GFP Control virus (two types of promoter CMV, CAG and CAG-Cutten)

1) Production of 3 types of pAAV-GFP recombinant viruses

2) Virus packaging

pAAV-GFP, AAV packaging construct, and serotype were each transfected into AAV-293 to produce three types of recombinant viruses expressing GFP.

The virus was purified using a CsCl gradient to obtain a high concentration of recombinant virus.

(2) Titration test of recombinant virus

To measure the titration of the AAV recombinant virus, it was measured by real-time PCR using ITR-specific primers of AAV.

Standard converted AAV DNA into copies, obtained a standard curve through CT values from 10 ⁹ to 10 ⁵ , and then extracted and measured gDNA from AAV.

The titration of the AAV recombinant virus was measured using a standard curve (Figure 1).

(3) Activity test of AAV recombinant virus expressing GFP gene

To measure the activity of the AAV recombinant virus, RPE was co-infected with each AAV-GFP promoter and GFP expression was evaluated (Figure 2).

In order to build a clinical database for patients with hereditary retinal diseases and discover candidate genes through this, as well as to develop highly efficient AAV-based gene therapy, the present inventors studied PDE6B-related hereditary retina, which is relatively common in Koreans but has not yet been developed as a gene therapy. We sought to develop gene therapy targeting diseases first.

After confirming and synthesizing the PDE6B gene sequence, pAAV-PDE6B-GFP / pAAV-GFP-AAV vector was cloned (Figure 3).

The development of a retinal disease-targeting AAV-based recombinant virus was carried out through the following process.

(1) pAAV-PDE6B, recombinant virus production for each promoter

(2) Virus packaging

A recombinant virus expressing PDE6B was produced by transfecting AAV-293 cells with pAAV-PDE6B and the AAV packaging construct, and then the virus was purified using a CsCl gradient to obtain a high concentration of recombinant virus.

(3) Titration test of AAV recombinant virus

To measure the titration of the AAV recombinant virus, it was measured by real-time PCR using ITR-specific primers of AAV.

Standard converted AAV DNA into copy number, obtained a standard curve through CT values from 10 ⁹ to 10 ⁵ , and then extracted and measured gDNA from AAV.

The titration of the AAV recombinant virus was measured using a standard curve (Figure 4).

< Example 2> High efficiency for in vitro conditions AAV Confirmation of biocompatibility and cell rescue effect of based gene therapy

The toxicity of the high-efficiency AAV gene therapy under in vitro conditions was confirmed and the effective safe concentration was established, and the intracellular gene transfer efficiency was verified through the use of the high-efficiency AAV gene therapy in cells.

Cell experiments were conducted to first confirm the toxicity and effective safe concentration of the AAV-PDE6B gene therapy produced using high-efficiency AAV, and safety and efficacy tests were also conducted on AAV-PDE6B.

One. AAV - GFP by promoter Confirmation of transduction and cytotoxicity (incucyte live cell image analysis)

RPE1 cells were seeded in a ⁹⁶ well plate at 5 promoter) (CMV, CAG-Cutten, CAG) was treated in wells at a concentration of 1 × 10 ⁹ to 5 × 10 ¹⁰ GC/ml. Live cells were observed in a bright field every hour using incucyte live cell imaging equipment, and transduction was confirmed by observing green fluorescence for a total of 24 hours.

As a result, it was confirmed that when AAV-GFP CMV and CAG were treated at high concentrations (5 × 10 ¹⁰ GC/ml), cell viability decreased to 20% and 80%, respectively. In the case of AAV-CAG-Cutten PDE6B, cell proliferation actually increased. In addition, transduction of AAV-GFP, confirmed by green fluorescence, showed that AAV-GFP CMV and CAG-cutten were dose dependent up to about 15% depending on the AAV concentration.

That is, AAV-CAG-Cutten PDE6B was confirmed to be a type with low cytotoxicity and high transduction rate (FIGS. 5 to 8).

2. AAV - of PDE6B by promoter Confirmation of transduction and cytotoxicity (WST-1 assay)

RPE1 cells were seeded in a 96 well plate at 5 × 10 ³ cells/well. After 24 hours, the existing media was removed and replaced with new cell culture media, and the promoter CAG, CAG (cutten), and CMV of AAV-PDE6B were grown at 1 × 10 ⁹ ~ 5 × 10 It was treated in the well at a concentration of ¹⁰ GC/ml. 24 hours after treating AAV-PDE6B, remove the existing media and add 100 ㎕ of EZ-cytox (Dogen, EZ-3000) diluted 1:10 with cell culture media into each well. give. After 1.5 hours, WST-1 assay was performed by measuring the OD value at 450 nm using a microplate reader device. In the analysis of the data, the OD measurement value of the well in which RPE1 cells (None) were cultured without EV treatment was set as 100%, and the OD values of the remaining samples were converted and presented in a graph (FIG. 9).

Unlike the cell phase results confirmed by Incucyte live cell image, there was no significant change in cell viability through WST-1 assay for all three promoters. This depends on the measurement method of each experiment. The incucyte live cell image confirms the morphology of the cell, and the WST-1 assay is a method to quantify cell proliferation ability or cell viability by colorimetric measurement.

< Example 3> High efficiency AAV based gene therapy preclinical ( preclinical ) in vivo Confirmation of safety and treatment efficiency in in vivo disease model

1. Establishment of disease animal model for hereditary retinal disease

The present inventors received PDE6B knock-out rats produced using CRISPR-Cas9 from the retinal staff of Asan Hospital's ophthalmology department (Yeo et al. IOVS 2019), and received permission to use them for experiments on the present invention, which was then purified and transferred to our laboratory. were brought into the SPF laboratory area, and after mating, preliminary experiments were conducted.

After mating the rat, genotyping was performed, and as can be seen in the previous experimental results above, it was confirmed that the PDE6B knock-out rat showed a phenotype in which the retinal electrophoresis was not detected through the ERG test, consistent with the genotyping results (Figure 10, red arrow).

Rats, in particular, have larger eyeballs compared to mice, making it easier to perform intraocular rAAV injection, and have the advantage of eye observation. The fundus photo above is a photo of the observation results after administering the actual BSS (vehicle) (FIG. 10).

2. High efficiency in animal models of hereditary retinal diseases AAV Confirmation of optimal effective concentration of gene therapy and verification of treatment effect

First, we plan to verify the rAAV-PDE6B gene therapy using PDE6B as a therapeutic gene, and analyze the therapeutic effect through intraocular administration of the rAAV-PDE6B gene therapy in PDE6B knock-out rats.

As a preliminary experimental study, AAV-GFP was injected into the vitreous cavity of rats (intravitreal injection), and after eye extraction, retinal tissue was stained using immunofluorescence with an anti-GFP antibody and observed under a fluorescence microscope. It was found that it was not toxic to retinal cells. As GFP fluorescence (red) was clearly visible in the retina without being observed, it was confirmed that AAV delivers GFP to the inner and outer layer cells of the retina with high efficiency (FIG. 11).

In addition, as part of a prior study, when AAV-PDE6B was administered before optimization into the vitreous cavity of PDE6B knock out homozygote rats as a pilot study, it was observed that the fluorescence expression of PDE6B in the inner retina was slightly increased, which showed that AAV-PDE6B It was indirectly confirmed that the gene therapy could operate normally (FIG. 12). However, since the intraocular or intravitreal injection used in this pilot study is thought to be insufficient to reach the photoreceptor area, which is the treatment target, the retina, which is closest to the photoreceptor and can administer the drug, is We plan to further verify the effect of AAV-PDE6B through subretinal injection.

3. AAV - PDE6B in vivo Results

(1) PDE6B protein expression in PDE6B KO rat retina

AAV-PDE6b was injected into the right eye of 8 PDE6B KO rats on the 12th day after birth. A dose of 1 uL 2.5 × 10 ¹² gc/ml was administered to each animal in the right eye. Fundus photographs and OCT (optical coherence tomography) were taken at different times to evaluate the retinal structure. As shown in Figure 14, the fundus photo is on the left, and as a result of checking the eyes on the 3rd, 6th, and 13th days of AAV administration, no special abnormalities were found in the left and right eyes, and special changes were observed in both eyes in the central and right OCT images. It didn't work.

(2) Immunohistochemical staining for PDE6B by extracting rat eyes injected with AAV-PDE6B

To confirm PDE6B expression, antibodies were purchased and tested. The antibodies used in the experiment were as follows. On the 12th day after birth, AAV-PDE6B was injected into the eye, and after injection, the eye was removed and subjected to immunofluorescence (IF) and immunohistochemistry (IHC) staining. Tissue processing was performed by cryofixation for IF and paraffin blocks for IHC.

Figure 15A is a control group that was not treated with antibodies and shows no color reaction. Figure 15B is an 11-week-old normal SD rat, and normal PDE6B expression is observed in the entire retina and photoreceptors. Figure 15C shows the results of an experiment in PDE6B KO rats (32 days after birth), in which photoreceptors were lost and PDE6B color reaction was not visible in the photoreceptors. Figure 15D shows the staining results of the eyes of PDE6b KO rats injected with AAV-PDE6B on the 12th day after birth and the eyes extracted on the 32nd day after birth. PDE6B expression appeared to be slightly increased in the entire retina compared to the opposite eye, Figure 15D. However, recovery of the photoreceptor structure was not observed.

As shown in Figure 16, in a PDE6B KO rat injected intraocularly with AAV-PDE6B, the left side is a retinal immunofluorescence staining image of the injected right eye, and the right side is a retinal image of the opposite eye that was not injected in the same rat. Similar to the previous immunohistochemical test results, it was observed that PDE6B expression in the inner retinal layer of the eye administered intraocular AAV-PDE6B was increased compared to the other eye.

As the specific parts of the present invention have been described in detail above, it is clear to those skilled in the art that these specific techniques are merely preferred embodiments and do not limit the scope of the present invention. something to do. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Sequence list electronic file attached

Claims (9)

CMV promoter gene or CAG promoter gene; Adenovirus recombinant vector containing the PDE6B gene and marker gene in sequence. The adenovirus recombinant vector according to claim 1, wherein the CMV promoter gene consists of a base sequence represented by SEQ ID NO: 1. The adenovirus recombinant vector according to claim 1, wherein the CAG promoter gene consists of the base sequence represented by SEQ ID NO: 2. The method of claim 1, wherein the marker gene is luciferase, enhanced green fluorescent protein (EGFP), green fluorescent protein (GFP), and yellow fluorescent protein (YFP). ), an adenovirus recombinant vector characterized in that it is a red fluorescent protein (RFP) or a cyan fluorescent protein (CFP). The method of claim 1, wherein the adenovirus recombinant vector is AAV-CMV-PDE6B-GFP consisting of the base sequence shown in SEQ ID NO: 3, AAV-CAG-PDE6B-GFP consisting of the base sequence shown in SEQ ID NO: 4, or SEQ ID NO. An adenovirus recombinant vector characterized in that it is AAV-CAG-PDE6B-GFP (Cutten) consisting of the base sequence indicated by 5. An adenovirus strain transfected with the adenovirus recombinant vector according to any one of claims 1 to 5. The strain according to claim 6, wherein the adenovirus is an adeno-associated virus (AAV). A pharmaceutical composition for preventing or treating hereditary retinal diseases comprising the adenovirus recombinant vector according to any one of claims 1 to 5 as an active ingredient. The pharmaceutical composition for preventing or treating hereditary retinal diseases according to claim 8, wherein the hereditary retinal disease is retinitis pigmentosa, Leber's congenital amaurosis, or cryptogenic macular dystrophy.