Cell conversion

Abstract

The present disclosure relates to compositions and methods for the conversion of source cells (such as macroglia) to retinal target cells by introducing transcription factors or upregulating transcription factors in the source cells, and associated methods for treating a retinal disease or degeneration.

Description

[0001] CELL CONVERSION

[0002] Technical Field

[0003] The present disclosure relates to compositions and methods for the conversion of source cells (such as macroglia) to retinal target cells by introducing transcription factors or upregulating transcription factors in the source cells, and associated methods for treating a retinal disease or degeneration.

[0004] Background to the invention

[0005] The retina contains multiple cell types. Neuronal cell types found in the retina include photoreceptors, bipolar cells, ganglion cells, horizontal cells, and amacrine cells. Photoreceptors are sensory neuronal cells found in all vertebrates and play a crucial role in the detection and transduction of light signals, which is essential for vision. Photoreceptors comprise cell types known as cones and rods. Rods are activated in low light and cones are activated in bright light of specific wavelengths, according to their expression of the photopigments rhodopsin or S / M / L opsin, respectively. Cones are mostly concentrated in the macula, a central region of the retina, and are required for central, high acuity vision, and colour perception. Bipolar cells are spatially located between photoreceptors and retinal ganglion cells (RGCs) and also transmit signals from photoreceptors to RGCs. RGCs receive signals from bipolar cells and transmit signals to the brain via their axons which form the optic nerve. Muller glia support the metabolism and nutrition of retinal neurons. The retinal pigment epithelium (RPE) is sandwiched between the neuroretina and the choroid, serving multiple roles including metabolic support of the retina, recycling of retinal chromophores, absorption of scattered light, and phagocytosis of shed photoreceptor outer segments. RPE cells form a cobblestone pigmented monolayer of polarised, highly specialised epithelium cells that are located directly adjacent to the light-sensing photoreceptors (rods and cones). Despite their importance in the retina, human rod and cone cells do not naturally regenerate following their loss in the event of disease, trauma, or injury. Progressive loss of photoreceptors and vision due to genetic mutation (inherited retinal dystrophies), pathological damage or environmental damage results in retinal degeneration, and activation of Muller glia, which would normally support the metabolism and nutrition of retinal neurons.

[0006] WO2019 / 195717 describes compositions and methods reported to treat vision loss through generation of rod photoreceptors from Muller glia. Also described is a nucleic acid molecule encoding at least one transcription factor selected from the group consisting of OTX2, CRX, NRL, NR2E3, and NUEROD [s / cj. The Examples describe a combined use of OTX2, CRX and NRL.

[0007] W02020 / 223308 describes nucleic acid molecules, compositions and methods alleged to stimulate regeneration of retinal interneurons from retinal Muller glia and reprogram the Muller glia into bipolar, amacrine, horizontal, and / or ganglion cells. The nucleic acid molecules encode two or more “proneural” basic helix-loop-helix (bHLH) transcription factors such as ASCLI, ATOH7, ATOH1, NEUROG2 and NEUROD1.

[0008] WO2021 / 034987 describes lists of transcription factors alleged to be “neuronal-specific” such as NEUROG3, SOX4, SOX9, KLF4, NR5A1, NEUROD1, SOX17, SMAD1, ATOH1, INSM1, NEUROG1, SOX18, RFX4, KLF7, SP8, OVOL1, NEUROG2, ERF, PRDM1, OLIG3, HIC1, SOX3, FOXJ1, SOX10, KLF6, ASCL1 , and PLAGL2. WO2021 / 253078 and WO2023 / 115147 describe methods reported to produce rod photoreceptor cells from glial cells by increasing the protein expression of one or more transcription factors selected from ASCL1 , NEUROD1, NRL, NR2E3, RAX, RORB, OTX2, CRX and PAX6. Specifically, Muller glia are reported to be reprogrammed to induced photoreceptor cells that are positive for rod photoreceptor cell markers.

[0009] WO2023 / 199036 describes methods and compositions for the conversion of source cells (such as Muller glia and astrocytes) to cone photoreceptor cells and / or RPE-like cells by introducing transcription factors, optionally one, two, three, or all of MEF2C, MEF2D, RXRG, and / or CRX, into the source cells, and methods for treating a retinal disease or degeneration.

[0010] WO2023 / 115146 describes methods and compositions allegedly suitable for in vitro or in vivo conversion, in particular transdifferentiation of a glial cell to a cone photoreceptor or cone photoreceptor-like cell using transcription factors wherein the transcription factors are one or more of those selected from NEUROG2, CRX, RAX, RORA, NEUROD1 , OTX2, ASCL1 , PAX6, THRB, MEF2C, FOXP1 and ONECUT1.

[0011] Numerous approaches to treating retinal disease or degeneration involving transcription factors have been previously proposed. However, there remains an unmet clinical need to provide an efficient means for photoreceptor reprogramming, especially in vivo reprogramming, which produces a clinically viable number of reprogrammed photoreceptors, an increased functional maturity of reprogrammed photoreceptors and improved specificity of reprogramming to photoreceptors, especially to cone photoreceptors. It is an object of the present invention to address one or more of these problems.

[0012] Summary of the invention

[0013] The inventors have for the first time shown that, surprisingly, FOXJ1 shifts the gene expression profile of Muller glia towards a photoreceptor gene expression profile more than any other single transcription factor tested and disclosed in the prior art. Furthermore, FOXJ1 has a strikingly specific effect to photoreceptors; no significant shift towards bipolar cells or an RPE gene expression profile is observed. The data disclosed herein highlight interactions between FOXJ1 and other transcription factors, suggesting that the use of FOXJ1 may reduce off-target effects driven by less photoreceptor-specific transcription factors. Delivery or upregulation of FOXJ1, optionally in combination with one or more further transcription factor, may therefore represent an advantageous approach for specifically reprogramming macroglia to photoreceptors and in treatments for retinal disease or degeneration.

[0014] According to a first aspect, the invention provides a nucleic acid molecule comprising a promoter operably linked to a nucleic acid sequence encoding Forkhead Box protein J1 (FOXJ1), or a functional variant thereof, wherein the promoter is for expression of FOXJ1 in macroglia.

[0015] According to a second aspect, the invention provides a system comprising one or more nucleic acid molecules configured to increase the expression of a gene encoding FOXJ1 , or a functional variant thereof, in macroglia.

[0016] According to a third aspect, the invention provides a vector comprising the nucleic acid molecule according to the first aspect or the system comprising one or more nucleic acid molecules according to the second aspect. According to a fourth aspect, the invention provides a composition comprising the nucleic acid molecule according to the first aspect, the system comprising one or more nucleic acid molecules according to the second aspect or the vector according to the third aspect, and a pharmaceutically acceptable carrier.

[0017] According to a fifth aspect, the invention provides a product comprising:

[0018] (a) a first nucleic acid molecule, encoding FOXJ1 , or a functional variant thereof, and

[0019] (b) a second nucleic acid molecule, encoding at least one transcription factor, or a functional variant thereof, selected from the group consisting of OTX2, NEUROD1 , CRX, MEF2C, MESP2, RAX2, NEUROG2, ASCL1 , ATOH7, ATOH1 , NRL, ONECUT1, RAX, MEF2D and RXRG; as a combined preparation for simultaneous, separate, or sequential use in the treatment of retinal disease or degeneration.

[0020] According to a sixth aspect, the invention provides a product comprising:

[0021] (a) a first nucleic acid molecule, configured to target for upregulation of FOXJ1 , or a functional variant thereof, and

[0022] (b) a second nucleic acid molecule, configured to target for upregulation of at least one transcription factor, or a functional variant thereof, selected from the group consisting of OTX2, NEUROD1, CRX, MEF2C, MESP2, RAX2, NEUROG2,ASCL1, ATOH7,ATOH1, NRL, ONECUT1, RAX, MEF2D and RXRG; as a combined preparation for simultaneous, separate, or sequential use in the treatment of retinal disease or degeneration.

[0023] According to a seventh aspect, the invention provides a kit for introducing and / or increasing the protein expression of FOXJ1, or a functional variant thereof, in macroglia.

[0024] According to an eighth aspect, the invention provides a method of converting a source cell to a target cell by introducing and / or increasing the protein expression of FOXJ1, or a functional variant thereof, into the source cell, thereby converting the source cell into the target cell.

[0025] According to a ninth aspect, the invention provides a cell produced by the method of the eighth aspect.

[0026] According to a tenth aspect, the invention provides the nucleic acid molecule according to the first aspect, the system comprising one or more nucleic acid molecules according to the second aspect, the vector according to the third aspect, the composition according to the fourth aspect, the kit according to the seventh aspect, or the cell according to the ninth aspect for use in the treatment of retinal disease or degeneration.

[0027] According to an eleventh aspect, the invention provides a method of treating retinal disease or degeneration in a subject in need thereof comprising administering to the subject a therapeutically effective amount of the nucleic acid molecule according to the first aspect, the system comprising one or more nucleic acid molecules according to the second aspect, the vector according to the third aspect, the composition according to the fourth aspect, the product according to the fifth aspect, the product according to the sixth aspect, the kit according to the seventh aspect, or the cell according to the ninth aspect. According to the twelfth aspect, the invention provides a nucleic acid molecule encoding CRX, NEUROD1 and OTX2 transcription factors, or functional variants thereof.

[0028] Any of the features described herein in respect of any of the above-mentioned aspects of the invention may be combined mutatis mutandis with the other aspects of the invention.

[0029] Brief description of the drawings

[0030] Figure 1. Significant upregulation of specific gene expression programs are observed upon transcription factortreatment (individual, monocistronic transcription factors). Differential expression scores are calculated as described in Example 1. For a given set of cell type marker genes, we averaged their differential expression scores and calculated the standard error. Additionally, we tested whether these are significantly upregulated from any random set of genes of the same size (one-sided t-test against 1000 random sets of genes of the same size as the original). As observed, FOXJ1 treatment upregulates specific cone, rod and photoreceptor gene expression programs, and its effect stands out when compared against other single transcription factor effects.

[0031] Figure 2. Summary of selected single transcription factor effects. Similarly to Figure 1, the differential expression scores are calculated as described in Example 1. For a given set of cell type marker genes, we averaged their differential expression scores and calculated the standard error. Additionally, we tested whether these are significantly upregulated from any random set of genes of the same size (one-sided t-test against 1000 random sets of genes of the same size as the original). Transcription factors are ordered vertically by decreasing difference between selected cell type markers and random sets of genes. FOXJ1 treatment upregulates specific cone, rod, and photoreceptor gene expression programs, while it does not upregulate RPE or bipolar cell gene expression programs. In contrast, NEUROG2 and NEUROD1 significantly upregulate the bipolar cells gene expression program.

[0032] Figure 3. Significant upregulation of specific gene expression programs are observed upon combined transcription factor- treatment (multiple monocistronic transcription factors). Differential expression scores are calculated as described in Example 2. For a given set of cell type marker genes, we average their differential expression scores and calculate the standard error. Additionally, we tested whether these are significantly upregulated from any random set of genes of the same size (e.g. one-sided t-test against 1000 random sets of genes of the same size as the original). Transcription factor combinations are ordered vertically by decreasing difference between selected cell type markers for each cell type. As observed, numerous combinations comprising FOXJ1 upregulate specific cone, rod and photoreceptor gene expression programs, and its effect outstands when compared against other single transcription factor effects in combination. Notably, even when FOXJ1 is combined with transcription factors that individually promote RPE or bipolar cell gene expression programs, no FOXJ1 containing combinations are here shown to significantly promote RPE or bipolar cell gene expression programs, suggesting that FOXJ1 may unexpectedly interact with other transcription factors to promote photoreceptor specific conversion.

[0033] Figure 4. Analysis of the effects of FOXJ1, NEUROD1, OTX2 and CRX using inference approaches as described in Example 2. Comparisons are made for any 2 transcription factor combination containing these 4 transcription factors against the i RFP control. Fold change and standard error are calculated between the selected cell type markers vs random gene set differential expression scores. Additionally, we test whether these changes are statistically different from random sets of genes of the same size (e.g. one-sided t-test against 1000 random sets of genes of the same size as the original). Transcription factors are ordered vertically by decreasing difference between selected cell type markers and random sets of markers. As observed, FOXJ1 combined with OTX2 upregulate specific cone, rod, and photoreceptor gene expression programs. Notably, OTX2 combined with either NEUROD1 or CRX upregulate bipolar or RPE gene expression programs respectively, while no upregulation of these is observed when combined with FOXJ1.

[0034] Figure 5. Analysis of the effects of FOXJ1, NEUROD1, OTX2 and CRX using inference approaches as described in Example 2. Comparisons are made for any 3 or 4 transcription factor combination containing these 4 transcription factors against the IRFP control. Fold change and standard error are calculated between the selected cell type markers vs random gene set differential expression scores. Additionally, we compare if these changes are statistically different from random sets of genes of the same size (e.g. one-sided t-test against 1000 random sets of genes of the same size as the original). Transcription factors are ordered vertically by decreasing difference between selected cell type markers and random set of markers. As observed, the inclusion of FOXJ1 significantly upregulate cone, rod, and photoreceptor gene expression programs. RPE and bipolar programs are only significantly upregulated if all the other 3 TFs (e.g., NEUROD1, OTX2 and CRX) are included in the combination, independently of FOXJ1 presence. Notably, adding FOXJ1 to NEUROD1:OTX2:CRX reduces the observed gene expression shift to RPE and bipolar specific programs.

[0035] Figure 6. Comparative analysis of FOXJ1:NEUROD1:OTX2:CRX, FOXJ1:NEUROD1:OTX2, and OTX2:NRL:CRX combinations, one panel per combination. This figure illustrates the 'lack' of cell type specificity of the OTX2:NRL:CRX combination and the improved specificity of FOXJ1 containing combinations FOXJ1 :NEUROD1 :OTX2 and FOXJ1 :NEUROD1 :OTX2:CRX.

[0036] Figure 7. Effects of transcription factor combinations in retinal organoids, prepared as described in Example 4. A) Forced-directed layout (FDL) plots depicting SLC1 A3-lineage traced, transgene positive (TagBFP2 expressing cells in ‘BFP control+' group; or NEUROD1_FOXJ1 and OTX2_CRX expressing cells in ‘TF+’ group) cells collected at day 10, and 21 post-transduction. A clear hybrid population was observed in the TF+ group. B) Stacked bar chart comprises the same S LC1 A3-lineage traced, transgene positive cells, showing the cell identity composition. Numbers on the bars represent the percentage out of all cells in that group. Cells expressing OTX2, CRX, NEUROD1, and FOXJ1 comprise greater proportions of Muller glia-cone photoreceptor hybrids and cone photoreceptors than the TagBFP2 control. The ‘other’ label comprises bipolar cells, ganglion cells, horizontal cells, amacrine cells, melanocytes, and RPE-like cells, and unknown cell types.

[0037] Figure 8. Effects of transcription factor combinations in retinal organoids. Heatmap, prepared as described in Example 4, showing the expression of well-known Muller glia and cone photoreceptor genes across groups of retinal organoid cells and primary cells from a publicly available human retina single cell RNA sequencing (scRNAseq) dataset. The plot depicts the transition from Muller glia to cone photoreceptor identity with the addition of OTX2, CRX, NEUROD1 , and FOXJ. Top annotations show the similarity scores between the groups of interest and the primary cell types, confirming that hybrid and converted cones with transcription factors have high primary cone scores when considering the entire transcriptome.

[0038] Figure 9. Stacked bar chart, prepared as described in Example 5, comparing the effect of FOXJ1 with NEUROD1 in retinal organoids - at day 21. Investigating the identity of cells based on their exogenous transcription factor expression shows that NEUROD1+ cells comprise a greater proportion of bipolar cells than the LV control, or NEUROD1+ FOXJ1+ cells. Conversely, NEUROD1+ FOXJ1+ cells comprise a greater proportion of cone photoreceptors than the AAV control or NEUROD1+ cells. Percentages in the bars represent the proportion of each cell type per group. The cell counts are written next to these percentages in parentheses. Bars are labelled by cell identify. The ‘other’ label comprises ganglion cells, horizontal cells, amacrine cells, melanocytes, and RPE-like cells, and unknown cell types. See example for caveats.

[0039] Figure 10. Histological section of the retina from an eye of an animal treated with AAV vectors to drive expression of FOXJ1 , NEUROD1 , CRX, and OTX2. The first panel shows cells that contain tdTomato, the glial cell lineage tracing florescent marker. Most cell bodies marked are in the inner nuclear layer (INL) and have the morphology consistent with Muller glia, however, some lineage traced cell bodies are found in the outer nuclear layer (ONL, white arrows) with a cellular morphology similar to surrounding photoreceptors. The second panel shows DAPI staining, which reveals the size and chromatin structure of nuclei. The nuclear morphology of lineage traced cells in the INL is consistent with Muller glia, but the nuclear morphology of lineage traced cells in the ONL is like surrounding photoreceptors. The third panel shows immunofluorescence staining for the photoreceptor marker, RECOVERIN. Lineage traced cells in the ONL are positive for this marker, as are surrounding photoreceptors, as expected. Scale bar = 20 pm.

[0040] Detailed description

[0041] According to a first aspect, the invention provides a nucleic acid molecule comprising a promoter operably linked to a nucleic acid sequence encoding Forkhead Box protein J1 (FOXJ1), or a functional variant thereof, wherein the promoter is for expression of FOXJ1 in macroglia. According to the invention, a nucleic acid molecule is provided comprising a promoter operably linked to a nucleic acid sequence encoding Forkhead Box protein J1 (FOXJ1), or a functional variant thereof, wherein the promoter is for expression of FOXJ1 in retinal macroglia. According to the invention, a nucleic acid molecule is provided comprising a promoter operably linked to a nucleic acid sequence encoding Forkhead Box protein J1 (FOXJ1), or a functional variant thereof, wherein the promoter is for expression of FOXJ1 in Muller glia. According to the invention, a nucleic acid molecule is provided comprising a promoter operably linked to a nucleic acid sequence encoding Forkhead Box protein J1 (FOXJ1), or a functional variant thereof, wherein the promoter is a macroglia selective or specific promoter. According to the invention, a nucleic acid molecule is provided comprising a promoter operably linked to a nucleic acid sequence encoding Forkhead Box protein J1 (FOXJ1 ), or a functional variant thereof, wherein the promoter is a retinal macroglia selective or specific promoter. According to the invention, a nucleic acid molecule is provided comprising a promoter operably linked to a nucleic acid sequence encoding Forkhead Box protein J1 (FOXJ1), or a functional variant thereof, wherein the promoter is a Muller glia selective or specific promoter. According to the invention, a nucleic acid molecule is provided comprising a promoter operably linked to a nucleic acid sequence encoding Forkhead Box protein J1 (FOXJ1), or a functional variant thereof, wherein the promoter is an astrocyte selective or specific promoter.

[0042] As used herein, “dual expression” refers to a promoter that is active in both the source cell and the resulting target cell, wherein the level of transcriptional activity may vary between the cell types. Thus, the promoter may drive expression in the source cell, such as a macroglial cell, and maintain expression in the target cell, such as a photoreceptor. In particular, the promoter may drive strong or maximal expression in the source cell, such as a macroglial cell, and maintain partial, reduced, or lower-level expression in the target cell, such as a photoreceptor. According to the invention, a nucleic acid molecule is provided comprising a promoter operably linked to a nucleic acid sequence encoding Forkhead Box protein J1 (FOXJ1), or a functional variant thereof, wherein the promoter is for dual expression of FOXJ1 in macroglia and in target cells (e.g. photoreceptors). According to the invention, a nucleic acid molecule is provided comprising a promoter operably linked to a nucleic acid sequence encoding Forkhead Box protein J1 (FOXJ1), or a functional variant thereof, wherein the promoter is for dual expression of FOXJ1 in retinal macroglia and in target cells (e.g. photoreceptors). According to the invention, a nucleic acid molecule is provided comprising a promoter operably linked to a nucleic acid sequence encoding Forkhead Box protein J1 (FOXJ1), or a functional variant thereof, wherein the promoter is for dual expression of FOXJ1 in Muller glia and in target cells (e.g. photoreceptors). According to the invention, a nucleic acid molecule is provided comprising a promoter operably linked to a nucleic acid sequence encoding Forkhead Box protein J1 (FOXJ1), or a functional variant thereof, wherein the promoter is for dual expression of FOXJ1 in astrocytes and in target cells (e.g. photoreceptors). According to the invention, a nucleic acid molecule is provided comprising a promoter operably linked to a nucleic acid sequence encoding Forkhead Box protein J1 (FOXJ1), or a functional variant thereof, wherein the promoter is selective or specific for dual expression of FOXJ1 in macroglia and in target cells (e.g. photoreceptors). According to the invention, a nucleic acid molecule is provided comprising a promoter operably linked to a nucleic acid sequence encoding Forkhead Box protein J1 (FOXJ1), or a functional variant thereof, wherein the promoter is selective or specific for dual expression of FOXJ1 in retinal macroglia and in target cells (e.g. photoreceptors). According to the invention, a nucleic acid molecule is provided comprising a promoter operably linked to a nucleic acid sequence encoding Forkhead Box protein J1 (FOXJ1), or a functional variant thereof, wherein the promoter is selective or specific for dual expression of FOXJ1 in Muller glia and in target cells (e.g. photoreceptors). According to the invention, a nucleic acid molecule is provided comprising a promoter operably linked to a nucleic acid sequence encoding Forkhead Box protein J1 (FOXJ1), ora functional variant thereof, wherein the promoter is selective or specific for dual expression of FOXJ1 in astrocytes and in target cells (e.g. photoreceptors).

[0043] According to the invention, a nucleic acid molecule is provided comprising a promoter operably linked to a nucleic acid sequence encoding Forkhead Box protein J1 (FOXJ1), or a functional variant thereof, wherein the promoter is for dual expression of FOXJ1 in multiple source cells, optionally selected from the group consisting of Muller glia, astrocytes, and other macroglial subtypes, and in target cells (e.g. photoreceptors). According to the invention, a nucleic acid molecule is provided comprising a promoter operably linked to a nucleic acid sequence encoding Forkhead Box protein J1 (FOXJ1), or a functional variant thereof, wherein the promoter is selective or specific for dual expression of FOXJ1 in multiple source cells, optionally selected from the group consisting of Muller glia, astrocytes, and other macroglial subtypes, and in target cells (e.g. photoreceptors).

[0044] According to the invention, a nucleic acid molecule is provided comprising a promoter operably linked to a nucleic acid sequence encoding Forkhead Box protein J1 (FOXJ1), or a functional variant thereof, wherein the promoter is for dual expression of F0XJ1 in macroglia and in multiple target cells, optionally selected from the group consisting of cone photoreceptors, rod photoreceptors, bipolar cells, ganglion cells, and other retinal neuronal subtypes. According to the invention, a nucleic acid molecule is provided comprising a promoter operably linked to a nucleic acid sequence encoding Forkhead Box protein J1 (FOXJ1), or a functional variant thereof, wherein the promoter is selective or specific for dual expression of FOXJ1 in macroglia and in multiple target cells, optionally selected from the group consisting of cone photoreceptors, rod photoreceptors, bipolar cells, ganglion cells, and other retinal neuronal subtypes.

[0045] According to the invention, a nucleic acid molecule is provided comprising a promoter operably linked to a nucleic acid sequence encoding Forkhead Box protein J1 (FOXJ1), or a functional variant thereof, wherein the promoter is for dual expression of FOXJ1 in multiple source cells and multiple target cells, optionally wherein the source cells are selected from Muller glia, astrocytes, and other macroglial subtypes, and the target cells are selected from cone photoreceptors, rod photoreceptors, bipolar cells, ganglion cells, and other retinal neuronal subtypes. According to the invention, a nucleic acid molecule is provided comprising a promoter operably linked to a nucleic acid sequence encoding Forkhead Box protein J1 (FOXJ1), or a functional variant thereof, wherein the promoter is selective or specific for dual expression of FOXJ1 in multiple source cells and multiple target cells, optionally wherein the source cells are selected from Muller glia, astrocytes, and other macroglial subtypes, and the target cells are selected from cone photoreceptors, rod photoreceptors, bipolar cells, ganglion cells, and other retinal neuronal subtypes.

[0046] The data disclosed herein surprisingly indicate that FOXJ1 shifts the gene expression profile of Muller glia towards a photoreceptor gene expression profile more than any other single transcription factor tested. Furthermore, FOXJ1 has a strikingly specific effect to photoreceptors; no significant shift towards bipolar cells or an RPE gene expression profile is observed. FOXJ1 therefore stands in contrast with other so called “neuronal specific” transcription factors NEUROD1 and NEUROG2 described generally in WO2021 / 034987, which are shown herein to specifically shift the gene expression profile of Muller glia towards a bipolar cell gene expression profile. Each of NEUROD1 and NEUROG2 have been previously associated with reprogramming Muller glia to bipolar cells (W02020 / 223308) and cone photoreceptors (WO2023 / 115146). Moreover, the data disclosed herein highlight interactions between FOXJ1 and other transcription factors, suggesting that the use of FOXJ1 may reduce off-target effects driven by less photoreceptor-specific transcription factors. Delivery or upregulation of FOXJ1, optionally in combination with one or more further transcription factor, may therefore represent an advantageous approach for specifically reprogramming macroglia to photoreceptors and in treatments for retinal disease or degeneration.

[0047] As used herein, “FOXJ1” refers to Forkhead Box protein J1. In humans it is encoded by the FOXJ1 gene, also known as Forkhead Box J1 , FKHL13, HFH-4 and HFH4. The mouse ortholog Fox J 1 is also known as Forkhead box protein J1. In humans, the Ensembl gene ID is ENSG00000129654, such as ENSG00000129654.8. An example of a transcript is the Ensembl transcript ID ENST00000322957, such as ENST00000322957.7 and the UniProt ID is Q92949, such as Q92949 v3; codon- optimised and alternatively spliced transcript variants are encompassed. In mice, an Ensembl gene ID is ENSMUSG00000034227. An example of a transcript is the Ensembl transcript ID ENSMUST00000036215, such as ENSMUST00000036215.8 and the UniProt ID is Q61660, such as Q61660 v2; codon-optimised and alternatively spliced transcript variants are encompassed. WO2021 / 034987 identifies FOXJ1 as one of many proposed “neuronal-specific” transcription factors alongside, for example, ASCL1, NEUROD1 and NEUROG2. The present inventors have identified surprising effects of FOXJ1 relative to, for example, ASCL1 , NEUROD1 and NEUROG2. F0XJ1 may refer to the human sequence having the following amino acid sequence, identified as SEQ ID NO: 1

[0048] SEQ ID NO: 1

[0049] MAESWLRLSGAGPAEEAGPEGGLEEPDALDDSLTSLQWLQEFSILNAKAPALPPGGTDPHGYHQVPGSAAPGSPLAADPACL

[0050] GQPHTPGKPTSSCTSRSAPPGLQAPPPDDVDYATNPHVKPPYSYATLICMAMQASKATKITLSAIYKWITDNFCYFRHADPTWQ

[0051] NSIRHNLSLNKCFIKVPREKDEPGKGGFWRIDPQYAERLLSGAFKKRRLPPVHIHPAFARQAAQEPSAVPRAGPLTVNTEAQQL

[0052] LREFEEATGEAGWGAGEGRLGHKRKQPLPKRVAKVPRPPSTLLPTPEEQGELEPLKGNFDWEAIFDAGTLGGELGALEALELS

[0053] PPLSPASHVDVDLTIHGRHIDCPATWGPSVEQAADSLDFDETFLATSFLQHPWDESGSGCLPPEPLFEAGDATLASDLQDWAS VGAFL

[0054] FOXJ1 may refer to the mouse sequence having the following amino acid sequence, identified as SEQ ID NO: 2

[0055] SEQ ID NO: 2

[0056] MAESWLRLCGAGPGEEAGPEGGMEEPDALDDSLTSLQWLQEFSILNAKAPTLPPGGTDPHGYHQVPGLVAPGSPLAADPACL

[0057] GQPHTPGKPTSSCTSRSAPPGLQAPPPDDVDYATNPHVKPPYSYATLICMAMQASKATKITLSAIYKWITDNFCYFRHADPTWQ

[0058] NSIRHNLSLNKCFIKVPREKDEPGKGGFWRIDPQYAERLLSGAFKKRRLPPVHIHPAFARQASQEPSAAPWGGPLTVNREAQQ

[0059] LLQEFEEATGEGGWGTGEGRLGHKRKQPLPKRVAKVLRPPSTLLLTQEEQGELEPLKGNFDWEAIFEAGALGEELSSLEGLEL

[0060] SPPLSPSSHGDVDLTVHGRHINCPATWGPPAEQAADSLDFDETFLATSFLQHPWDESGSGCLPPEPIFEAGDATLAADLQDWA SVGAFL

[0061] FOXJ1 may be encoded by the following human coding sequence, identified as SEQ ID NO: 3

[0062] SEQ ID NO: 3

[0063] ATGGCGGAGAGCTGGCTGCGCCTCTCGGGAGCCGGGCCGGCGGAGGAGGCCGGGCCGGAGGGCGGCCTGGAGGAG

[0064] CCCGACGCCCTGGATGACAGCCTGACCAGCCTGCAGTGGCTGCAGGAATTCTCCATTCTCAACGCCAAGGCCCCCGCC

[0065] CTGCCCCCGGGGGGCACCGACCCCCACGGCTACCACCAGGTGCCAGGTTCAGCGGCGCCCGGGTCCCCCCTGGCGG

[0066] CCGACCCCGCCTGCCTGGGGCAGCCACACACGCCGGGCAAGCCCACGTCGTCGTGCACGTCGCGGAGCGCGCCCCC

[0067] GGGGCTGCAGGCCCCACCCCCCGACGACGTGGACTACGCCACCAATCCGCACGTGAAGCCTCCCTACTCGTATGCCAC

[0068] GCTCATCTGCATGGCCATGCAGGCCAGCAAGGCCACCAAGATCACCCTGTCGGCCATCTACAAGTGGATCACGGACAAC

[0069] TTCTGCTACTTCCGCCACGCAGATCCCACCTGGCAGAATTCAATCCGCCACAACCTGTCTCTGAACAAGTGCTTCATCAAA

[0070] GTGCCTCGGGAGAAGGACGAACCAGGCAAGGGGGGCTTCTGGCGCATTGACCCCCAGTACGCGGAGCGGCTACTGAG

[0071] CGGCGCTTTCAAGAAGCGGCGACTGCCCCCTGTCCACATCCACCCAGCCTTTGCCCGCCAGGCCGCGCAGGAGCCCAG

[0072] CGCTGTCCCCCGGGCCGGGCCGCTGACGGTGAATACCGAGGCCCAGCAGCTGCTGCGGGAGTTCGAGGAGGCCACCG

[0073] GGGAGGCGGGCTGGGGTGCAGGCGAGGGCAGGCTGGGGCATAAGCGCAAACAGCCGCTGCCCAAGCGGGTGGCCAA

[0074] GGTCCCGCGGCCCCCCAGCACCCTGCTGCCCACCCCGGAGGAGCAGGGTGAGCTGGAACCCCTCAAAGGCAACTTTG

[0075] ACTGGGAGGCCATCTTCGACGCCGGCACTCTGGGCGGGGAGCTGGGTGCACTGGAGGCCCTGGAGCTGAGCCCGCCT

[0076] CTGAGCCCCGCCTCACACGTGGACGTGGACCTCACCATCCACGGCCGCCACATCGACTGCCCTGCCACCTGGGGGCCT

[0077] TCGGTGGAGCAGGCTGCCGACAGCCTGGACTTCGATGAGACCTTCCTGGCCACATCCTTCCTGCAGCACCCCTGGGAC GAGAGCGGCAGTGGCTGCCTGCCCCCGGAGCCCCTCTTTGAGGCTGGGGATGCCACCCTGGCCTCCGACCTGCAGGA

[0078] CTGGGCCAGCGTGGGGGCCTTCTTGTAA

[0079] F0XJ1 may be encoded by the following mouse coding sequence, identified as SEQ ID NO: 4

[0080] SEQ ID NO: 4

[0081] ATGGCGGAGAGCTGGCTGCGCCTCTGCGGAGCGGGTCCCGGAGAGGAAGCCGGGCCGGAGGGCGGCATGGAGGAGC

[0082] CGGACGCCCTGGATGACAGCCTGACCAGCCTGCAATGGCTGCAGGAATTCTCCATTCTCAACGCCAAGGCTCCCACTCT

[0083] TCCCCCAGGAGGCACAGACCCCCACGGCTACCACCAAGTGCCGGGCTTGGTGGCGCCCGGGTCACCGCTGGCGGCAG

[0084] ACCCTGCCTGCCTTGGGCAGCCGCACACACCCGGCAAGCCCACATCGTCGTGCACATCTCGAAGCGCGCCCCCGGGGC

[0085] TGCAGGCCCCGCCCCCTGACGACGTGGACTATGCCACCAACCCACACGTGAAGCCACCCTACTCCTATGCCACTCTCAT

[0086] CTGCATGGCCATGCAAGCCAGCAAGGCCACCAAGATCACTCTGTCGGCCATCTACAAGTGGATCACGGACAACTTCTGCT

[0087] ACTTCCGCCATGCAGACCCCACCTGGCAGAATTCCATCCGCCACAACCTGTCCTTGAACAAGTGCTTCATCAAAGTGCCT

[0088] CGGGAGAAGGATGAGCCCGGCAAGGGGGGTTTCTGGCGCATCGACCCCCAGTACGCAGAGCGCCTGCTCAGTGGGGC

[0089] CTTCAAGAAGCGGAGGCTGCCCCCAGTCCACATCCACCCTGCCTTTGCCCGCCAGGCCTCCCAGGAACCTAGCGCTGC

[0090] CCCCTGGGGTGGGCCTCTGACCGTGAACAGGGAGGCCCAGCAGCTGCTTCAGGAGTTTGAGGAGGCCACAGGGGAGG

[0091] GGGGCTGGGGCACAGGAGAGGGCAGGCTGGGGCATAAGCGAAAGCAGCCGCTGCCCAAGAGGGTGGCCAAGGTCCTG

[0092] CGGCCTCCCAGCACCTTACTGCTGACCCAGGAGGAGCAGGGTGAGCTGGAACCACTCAAAGGTAACTTTGACTGGGAG

[0093] GCCATCTTTGAGGCTGGCGCACTGGGGGAGGAGCTGAGCTCACTGGAGGGTCTGGAGCTAAGCCCCCCGCTAAGCCCC

[0094] AGCTCACATGGAGATGTGGATCTTACAGTCCATGGCCGGCACATCAACTGCCCTGCTACCTGGGGACCTCCAGCGGAGC

[0095] AGGCTGCTGACAGCCTGGACTTTGATGAGACCTTCTTGGCCACATCCTTCCTACAGCATCCCTGGGATGAGAGTGGTAGT

[0096] GGCTGCCTGCCCCCAGAACCCATCTTTGAAGCAGGGGATGCCACCCTGGCCGCTGACCTGCAGGACTGGGCCAGTGTG

[0097] GGTGCCTTCTTGTAA

[0098] FOXJ1 may be encoded by the following codon optimised human sequence, identified as SEQ ID NO: 5

[0099] SEQ ID NO: 5

[0100] ATGGCTGAAAGCTGGTTAAGACTGAGTGGCGCTGGTCCCGCTGAAGAAGCTGGCCCAGAAGGCGGGTTGGAAGAACCT

[0101] GATGCTCTCGACGATTCCCTTACATCCCTTCAATGGTTACAAGAGTTTAGTATCTTAAATGCAAAAGCTCCTGCGCTCCCAC

[0102] CAGGTGGGACAGATCCACATGGTTATCATCAAGTTCCGGGCAGCGCCGCTCCTGGCAGCCCGCTCGCAGCAGATCCAGC

[0103] ATGTCTCGGCCAACCTCATACTCCTGGGAAACCTACTAGTAGTTGTACAAGTAGGTCCGCACCGCCAGGTCTCCAAGCTC

[0104] CCCCACCAGATGATGTTGATTATGCAACTAACCCACATGTCAAACCGCCATATTCATACGCTACTCTTATCTGTATGGCTATG

[0105] CAAGCCAGCAAAGCAACCAAAATTACGCTTAGTGCTATTTACAAGTGGATTACAGACAATTTCTGTTATTTTCGGCACGCTG

[0106] ACCCCACATGGCAAAACTCTATTAGACATAACTTGAGCCTTAACAAATGTTTTATTAAGGTCCCCCGCGAGAAAGATGAGCC

[0107] CGGCAAAGGCGGGTTTTGGCGCATTGATCCTCAATATGCTGAAAGACTTCTTAGTGGAGCATTTAAGAAGCGCCGGTTGC

[0108] CACCCGTACATATTCATCCGGCTTTCGCAAGACAAGCTGCACAAGAACCTTCCGCCGTGCCAAGGGCAGGCCCCCTCACT

[0109] GTAAACACAGAAGCTCAACAACTCCTCAGGGAATTTGAAGAAGCGACGGGCGAAGCCGGATGGGGCGCTGGGGAAGGG

[0110] CGGTTAGGTCACAAACGGAAGCAACCATTGCCTAAAAGAGTCGCTAAAGTACCTCGACCACCTTCCACTCTCCTTCCAACA

[0111] CCAGAAGAACAAGGCGAACTTGAGCCCTTAAAGGGAAATTTCGATTGGGAAGCTATCTTTGATGCTGGAACCTTGGGTGG

[0112] AGAATTAGGAGCTCTCGAAGCACTCGAACTCTCACCACCCCTTTCACCAGCAAGTCATGTTGATGTTGATCTGACTATTCAT GGTAGGCATATTGATTGTCCCGCTACTTGGGGCCCGAGTGTTGAACAAGCGGCAGATTCATTAGATTTTGACGAAACATTT CTCGCTACGAGTTTTCTTCAACATCCTTGGGATGAATCTGGTAGCGGATGTCTTCCACCCGAACCTCTTTTCGAAGCCGGC GACGCAACGCTCGCTTCTGATTTGCAAGATTGGGCAAGTGTCGGAGCATTTCTGTGA

[0113] The functional variant of FOXJ1 may comprise an amino acid sequence at least 70% identical to SEQ ID NO: 1 or SEQ ID NO: 2. The functional variant of FOXJ1 may comprise an amino acid sequence at least 80% identical to SEQ ID NO: 1 or SEQ ID NO: 2. The functional variant of FOXJ1 may comprise an amino acid sequence at least 85% identical to SEQ ID NO: 1 or SEQ ID NO: 2. The functional variant of FOXJ1 may comprise an amino acid sequence at least 90% identical to SEQ ID NO: 1 or SEQ ID NO: 2. The functional variant of FOXJ1 may comprise an amino acid sequence at least 95% identical to SEQ ID NO: 1 or SEQ ID NO: 2. The functional variant of FOXJ1 may comprise an amino acid sequence at least 96% identical to SEQ ID NO: 1 or SEQ ID NO: 2. The functional variant of FOXJ1 may comprise an amino acid sequence at least 97% identical to SEQ ID NO: 1 or SEQ ID NO: 2. The functional variant of FOXJ1 may comprise an amino acid sequence at least 98% identical to SEQ ID NO: 1 or SEQ ID NO: 2. The functional variant of FOXJ1 may comprise an amino acid sequence at least 99% identical to SEQ ID NO: 1 or SEQ ID NO: 2. SEQ ID NO: 1 and SEQ ID NO: 2 share 400 identical amino acids out of 421 and thus are at least 95% identical to one another. The nucleic acid sequence may comprise any nucleic acid sequence encoding a functional variant of FOXJ1. Therefore, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 70% identical to SEQ ID NO: 1 or SEQ ID NO: 2. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 90% identical to SEQ I D NO: 1 or SEQ ID NO: 2. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 95% identical to SEQ ID NO: 1 or SEQ ID NO: 2. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 96% identical to SEQ ID NO: 1 or SEQ ID NO: 2.

[0114] The functional variant of FOXJ1 may consist essentially of an amino acid sequence at least 70% identical to SEQ ID NO: 1 or SEQ ID NO: 2. The functional variant of FOXJ1 may consist essentially of any amino acid sequence described elsewhere herein as a sequence that the functional variant of FOXJ1 may comprise.

[0115] The nucleic acid sequence may comprise any nucleic acid sequence encoding FOXJ1. FOXJ1 may comprise an amino acid sequence according to SEQ ID NO: 1 or SEQ ID NO: 2. Therefore, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 1 or SEQ ID NO: 2. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 1. Alternatively, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 2.

[0116] The nucleotide sequence encoding FOXJ1, or a functional variant thereof may comprise a nucleic acid sequence encoding:

[0117] (a) SEQ ID NO: 1,

[0118] (b) SEQ ID NO: 2,

[0119] (c) an amino acid sequence having at least 70% identity to SEQ ID NO: 1 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 1 , or

[0120] (d) an amino acid sequence having at least 70% identity to SEQ ID NO: 2 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 2. The nucleotide sequence encoding FOXJ1 , or a functional variant thereof may consist essentially of a nucleic acid sequence encoding:

[0121] (a) SEQ ID NO: 1,

[0122] (b) SEQ ID NO: 2,

[0123] (c) an amino acid sequence having at least 70% identity to SEQ ID NO: 1 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 1 , or

[0124] (d) an amino acid sequence having at least 70% identity to SEQ ID NO: 2 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 2.

[0125] The nucleotide sequence encoding FOXJ1 , or a functional variant thereof may consist essentially of any nucleic acid sequence described elsewhere herein as a sequence that may encode FOXJ1 or functional variant of FOXJ1.

[0126] The nucleotide sequence encoding FOXJ1, or a functional variant thereof may comprise a nucleic acid sequence encoding:

[0127] (a) SEQ ID NO: 1,

[0128] (b) SEQ ID NO: 2,

[0129] (c) an amino acid sequence having at least 97% identity to SEQ ID NO: 1 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 1 , or

[0130] (d) an amino acid sequence having at least 97% identity to SEQ ID NO: 2 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 2.

[0131] The nucleotide sequence encoding FOXJ1, or a functional variant thereof may comprise:

[0132] (a) SEQ ID NO: 3,

[0133] (b) SEQ ID NO: 4,

[0134] (c) SEQ ID NO: 5, or

[0135] (d) a nucleotide sequence having at least 60% identity to SEQ ID NO: 3 or SEQ ID NO: 5, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 1 , or

[0136] (e) a nucleotide sequence having at least 60% identity to SEQ ID NO: 4, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 2.

[0137] The nucleotide sequence encoding FOXJ1 or a functional variant thereof may comprise a nucleic acid sequence having at least 60% identity to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5. The nucleotide sequence having at least 60% identity to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5 may have at least 70%, 75%, 80%, 85%, 90% or 95% identity to SEQ ID NO: 3, SEQ ID NO: 4, or SEQ ID NO: 5, respectively. SEQ ID NO: 3 and SEQ ID NO: 4 share 1115 identical nucleotides out of 1266 and thus are at least 88% identical to one another. SEQ ID NO: 3 and SEQ ID NO: 5 share 835 identical nucleotides out of 1263 and therefore have at least 66% sequence identity to each other and encode the same protein sequence. The non-identical nucleotides may represent silent mutations (i.e. mutations which do not alter the sequence of the encoded amino acid). The non-identical nucleotides may alter the amino acid sequence of the encoded amino acid, for example by one or more conservative amino acid mutation. The non-identical nucleotides may alter the amino acid sequence of the encoded amino acid by up to 20, up to 15, up to 10, up to 9, up to 8, up to 7, up to 6, up to 5, up to 4, up to 3, up to 2 or up to 1 conservative amino acid mutation. The nucleotide sequence encoding FOXJ1, or a functional variant thereof may comprise:

[0138] (a) SEQ ID NO: 3,

[0139] (b) SEQ ID NO: 4,

[0140] (c) SEQ ID NO: 5, or

[0141] (d) a nucleotide sequence having at least 66% identity to SEQ ID NO: 3 or SEQ ID NO: 5, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 1 , or

[0142] (e) a nucleotide sequence having at least 66% identity to SEQ ID NO: 4, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 2.

[0143] The nucleotide sequence encoding FOXJ1, or a functional variant thereof may comprise:

[0144] (a) SEQ ID NO: 3,

[0145] (b) SEQ ID NO: 4,

[0146] (c) SEQ ID NO: 5, or

[0147] (d) a nucleotide sequence having at least 88% identity to SEQ ID NO: 3 or SEQ ID NO: 5, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 1 , or

[0148] (e) a nucleotide sequence having at least 88% identity to SEQ ID NO: 4, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 2.

[0149] The nucleic acid sequence may encode FOXJ1. The nucleotide sequence encoding FOXJ1 may comprise:

[0150] (a) SEQ ID NO: 3,

[0151] (b) SEQ ID NO: 4, or

[0152] (c) SEQ ID NO: 5.

[0153] The nucleic acid molecule may encode at least two transcription factors, or functional variants thereof, wherein a first transcription factor is FOXJ1.

[0154] The nucleic acid molecule may encode at least two transcription factors, or functional variants thereof, wherein one transcription factor is FOXJ1 and wherein the at least two transcription factors further comprise at least one transcription factor selected from the group consisting of OTX2, NEUROD1, CRX, MEF2C, MESP2, RAX2, NEUROG2, ASCL1, ATOH7, ATOH1, NRL, ONECUT1, RAX, MEF2D and RXRG.

[0155] The nucleic acid molecule may encode at least two transcription factors, or functional variants thereof, wherein one transcription factor is FOXJ1 and wherein the at least two transcription factors further comprise at least one transcription factor selected from the group consisting of NEUROD1 , NEUROG2, ASCL1 , ATOH7 and ATOH1.

[0156] The nucleic acid molecule may encode at least two transcription factors, or functional variants thereof, wherein one transcription factor is FOXJ1 and wherein the at least two transcription factors further comprise at least one transcription factor selected from the group consisting of OTX2, NEUROD1 and CRX. According to any aspect of the invention, the transcription factors may comprise FOXJ1, and any one or more transcription factor selected from the group consisting of OTX2, NEUROD1, CRX, MEF2C, MESP2, RAX2, NEUROG2, ASCL1, ATOH7, ATOH1, NRL, ONECUT1, RAX, MEF2D and RXRG.

[0157] According to any aspect of the invention, the transcription factors may comprise FOXJ1, and any two or more transcription factors selected from the group consisting of OTX2, NEUROD1, CRX, MEF2C, MESP2, RAX2, NEUROG2, ASCL1, ATOH7, ATOH1, NRL, ONECUT1, RAX, MEF2D and RXRG.

[0158] According to any aspect of the invention, the transcription factors may comprise FOXJ1, and any three or more transcription factors selected from the group consisting of OTX2, NEUROD1, CRX, MEF2C, MESP2, RAX2, NEUROG2, ASCL1, ATOH7, ATOH1, NRL, ONECUT1, RAX, MEF2D and RXRG.

[0159] According to any aspect of the invention, the transcription factors may comprise:

[0160] (a) FOXJ1 and OTX2;

[0161] (b) FOXJ1 and NEUROD1; or

[0162] (c) FOXJ1 and CRX.

[0163] The present inventors have identified evidence of an interaction between FOXJ1 and OTX2. In particular, FOXJ1 and OTX2 appear to cause a statistically significant shift in the expression profile of Muller glia to cones, rods, or photoreceptors in general, but not to bipolar cells or RPE. OTX2 alone is herein shown to cause a statistically significant shift in the expression profile of Muller glia to cones, rods, photoreceptors in general, and to RPE. Therefore, the combination of OTX2 with FOXJ1 selectively negates the shift towards an RPE expression profile seen with OTX2 alone, whilst maintaining the effects of each transcription factor on promoting the expression profile of cones, rods, photoreceptors in general. Without being bound by theory, the combination of FOXJ1 and OTX2 therefore provides a surprising advance in addressing the technical problem of reprogramming to photoreceptors while minimising off target conversions. Therefore, according to any aspect of the invention, the transcription factors may comprise FOXJ1 and OTX2. According to any aspect of the invention, the transcription factors may consist of FOXJ1 and OTX2.

[0164] According to any aspect of the invention, the transcription factors may comprise:

[0165] (a) FOXJ1, OTX2 and NEUROD1;

[0166] (b) FOXJ1, 0TX2 and CRX;

[0167] (c) FOXJ1, OTX2 and MEF2C;

[0168] (d) FOXJ1, 0TX2 and MESP2;

[0169] (e) FOXJ1, OTX2 and RAX2;

[0170] (f) FOXJ1, 0TX2, NEUROD1 and CRX; or

[0171] (g) FOXJ1, 0TX2 and one or more further transcription factor.

[0172] The present inventors have identified evidence of an interaction between FOXJ1 and NEUROD1. In particular, FOXJ1 and NEUROD1 appear to cause a notable expansion of the photoreceptor (especially cone cell) population in retinal organoids, with little or no expansion of the smaller bipolar cell population. In contrast, NEUROD1 delivered to retinal organoids in the absence of FOXJ1 appears to cause a notable expansion of the bipolar cell population, with little or no expansion of the smaller cone cell population (results consistent with the role of NEUROD1 alone in 2D culture). Therefore, the combination of NEUROD1 with FOXJ1 may selectively negate the expansion of bipolar cells and / or shift towards a bipolar cell expression profile seen with NEUROD1 alone, whilst maintaining the effect of FOXJ1 on promoting the expansion of photoreceptors (especially cones) and / or shift towards an expression profile of cones, rods, photoreceptors in general. Without being bound by theory, the combination of FOXJ1 and NEUROD1 therefore provides a surprising advance in addressing the technical problem of reprogramming to photoreceptors while minimising off target conversions. Therefore, according to any aspect of the invention, the transcription factors may comprise FOXJ1 and NEUROD1. According to any aspect of the invention, the transcription factors may consist of FOXJ1 and NEUROD1.

[0173] According to any aspect of the invention, the transcription factors may comprise:

[0174] (a) FOXJ1, NEUROD1 and OTX2;

[0175] (b) FOXJ1, NEUROD1 and CRX;

[0176] (c) FOXJ1, NEUROD1, CRX, and OTX2; or

[0177] (d) FOXJ1, NEUROD1 and one or more further transcription factor.

[0178] Without being bound by theory, on the basis of the similar individual effects of NEUROD1 and NEUROG2, and the fact that they are both classified as basic helix-loop-helix (bHLH) transcription factors, the interaction between FOXJ1 and NEUROD1 described herein may also be observed between FOXJ1 and NEUROG2. Therefore, according to any aspect of the invention, the transcription factors may comprise:

[0179] (a) FOXJ1, NEUROG2 and OTX2;

[0180] (b) FOXJ1, NEUROG2 and CRX; or

[0181] (c) FOXJ1 , NEUROG2 and one or more further transcription factor.

[0182] Without being bound by theory, on the basis that ASCL1,ATOH 7 and ATOH1 are identified alongside NEUROD1 and NEUROG2 as “proneural” bHLH transcription factors alleged in W02020 / 223308 to reprogram Muller glia into retinal interneurons including bipolar cells, the interaction between FOXJ1 and NEUROD1 described herein may also be observed between FOXJ1 and one or more proneural bHLH transcription factor, for example a proneural bHLH transcription factor selected from the group consisting of ASCL1, ATOH7 andATOHI. Furthermore, the individual effects of ASCL1 described herein follow a similar pattern to those of NEUROD1 and NEUROG2. Specifically, ASCL1 clearly shows no shift in expression profile towards cones, rods, photoreceptors or RPE cells. Moreover, ASCL1 shows a possible shift towards the expression profile of bipolar cells, albeit a shift that is marginally non-significant and smaller in magnitude than that observed with either of NEUROD1 and NEUROG2. Therefore, according to any aspect of the invention, the transcription factors may comprise FOXJ1 and one or more bHLH transcription factor. The one or more bHLH transcription factor may be a “proneural” transcription factor. The proneural bHLH transcription factor may be selected from the group consisting of NEUROD1, NEUROG2, ASCL1, ATOH7 and ATOH1. The proneural bHLH transcription factor may be selected from the group consisting of NEUROD1, NEUROG2 and ASCL1. The proneural bHLH transcription factor may be selected from the group consisting of NEUROD1 and NEUROG2. The proneural bHLH transcription factor may be selected from the group consisting of ASCL1, ATOH7 and ATOH1. Therefore, according to any aspect of the invention, the transcription factors may comprise:

[0183] (a) FOXJ1 and one or more proneural bHLH transcription factor; (b) F0XJ1 and one or more further transcription factor selected from the group consisting of NEUROD1 , NEUROG2, ASCL1,ATOH7 andATOH1;

[0184] (c) FOXJ1, OTX2 and one or more further transcription factor selected from the group consisting of NEUROD1, NEUROG2, ASCL1, ATOH7 and ATOH1 ; or

[0185] (d) FOXJ1, CRX and one or more further transcription factor selected from the group consisting of NEUROD1, NEUROG2, ASCL1 , ATOH7 and ATOH1.

[0186] As used herein, “NEUROD1” refers to Neurogenic differentiation factor 1. In humans it is encoded by the NEUR0D1 gene, also known as Neuronal Differentiation 1 BETA2, BHF-1, BHLHA3, MODY6, and NEURODl.The mouse ortholog NEUROD1 is also known as Neurogenic differentiation factor 1. In humans, the Ensembl gene ID is ENSG00000162992, such as ENSG00000162992.3. An example of a transcript is the Ensembl transcript ID ENST00000295108, such as ENST00000295108.3 and the UniProt ID is Q13562, such as Q13562 v3; codon-optimised and alternatively spliced transcript variants are encompassed. In mice, an Ensembl gene ID is ENSMUSG00000034701. An example of a transcript is the Ensembl transcript ID ENSMUST00000041099, such as ENSMUST00000041099.5 and the UniProt ID is Q60867, such as Q60867 v2; codon-optimised and alternatively spliced transcript variants are encompassed.

[0187] NEUROD1 may refer to the human sequence having the following amino acid sequence, identified as SEQ ID NO: 6

[0188] SEQ ID NO: 6

[0189] MTKSYSESGLMGEPQPQGPPSWTDECLSSQDEEHEADKKEDDLETMNAEEDSLRNGGEEEDEDEDLEEEEEEEEEDDDQK PKRRGPKKKKMTKARLERFKLRRMKANARERNRMHGLNAALDNLRKWPCYSKTQKLSKIETLRLAKNYIWALSEILRSGKSP DLVSFVQTLCKGLSQPTTNLVAGCLQLNPRTFLPEQNQDMPPHLPTASASFPVHPYSYQSPGLPSPPYGTMDSSHVFHVKPPP HAYSAALEPFFESPLTDCTSPSFDGPLSPPLSINGNFSFKHEPSAEFEKNYAFTMHYPAATLAGAQSHGSIFSGTAAPRCEIPIDN IMSFDSHSHHERVMSAQLNAIFHD

[0190] NEUROD1 may refer to the mouse sequence having the following amino acid sequence, identified as SEQ ID NO: 7

[0191] SEQ ID NO: 7

[0192] MTKSYSESGLMGEPQPQGPPSWTDECLSSQDEEHEADKKEDELEAMNAEEDSLRNGGEEEEEDEDLEEEEEEEEEEEDQK PKRRGPKKKKMTKARLERFKLRRMKANARERNRMHGLNAALDNLRKWPCYSKTQKLSKIETLRLAKNYIWALSEILRSGKSP DLVSFVQTLCKGLSQPTTNLVAGCLQLNPRTFLPEQNPDMPPHLPTASASFPVHPYSYQSPGLPSPPYGTMDSSHVFHVKPPP HAYSAALEPFFESPLTDCTSPSFDGPLSPPLSINGNFSFKHEPSAEFEKNYAFTMHYPAATLAGPQSHGSIFSSGAAAPRCEIPI DNIMSFDSHSHHERVMSAQLNAIFHD

[0193] NEUROD1 may be encoded by the following human coding sequence, identified as SEQ ID NO: 8

[0194] SEQ ID NO: 8

[0195] ATGACCAAATCGTACAGCGAGAGTGGGCTGATGGGCGAGCCTCAGCCCCAAGGTCCTCCAAGCTGGACAGACGAGTGT CTCAGTTCTCAGGACGAGGAGCACGAGGCAGACAAGAAGGAGGACGACCTCGAAACCATGAACGCAGAGGAGGACTCA CTGAGGAACGGGGGAGAGGAGGAGGACGAAGATGAGGACCTGGAAGAGGAGGAAGAAGAGGAAGAGGAGGATGACGA TCAAAAGCCCAAGAGACGCGGCCCCAAAAAGAAGAAGATGACTAAGGCTCGCCTGGAGCGTTTTAAATTGAGACGCATGA

[0196] AGGCTAACGCCCGGGAGCGGAACCGCATGCACGGACTGAACGCGGCGCTAGACAACCTGCGCAAGGTGGTGCCTTGCT

[0197] ATTCTAAGACGCAGAAGCTGTCCAAAATCGAGACTCTGCGCTTGGCCAAGAACTACATCTGGGCTCTGTCGGAGATCCTG

[0198] CGCTCAGGCAAAAGCCCAGACCTGGTCTCCTTCGTTCAGACGCTTTGCAAGGGCTTATCCCAACCCACCACCAACCTGG

[0199] TTGCGGGCTGCCTGCAACTCAATCCTCGGACTTTTCTGCCTGAGCAGAACCAGGACATGCCCCCCCACCTGCCGACGGC

[0200] CAGCGCTTCCTTCCCTGTACACCCCTACTCCTACCAGTCGCCTGGGCTGCCCAGTCCGCCTTACGGTACCATGGACAGCT

[0201] CCCATGTCTTCCACGTTAAGCCTCCGCCGCACGCCTACAGCGCAGCGCTGGAGCCCTTCTTTGAAAGCCCTCTGACTGAT

[0202] TGCACCAGCCCTTCCTTTGATGGACCCCTCAGCCCGCCGCTCAGCATCAATGGCAACTTCTCTTTCAAACACGAACCGTC

[0203] CGCCGAGTTTGAGAAAAATTATGCCTTTACCATGCACTATCCTGCAGCGACACTGGCAGGGGCCCAAAGCCACGGATCAA

[0204] TCTTCTCAGGCACCGCTGCCCCTCGCTGCGAGATCCCCATAGACAATATTATGTCCTTCGATAGCCATTCACATCATGAGC

[0205] GAGTCATGAGTGCCCAGCTCAATGCCATATTTCATGATTAG

[0206] NEUR0D1 may be encoded by the following mouse coding sequence, identified as SEQ ID NO: 9

[0207] SEQ ID NO: 9

[0208] ATGACCAAATCATACAGCGAGAGCGGGCTGATGGGCGAGCCTCAGCCCCAAGGTCCCCCAAGCTGGACAGATGAGTGTC

[0209] TCAGTTCTCAGGACGAGGAACACGAGGCAGACAAGAAAGAGGACGAGCTTGAAGCCATGAATGCAGAGGAGGACTCTCT

[0210] GAGAAACGGGGGAGAGGAGGAGGAGGAAGATGAGGATCTAGAGGAAGAGGAGGAAGAAGAAGAGGAGGAGGAGGATC

[0211] AAAAGCCCAAGAGACGGGGTCCCAAAAAGAAAAAGATGACCAAGGCGCGCCTAGAACGTTTTAAATTAAGGCGCATGAAG

[0212] GCCAACGCCCGCGAGCGGAACCGCATGCACGGGCTGAACGCGGCGCTGGACAACCTGCGCAAGGTGGTACCTTGCTAC

[0213] TCCAAGACCCAGAAACTGTCTAAAATAGAGACACTGCGCTTGGCCAAGAACTACATCTGGGCTCTGTCAGAGATCCTGCG

[0214] CTCAGGCAAAAGCCCTGATCTGGTCTCCTTCGTACAGACGCTCTGCAAAGGTTTGTCCCAGCCCACTACCAATTTGGTCG

[0215] CCGGCTGCCTGCAGCTCAACCCTCGGACTTTCTTGCCTGAGCAGAACCCGGACATGCCCCCGCATCTGCCAACCGCCAG

[0216] CGCTTCCTTCCCGGTGCATCCCTACTCCTACCAGTCCCCTGGACTGCCCAGCCCGCCCTACGGCACCATGGACAGCTCC

[0217] CACGTCTTCCACGTCAAGCCGCCGCCACACGCCTACAGCGCAGCTCTGGAGCCCTTCTTTGAAAGCCCCCTAACTGACT

[0218] GCACCAGCCCTTCCTTTGACGGACCCCTCAGCCCGCCGCTCAGCATCAATGGCAACTTCTCTTTCAAACACGAACCATCC

[0219] GCCGAGTTTGAAAAAAATTATGCCTTTACCATGCACTACCCTGCAGCGACGCTGGCAGGGCCCCAAAGCCACGGATCAAT

[0220] CTTCTCTTCCGGTGCCGCTGCCCCTCGCTGCGAGATCCCCATAGACAACATTATGTCTTTCGATAGCCATTCGCATCATGA

[0221] GCGAGTCATGAGTGCCCAGCTTAATGCCATCTTTCACGATTAG

[0222] NEUROD1 may be encoded by the following codon optimised human sequence, identified as SEQ ID NO: 10

[0223] SEQ ID NO: 10

[0224] ATGACTAAATCTTATAGTGAATCTGGACTTATGGGAGAACCCCAACCACAGGGCCCGCCGTCATGGACGGATGAATGCCTG

[0225] TCTAGCCAAGATGAAGAACATGAAGCCGATAAGAAGGAAGATGATCTTGAGACAATGAATGCCGAAGAAGATTCCTTGCGG

[0226] AATGGCGGGGAAGAAGAAGATGAGGACGAAGATCTGGAAGAAGAAGAGGAAGAAGAGGAAGAAGACGATGACCAGAAA

[0227] CCTAAACGCCGTGGACCAAAGAAGAAGAAAATGACGAAAGCCAGGCTTGAACGGTTCAAGCTGCGGAGAATGAAAGCCA

[0228] ATGCTAGAGAACGCAATCGGATGCATGGCCTCAATGCAGCCTTGGATAATTTGCGGAAAGTCGTCCCCTGTTACAGTAAAA

[0229] CCCAGAAATTGAGCAAGATTGAAACCTTGCGACTCGCTAAGAATTATATTTGGGCCTTGTCCGAAATTCTTAGATCTGGAAA

[0230] GTCCCCCGATCTCGTGAGCTTTGTGCAAACACTGTGTAAAGGTTTGAGCCAGCCTACAACAAATCTCGTGGCTGGTTGTC TTCAGCTGAACCCAAGGACCTTCTTGCCAGAACAAAATCAAGATATGCCCCCGCATTTGCCAACAGCTTCAGCCTCTTTTC CCGTTCATCCATATAGCTATCAAAGCCCAGGTCTCCCATCACCCCCGTATGGGACAATGGATTCTAGCCACGTGTTTCATGT GAAACCCCCGCCCCATGCTTATTCAGCCGCACTCGAACCATTCTTCGAGTCTCCCTTGACCGACTGTACATCCCCAAGTTT CGACGGTCCACTGAGTCCCCCTCTGTCAATTAACGGGAATTTTAGTTTTAAGCATGAGCCTAGTGCAGAATTCGAAAAGAA CTACGCATTCACAATGCATTACCCAGCTGCCACGTTGGCTGGAGCTCAGTCCCATGGCAGCATCTTTTCCGGAACAGCCG CGCCCAGGTGTGAAATTCCTATTGATAACATAATGAGTTTTGACTCACACAGCCACCACGAACGCGTGATGTCCGCTCAAC TGAACGCAATCTTCCACGACT

[0231] The functional variant of NEUROD1 may comprise an amino acid sequence at least 70% identical to SEQ ID NO: 6 or SEQ ID NO: 7. The functional variant of NEUROD1 may comprise an amino acid sequence at least 80% identical to SEQ ID NO: 6 or SEQ ID NO: 7. The functional variant of NEUROD1 may comprise an amino acid sequence at least 85% identical to SEQ ID NO: 6 or SEQ ID NO: 7. The functional variant of NEUROD1 may comprise an amino acid sequence at least 90% identical to SEQ ID NO: 6 or SEQ ID NO: 7. The functional variant of NEUROD1 may comprise an amino acid sequence at least 95% identical to SEQ ID NO: 6 or SEQ ID NO: 7. The functional variant of NEUROD1 may comprise an amino acid sequence at least 96% identical to SEQ ID NO: 6 or SEQ ID NO: 7. The functional variant of NEUROD1 may comprise an amino acid sequence at least 97% identical to SEQ ID NO: 6 or SEQ ID NO: 7. The functional variant of NEUROD1 may comprise an amino acid sequence at least 98% identical to SEQ ID NO: 6 or SEQ ID NO: 7. The functional variant of NEUROD1 may comprise an amino acid sequence at least 99% identical to SEQ ID NO: 6 or SEQ ID NO: 7. SEQ ID NO: 6 and SEQ ID NO: 7 share 352 identical amino acids out of 357 and thus are at least 98% identical to one another. The nucleic acid sequence may comprise any nucleic acid sequence encoding a functional variant of NEUROD1. Therefore, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 70% identical to SEQ ID NO: 6 or SEQ ID NO: 7. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 90% identical to SEQ ID NO: 6 or SEQ ID NO: 7. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 97% identical to SEQ ID NO: 6 or SEQ ID NO: 7. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 99% identical to SEQ ID NO: 6 or SEQ ID NO: 7.

[0232] The functional variant of NEUROD1 may consist essentially of an amino acid sequence at least 70% identical to SEQ ID NO: 6 or SEQ ID NO: 7. The functional variant of NEUROD1 may consist essentially of any amino acid sequence described elsewhere herein as a sequence that the functional variant of NEUROD1 may comprise.

[0233] The nucleic acid sequence may comprise any nucleic acid sequence encoding NEUROD1. NEUROD1 may comprise an amino acid sequence according to SEQ ID NO: 6 or SEQ ID NO: 7. Therefore, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 6 or SEQ ID NO: 7. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 6. Alternatively, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 7.

[0234] The nucleotide sequence encoding NEUROD1, ora functional variant thereof may comprise a nucleic acid sequence encoding:

[0235] (a) SEQ ID NO: 6,

[0236] (b) SEQ ID NO: 7, (c) an amino acid sequence having at least 70% identity to SEQ ID NO: 6 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 6, or

[0237] (d) an amino acid sequence having at least 70% identity to SEQ ID NO: 7 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 7.

[0238] The nucleotide sequence encoding NEUROD1 , or a functional variant thereof may consist essentially of a nucleic acid sequence encoding:

[0239] (a) SEQ ID NO: 6,

[0240] (b) SEQ ID NO: 7,

[0241] (c) an amino acid sequence having at least 70% identity to SEQ ID NO: 6 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 6, or

[0242] (d) an amino acid sequence having at least 70% identity to SEQ ID NO: 7 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 7.

[0243] The nucleotide sequence encoding NEUROD1, or a functional variant thereof may consist essentially of any nucleic acid sequence described elsewhere herein as a sequence that may encode NEUROD1 or functional variant of NEUROD1.

[0244] The nucleotide sequence encoding NEUROD1, ora functional variant thereof may comprise a nucleic acid sequence encoding:

[0245] (a) SEQ ID NO: 6,

[0246] (b) SEQ ID NO: 7,

[0247] (c) an amino acid sequence having at least 98% identity to SEQ ID NO: 6 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 6, or

[0248] (d) an amino acid sequence having at least 98% identity to SEQ ID NO: 7 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 7.

[0249] The nucleotide sequence encoding NEUROD1 , or a functional variant thereof may comprise:

[0250] (a) SEQ ID NO: 8,

[0251] (b) SEQ ID NO: 9,

[0252] (c) SEQ ID NO: 10, or

[0253] (d) a nucleotide sequence having at least 60% identity to SEQ ID NO: 8 or SEQ ID NO: 10, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 6, or

[0254] (e) a nucleotide sequence having at least 60% identity to SEQ ID NO: 9, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 7.

[0255] The nucleotide sequence encoding NEUROD1 or a functional variant thereof may comprise a nucleic acid sequence having at least 60% identity to SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10. The nucleotide sequence having at least 60% identity to SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10 may have at least 70%, 75%, 80%, 85%, 90% or 95% identity to SEQ ID NO: 8, SEQ ID NO: 9, or SEQ ID NO: 10, respectively. SEQ ID NO: 8 and SEQ ID NO: 9 share 975 identical nucleotides out of 1074 and thus are at least 90% identical to one another. SEQ ID NO: 8 and SEQ ID NO: 10 share 653 identical nucleotides out of 1071 and therefore have at least 60% sequence identity to each other and encode the same protein sequence. The non- identical nucleotides may represent silent mutations (i.e. mutations which do not alter the sequence of the encoded amino acid). The non-identical nucleotides may alter the amino acid sequence of the encoded amino acid, for example by one or more conservative amino acid mutation. The non-identical nucleotides may alter the amino acid sequence of the encoded amino acid by up to 20, up to 15, up to 10, up to 9, up to 8, up to 7, up to 6, up to 5, up to 4, up to 3, up to 2 or up to 1 conservative amino acid mutation.

[0256] The nucleotide sequence encoding NEUROD1 , or a functional variant thereof may comprise:

[0257] (a) SEQ ID NO: 8,

[0258] (b) SEQ ID NO: 9,

[0259] (c) SEQ ID NO: 10, or

[0260] (d) a nucleotide sequence having at least 60% identity to SEQ ID NO: 8 or SEQ ID NO: 10, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 6, or

[0261] (e) a nucleotide sequence having at least 60% identity to SEQ ID NO: 9, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 7.

[0262] The nucleotide sequence encoding NEUROD1 , or a functional variant thereof may comprise:

[0263] (a) SEQ ID NO: 8,

[0264] (b) SEQ ID NO: 9,

[0265] (c) SEQ ID NO: 10, or

[0266] (d) a nucleotide sequence having at least 90% identity to SEQ ID NO: 8 or SEQ ID NO: 10, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 6, or

[0267] (e) a nucleotide sequence having at least 90% identity to SEQ ID NO: 9, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 7.

[0268] The nucleic acid sequence may encode NEUROD1. The nucleotide sequence encoding NEUROD1 may comprise:

[0269] (a) SEQ ID NO: 8,

[0270] (b) SEQ ID NO: 9, or

[0271] (c) SEQ ID NO: 10.

[0272] In an alternative statement of the first aspect, the nucleic acid molecule may encode at least two transcription factors, or functional variants thereof, wherein one transcription factor is NEUROD1 and wherein the at least two transcription factors further comprise at least one transcription factor selected from the group consisting of OTX2, FOXJ1 and CRX.

[0273] In an alternative statement, the transcription factors may comprise:

[0274] (a) NEUROD1 and OTX2;

[0275] (b) NEUROD1 and FOXJ1; or

[0276] (c) NEUROD1 and CRX.

[0277] In an alternative statement, the transcription factors may comprise:

[0278] (a) NEUROD1, FOXJ1 and OTX2; (b) NEUR0D1, F0XJ1 and CRX;

[0279] (c) NEUR0D1, F0XJ1, CRX and 0TX2; or

[0280] (d) NEUROD1, FOXJ1 and one or more further transcription factor.

[0281] In any of the alternative statements comprising NEUROD1, the at least two transcription factors may further comprise one or more further transcription factor, such as one or more proneural bHLH transcription factor as described herein.

[0282] As used herein, “OTX2” refers to Homeobox protein OTX2. In humans it is encoded by the 0TX2 gene, also known as orthodenticle homeobox 2, Orthodenticle Homolog 2, Homeobox Protein OTX2, Orthodenticle Homolog 2 (Drosophila) 2, MCOPS5, and CPHD6. The mouse ortholog Otx2 is also known as orthodenticle homeobox 2. In humans, the Ensembl gene ID is ENSG00000165588, such as ENSG00000165588.16. An example of a transcript is the Ensembl transcript ID ENST00000339475, such as ENST00000339475.9 and the UniProt ID is P32243-1, such as P32243-1 v1; codon-optimised and alternatively spliced transcript variants are encompassed. In mice, an Ensembl gene ID is ENSMUSG00000021848. An example of a transcript is the Ensembl transcript ID ENSMUST00000119070, such as ENSMUST00000119070.8 and the UniProt ID is Q8R0B5, such as Q8R0B5 v1 ; codon-optimised and alternatively spliced transcript variants are encompassed.

[0283] OTX2 may refer to the human sequence having the following amino acid sequence, identified as SEQ ID NO: 11

[0284] SEQ ID NO: 11

[0285] MMSYLKQPPYAVNGLSLTTSGMDLLHPSVGYPGPWASCPAATPRKQRRERTTFTRAQLDVLEALFAKTRYPDIFMREEVALKIN LPESRVQVWFKNRRAKCRQQQQQQQNGGQNKVRPAKKKTSPAREVSSESGTSGQFTPPSSTSVPTIASSSAPVSIWSPASIS PLSDPLSTSSSCMQRSYPMTYTQASGYSQGYAGSTSYFGGMDCGSYLTPMHHQLPGPGATLSPMGTNAVTSHLNQSPASLS TQGYGASSLGFNSTTDCLDYKDQTASWKLNFNADCLDYKDQTSSWKFQVL

[0286] OTX2 may refer to the mouse sequence having the following amino acid sequence, identified as SEQ ID NO: 12

[0287] SEQ ID NO: 12

[0288] MMSYLKQPPYAVNGLSLTTSGMDLLHPSVGYPGPWASCPAATPRKQRRERTTFTRAQLDVLEALFAKTRYPDIFMREEVALKIN LPESRVQVWFKNRRAKCRQQQQQQQNGGQNKVRPAKKKSSPAREVSSESGTSGQFSPPSSTSVPTIASSSAPVSIWSPASIS PLSDPLSTSSSCMQRSYPMTYTQASGYSQGYAGSTSYFGGMDCGSYLTPMHHQLPGPGATLSPMGTNAVTSHLNQSPASLS TQGYGASSLGFNSTTDCLDYKDQTASWKLNFNADCLDYKDQTSSWKFQVL

[0289] OTX2 may be encoded by the following human coding sequence, identified as SEQ ID NO: 13

[0290] SEQ ID NO: 13

[0291] ATGATGTCTTATCTTAAGCAACCGCCTTACGCAGTCAATGGGCTGAGTCTGACCACTTCGGGTATGGACTTGCTGCACCCC TCCGTGGGCTACCCGGGGCCCTGGGCTTCTTGTCCCGCAGCCACCCCCCGGAAACAGCGCCGGGAGAGGACGACGTT CACTCGGGCGCAGCTAGATGTGCTGGAAGCACTGTTTGCCAAGACCCGGTACCCAGACATCTTCATGCGAGAGGAGGTG GCACTGAAAATCAACTTGCCCGAGTCGAGGGTGCAGGTATGGTTTAAGAATCGAAGAGCTAAGTGCCGCCAACAACAGCA ACAACAGCAGAATGGAGGTCAAAACAAAGTGAGACCTGCCAAAAAGAAGACATCTCCAGCTCGGGAAGTGAGTTCAGAG AGTGGAACAAGTGGCCAATTCACTCCCCCCTCTAGCACCTCAGTCCCGACCATTGCCAGCAGCAGTGCTCCTGTGTCTAT

[0292] CTGGAGCCCAGCTTCCATCTCCCCACTGTCAGATCCCTTGTCCACCTCCTCTTCCTGCATGCAGAGGTCCTATCCCATGA

[0293] CCTATACTCAGGCTTCAGGTTATAGTCAAGGATATGCTGGCTCAACTTCCTACTTTGGGGGCATGGACTGTGGATCATATTT

[0294] GACCCCTATGCATCACCAGCTTCCCGGACCAGGGGCCACACTCAGTCCCATGGGTACCAATGCAGTCACCAGCCATCTCA

[0295] ATCAGTCCCCAGCTTCTCTTTCCACCCAGGGATATGGAGCTTCAAGCTTGGGTTTTAACTCAACCACTGATTGCTTGGATTA

[0296] TAAGGACCAAACTGCCTCCTGGAAGCTTAACTTCAATGCTGACTGCTTGGATTATAAAGATCAGACATCCTCGTGGAAATTC CAGGTTTTGTGA

[0297] 0TX2 may be encoded by the following mouse coding sequence, identified as SEQ ID NO: 14

[0298] SEQ ID NO: 14

[0299] ATGATGTCTTATCTAAAGCAACCGCCTTACGCAGTCAATGGGCTGAGTCTGACCACTTCGGGTATGGACTTGCTGCATCCC

[0300] TCCGTGGGCTACCCCGGGCCCTGGGCTTCTTGTCCTGCAGCCACCCCCCGGAAACAGCGAAGGGAGAGGACGACATTT

[0301] ACTAGGGCACAGCTCGACGTTCTGGAAGCTCTGTTTGCCAAGACCCGGTACCCAGACATCTTCATGAGGGAAGAGGTGG

[0302] CACTGAAAATCAACTTGCCAGAATCCAGGGTGCAGGTATGGTTTAAGAATCGAAGAGCTAAGTGCCGCCAACAGCAGCAG

[0303] CAGCAGCAGAATGGAGGTCAGAACAAAGTGAGGCCTGCCAAGAAGAAGAGCTCTCCAGCTCGGGAAGTGAGTTCAGAG

[0304] AGTGGAACAAGTGGCCAGTTCAGTCCCCCCTCTAGTACCTCAGTCCCAACCATTGCCAGCAGCAGTGCTCCAGTGTCTAT

[0305] CTGGAGCCCAGCGTCCATCTCCCCACTGTCTGACCCCTTGTCCACTTCCTCCTCCTGCATGCAGAGGTCCTATCCCATGA

[0306] CCTATACTCAGGCTTCAGGTTATAGTCAAGGCTATGCTGGCTCAACTTCCTACTTTGGGGGCATGGACTGTGGATCTTATTT

[0307] GACCCCTATGCATCACCAGCTTCCTGGACCAGGGGCCACACTCAGTCCCATGGGTACCAATGCTGTTACCAGCCATCTCA

[0308] ATCAGTCCCCAGCTTCTCTTTCCACCCAGGGATATGGAGCTTCAAGCTTGGGTTTTAACTCAACCACTGATTGCTTGGATTA

[0309] TAAGGACCAAACTGCCTCTTGGAAGCTTAACTTCAATGCTGACTGCTTGGATTATAAAGATCAGACGTCCTCATGGAAATTC CAGGTTTTGTGA

[0310] OTX2 may be encoded by the following codon optimised human sequence, identified as SEQ ID NO: 15

[0311] SEQ ID NO: 15

[0312] ATGATGTCCTACCTGAAACAGCCACCATATGCCGTAAACGGCTTGTCTTTGACTACAAGCGGAATGGATCTGCTTCATCCTA

[0313] GCGTTGGTTATCCTGGCCCTTGGGCAAGCTGCCCTGCCGCTACACCAAGAAAGCAAAGACGCGAACGGACCACCTTTAC

[0314] ACGCGCACAACTGGACGTTCTTGAGGCTCTCTTCGCTAAAACACGGTATCCCGATATTTTCATGAGGGAAGAAGTTGCTCT

[0315] CAAGATAAATCTTCCTGAATCAAGAGTACAAGTGTGGTTCAAGAACCGGCGGGCCAAATGTAGGCAGCAGCAACAGCAGC

[0316] AACAAAACGGCGGGCAGAATAAGGTACGCCCAGCGAAGAAGAAAACCAGCCCCGCACGCGAGGTCAGCTCTGAAAGCG

[0317] GTACTTCAGGGCAGTTTACACCCCCGAGTTCAACTTCTGTGCCCACTATCGCTTCAAGTTCAGCCCCCGTAAGTATTTGGT

[0318] CTCCCGCATCAATTAGCCCCTTGTCCGACCCGCTTTCTACGAGCAGCTCTTGTATGCAACGGAGCTACCCGATGACGTACA

[0319] CACAAGCATCTGGGTACAGCCAGGGCTACGCCGGAAGCACCAGTTATTTCGGCGGGATGGATTGCGGGAGCTACCTTAC

[0320] ACCCATGCACCATCAACTGCCGGGCCCCGGCGCTACTCTGAGCCCGATGGGCACAAACGCGGTGACATCTCATCTTAAC

[0321] CAAAGCCCGGCCAGCTTGAGCACGCAAGGGTACGGTGCCTCTTCCCTGGGATTCAATTCTACGACAGACTGTCTCGACTA

[0322] CAAAGATCAGACCGCTTCATGGAAACTGAATTTTAACGCCGATTGTCTTGACTACAAGGACCAAACCTCTTCCTGGAAGTT TCAAGTGCTGTAA The functional variant of OTX2 may comprise an amino acid sequence at least 70% identical to SEQ ID NO: 11 or SEQ ID NO: 12. The functional variant of OTX2 may comprise an amino acid sequence at least 80% identical to SEQ ID NO: 11 or SEQ ID NO: 12. The functional variant of OTX2 may comprise an amino acid sequence at least 85% identical to SEQ ID NO: 11 or SEQ ID NO: 12. The functional variant of OTX2 may comprise an amino acid sequence at least 90% identical to SEQ ID NO: 11 or SEQ ID NO: 12. The functional variant of OTX2 may comprise an amino acid sequence at least 95% identical to SEQ ID NO: 11 or SEQ ID NO: 12. The functional variant of OTX2 may comprise an amino acid sequence at least 96% identical to SEQ ID NO: 11 or SEQ ID NO: 12. The functional variant of OTX2 may comprise an amino acid sequence at least 97% identical to SEQ ID NO: 11 or SEQ ID NO: 12. The functional variant of OTX2 may comprise an amino acid sequence at least 98% identical to SEQ ID NO: 11 or SEQ ID NO: 12. The functional variant of OTX2 may comprise an amino acid sequence at least 99% identical to SEQ ID NO: 11 or SEQ ID NO: 12. SEQ ID NO: 11 and SEQ ID NO: 12 share 295 identical amino acids out of 297 and thus are at least 99% identical to one another. The nucleic acid sequence may comprise any nucleic acid sequence encoding a functional variant of OTX2. Therefore, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 70% identical to SEQ ID NO: 11 or SEQ ID NO: 12. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 90% identical to SEQ ID NO: 11 or SEQ ID NO: 12. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 99% identical to SEQ ID NO: 11 or SEQ ID NO: 12. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 99.5% identical to SEQ ID NO: 11 or SEQ ID NO: 12.

[0323] The functional variant of OTX2 may consist essentially of an amino acid sequence at least 70% identical to SEQ ID NO: 11 or SEQ ID NO: 12. The functional variant of OTX2 may consist essentially of any amino acid sequence described elsewhere herein as a sequence that the functional variant of OTX2 may comprise.

[0324] The nucleic acid sequence may comprise any nucleic acid sequence encoding OTX2. OTX2 may comprise an amino acid sequence according to SEQ ID NO: 11 or SEQ ID NO: 12. Therefore, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 11 or SEQ ID NO: 12. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 11. Alternatively, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 12.

[0325] The nucleotide sequence encoding OTX2, or a functional variant thereof may comprise a nucleic acid sequence encoding:

[0326] (a) SEQ ID NO: 11,

[0327] (b) SEQ ID NO: 12,

[0328] (c) an amino acid sequence having at least 70% identity to SEQ ID NO: 11 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 11, or

[0329] (d) an amino acid sequence having at least 70% identity to SEQ ID NO: 12 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 12.

[0330] The nucleotide sequence encoding OTX2, or a functional variant thereof may consist essentially of a nucleic acid sequence encoding:

[0331] (a) SEQ ID NO: 11,

[0332] (b) SEQ ID NO: 12, (c) an amino acid sequence having at least 70% identity to SEQ ID NO: 11 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 11, or

[0333] (d) an amino acid sequence having at least 70% identity to SEQ ID NO: 12 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 12.

[0334] The nucleotide sequence encoding OTX2, or a functional variant thereof may consist essentially of any nucleic acid sequence described elsewhere herein as a sequence that may encode OTX2 or functional variant of OTX2.

[0335] The nucleotide sequence encoding OTX2, or a functional variant thereof may comprise a nucleic acid sequence encoding:

[0336] (a) SEQ ID NO: 11,

[0337] (b) SEQ ID NO: 12,

[0338] (c) an amino acid sequence having at least 99% identity to SEQ ID NO: 11 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 11, or

[0339] (d) an amino acid sequence having at least 99% identity to SEQ ID NO: 12 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 12.

[0340] The nucleotide sequence encoding OTX2, or a functional variant thereof may comprise:

[0341] (a) SEQ ID NO: 13,

[0342] (b) SEQ ID NO: 14,

[0343] (c) SEQ ID NO: 15, or

[0344] (d) a nucleotide sequence having at least 60% identity to SEQ ID NO: 13 or SEQ ID NO: 15, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by S EQ I D NO: 11 , or

[0345] (e) a nucleotide sequence having at least 60% identity to SEQ ID NO: 14, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 12.

[0346] The nucleotide sequence encoding OTX2 or a functional variant thereof may comprise a nucleic acid sequence having at least 60% identity to SEQ ID NO: 13, SEQ ID NO: 14, or SEQ ID NO: 15. The nucleotide sequence having at least 60% identity to SEQ ID NO: 13, SEQ ID NO: 14, or SEQ ID NO: 15 may have at least 70%, 75%, 80%, 85%, 90% or 95% identity to SEQ ID NO: 13, SEQ ID NO: 14, or SEQ ID NO: 15, respectively. SEQ ID NO: 13 and SEQ ID NO: 14 share 848 identical nucleotides out of 894 and thus are at least 94% identical to one another. S EQ I D NO: 13 and S EQ I D NO: 15 share 566 identical nucleotides out of 894 and therefore have at least 63% sequence identity to each other and encode the same protein sequence. The nonidentical nucleotides may represent silent mutations (i.e. mutations which do not alter the sequence of the encoded amino acid). The non-identical nucleotides may alter the amino acid sequence of the encoded amino acid, for example by one or more conservative amino acid mutation. The non-identical nucleotides may alter the amino acid sequence of the encoded amino acid by up to 20, up to 15, up to 10, up to 9, up to 8, up to 7, up to 6, up to 5, up to 4, up to 3, up to 2 or up to 1 conservative amino acid mutation.

[0347] The nucleotide sequence encoding OTX2, or a functional variant thereof may comprise:

[0348] (a) SEQ ID NO: 13,

[0349] (b) SEQ ID NO: 14, (c) SEQ ID NO: 15, or

[0350] (d) a nucleotide sequence having at least 63% identity to SEQ ID NO: 13 or SEQ ID NO: 15, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 11, or

[0351] (e) a nucleotide sequence having at least 63% identity to SEQ ID NO: 14, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 12.

[0352] The nucleotide sequence encoding OTX2, or a functional variant thereof may comprise:

[0353] (a) SEQ ID NO: 13,

[0354] (b) SEQ ID NO: 14,

[0355] (c) SEQ ID NO: 15, or

[0356] (d) a nucleotide sequence having at least 94% identity to SEQ ID NO: 13 or SEQ ID NO: 15, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by S EQ I D NO: 11 , or

[0357] (e) a nucleotide sequence having at least 94% identity to SEQ ID NO: 14, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 12.

[0358] The nucleic acid sequence may encode OTX2. The nucleotide sequence encoding OTX2 may comprise:

[0359] (a) SEQ ID NO: 13,

[0360] (b) SEQ ID NO: 14, or

[0361] (c) SEQ ID NO: 15.

[0362] In an alternative statement of the first aspect, the nucleic acid molecule may encode at least two transcription factors, or functional variants thereof, wherein one transcription factor is OTX2 and wherein the at least two transcription factors further comprise at least one transcription factor selected from the group consisting of NEUROD1, FOXJ1 and CRX.

[0363] In an alternative statement, the transcription factors may comprise:

[0364] (a) OTX2 and NEUROD1;

[0365] (b) OTX2 and FOXJ1; or

[0366] (c) OTX2 and CRX.

[0367] In an alternative statement, the transcription factors may comprise:

[0368] (a) OTX2, CRX and FOXJ1;

[0369] (b) OTX2, FOXJ1 and NEUROD1;

[0370] (c) OTX2, FOXJ1 and RAX2;

[0371] (d) OTX2, FOXJ1, NEUROD1 and CRX; or

[0372] (e) OTX2, FOXJ1 and one or more further transcription factor.

[0373] In any of the alternative statements comprising OTX2, the at least two transcription factors may further comprise one or more further transcription factor, such as one or more proneural bHLH transcription factor as described herein. As used herein, “CRX” refers to Cone-rod homeobox protein. In humans it is encoded by the CRX gene, also known as CORD2, CRD, LCA7 and OTX3. The mouse ortholog Crx is also known as Cone-rod homeobox protein. In humans, the Ensembl gene ID is ENSG00000105392, such as ENSG00000105392.16. An example of a transcript is the Ensembl transcript ID ENST00000221996, such as ENST00000221996.12 and the UniProt ID is 043186, such as 043186 v1 ; codon-optimised and alternatively spliced transcript variants are encompassed. In mice, an Ensembl gene ID is ENSMUSG00000041578. An example of a transcript is the Ensembl transcript ID ENSMUST00000044434, such as ENSMUST00000044434.13 and the UniProt ID is 054751 , such as 054751 v1 ; codon-optimised and alternatively spliced transcript variants are encompassed.

[0374] CRX may refer to the human sequence having the following amino acid sequence, identified as SEQ ID NO: 16

[0375] SEQ ID NO: 16

[0376] MMAYMNPGPHYSVNALALSGPSVDLMHQAVPYPSAPRKQRRERTTFTRSQLEELEALFAKTQYPDVYAREEVALKINLPESRV QVWFKNRRAKCRQQRQQQKQQQQPPGGQAKARPAKRKAGTSPRPSTDVCPDPLGISDSYSPPLPGPSGSPTTAVATVSIWS PASESPLPEAQRAGLVASGPSLTSAPYAMTYAPASAFCSSPSAYGSPSSYFSGLDPYLSPMVPQLGGPALSPLSGPSVGPSLA QSPTSLSGQSYGAYSPVDSLEFKDPTGTWKFTYNPMDPLDYKDQSAWKFQIL

[0377] CRX may refer to the mouse sequence having the following amino acid sequence, identified as SEQ ID NO: 17

[0378] SEQ ID NO: 17

[0379] MMAYMNPGPHYSVNALALSGPNVDLMHQAVPYSSAPRKQRRERTTFTRSQLEELEALFAKTQYPDVYAREEVALKINLPESRV QVWFKNRRAKCRQQRQQQKQQQQPPGAQTKARPAKRKAGTSPRPSTDVCTDPLGISDSYSPSLPGPSGSPTTAVATVSIWS PASEAPLPEAQRAGLVASGPSLTSAPYAMTYAPASAFCSSPSAYASPSSYFSGLDPYLSPMVPQLGGPALSPLSGPSVGPSLAQ SPTSLSGQSYSTYSPVDSLEFKDPTGTWKFTYNPMDPLDYKDQSAWKFQIL

[0380] CRX may be encoded by the following human coding sequence, identified as SEQ ID NO: 18

[0381] SEQ ID NO: 18

[0382] ATGATGGCGTATATGAACCCGGGGCCCCACTATTCTGTCAACGCCTTGGCCCTAAGTGGCCCCAGTGTGGATCTGATGCA CCAGGCTGTGCCCTACCCAAGCGCCCCCAGGAAGCAGCGGCGGGAGCGCACCACCTTCACCCGGAGCCAACTGGAGG AGCTGGAGGCACTGTTTGCCAAGACCCAGTACCCAGACGTCTATGCCCGTGAGGAGGTGGCTCTGAAGATCAATCTGCC TGAGTCCAGGGTTCAGGTTTGGTTCAAGAACCGGAGGGCTAAATGCAGGCAGCAGCGACAGCAGCAGAAACAGCAGCA GCAGCCCCCAGGGGGCCAGGCCAAGGCCCGGCCTGCCAAGAGGAAGGCGGGCACGTCCCCAAGACCCTCCACAGATG TGTGTCCAGACCCTCTGGGCATCTCAGATTCCTACAGTCCCCCTCTGCCCGGCCCCTCAGGCTCCCCAACCACGGCAGT GGCCACTGTGTCCATCTGGAGCCCAGCCTCAGAGTCCCCTTTGCCTGAGGCGCAGCGGGCTGGGCTGGTGGCCTCAGG GCCGTCTCTGACCTCCGCCCCCTATGCCATGACCTACGCCCCGGCCTCCGCTTTCTGCTCTTCCCCCTCCGCCTATGGGT CTCCGAGCTCCTATTTCAGCGGCCTAGACCCCTACCTTTCTCCCATGGTGCCCCAGCTAGGGGGCCCGGCTCTTAGCCC CCTCTCTGGCCCCTCCGTGGGACCTTCCCTGGCCCAGTCCCCCACCTCCCTATCAGGCCAGAGCTATGGCGCCTACAGC CCCGTGGATAGCTTGGAATTCAAGGACCCCACGGGCACCTGGAAATTCACCTACAATCCCATGGACCCTCTGGACTACAA GGATCAGAGTGCCTGGAAGTTTCAGATCTTGTAG CRX may be encoded by the following mouse coding sequence, identified as SEQ ID NO: 19

[0383] SEQ ID NO: 19

[0384] ATGATGGCATATATGAACCCGGGGCCTCACTATTCAGTCAATGCCTTGGCTCTGAGTGGCCCCAATGTGGACCTGATGCAC CAGGCTGTCCCATACTCAAGTGCCCCTAGGAAGCAGCGGCGGGAGCGGACCACATTCACCAGGAGCCAGCTGGAGGAG CTGGAGGCCCTGTTTGCCAAGACCCAGTACCCGGATGTGTATGCACGTGAGGAGGTTGCTCTTAAGATCAATCTGCCTGA GTCCAGGGTCCAGGTCTGGTTCAAGAATCGTAGGGCGAAATGCAGACAGCAGCGACAGCAGCAGAAACAGCAACAGCA GCCCCCGGGGGCACAGACCAAGGCTCGTCCTGCGAAGAGGAAGGCAGGGACATCCCCGAGACCCTCTACAGATGTTTG TACAGATCCTTTGGGCATCTCAGATTCTTACAGCCCATCTCTGCCTGGCCCCTCAGGTTCACCTACCACAGCAGTGGCCA CCGTGTCCATTTGGAGTCCAGCCTCAGAGGCTCCTTTGCCTGAGGCCCAGAGAGCCGGCCTAGTGGCTTCTGGGCCCTC TCTCACCTCAGCCCCTTATGCCATGACCTATGCCCCGGCTTCTGCTTTCTGTTCTTCCCCTTCAGCTTATGCATCTCCAAGT

[0385] TCCTATTTCAGTGGGTTGGATCCCTACCTTTCGCCCATGGTGCCCCAACTTGGGGGTCCGGCTCTCAGCCCCCTCTCAGG CCCCTCTGTGGGGCCATCCCTGGCCCAGTCCCCCACCTCCTTGTCAGGCCAGAGCTATAGCACCTACAGTCCTGTGGAC AGCCTGGAATTCAAGGACCCCACAGGCACCTGGAAATTTACCTACAATCCCATGGACCCTCTGGACTACAAAGATCAGAGT GCCTGGAAGTTTCAGATCTTGTAG

[0386] CRX may be encoded by the following codon optimised human sequence, identified as SEQ ID NO: 20

[0387] SEQ ID NO: 20

[0388] ATGATGTCCTACCTGAAACAGCCACCATATGCCGTAAACGGCTTGTCTTTGACTACAAGCGGAATGGATCTGCTTCATCCTA GCGTTGGTTATCCTGGCCCTTGGGCAAGCTGCCCTGCCGCTACACCAAGAAAGCAAAGACGCGAACGGACCACCTTTAC ACGCGCACAACTGGACGTTCTTGAGGCTCTCTTCGCTAAAACACGGTATCCCGATATTTTCATGAGGGAAGAAGTTGCTCT

[0389] CAAGATAAATCTTCCTGAATCAAGAGTACAAGTGTGGTTCAAGAACCGGCGGGCCAAATGTAGGCAGCAGCAACAGCAGC AACAAAACGGCGGGCAGAATAAGGTACGCCCAGCGAAGAAGAAAACCAGCCCCGCACGCGAGGTCAGCTCTGAAAGCG GTACTTCAGGGCAGTTTACACCCCCGAGTTCAACTTCTGTGCCCACTATCGCTTCAAGTTCAGCCCCCGTAAGTATTTGGT CTCCCGCATCAATTAGCCCCTTGTCCGACCCGCTTTCTACGAGCAGCTCTTGTATGCAACGGAGCTACCCGATGACGTACA CACAAGCATCTGGGTACAGCCAGGGCTACGCCGGAAGCACCAGTTATTTCGGCGGGATGGATTGCGGGAGCTACCTTAC ACCCATGCACCATCAACTGCCGGGCCCCGGCGCTACTCTGAGCCCGATGGGCACAAACGCGGTGACATCTCATCTTAAC CAAAGCCCGGCCAGCTTGAGCACGCAAGGGTACGGTGCCTCTTCCCTGGGATTCAATTCTACGACAGACTGTCTCGACTA CAAAGATCAGACCGCTTCATGGAAACTGAATTTTAACGCCGATTGTCTTGACTACAAGGACCAAACCTCTTCCTGGAAGTT

[0390] TCAAGTGCTGTAA

[0391] The functional variant of CRX may comprise an amino acid sequence at least 70% identical to SEQ ID NO: 16 or SEQ ID NO: 17. The functional variant of CRX may comprise an amino acid sequence at least 80% identical to SEQ ID NO: 16 or SEQ ID NO: 17. The functional variant of CRX may comprise an amino acid sequence at least 85% identical to SEQ ID NO: 16 or SEQ ID NO: 17. The functional variant of CRX may comprise an amino acid sequence at least 90% identical to SEQ ID NO: 16 or SEQ ID NO: 17. The functional variant of CRX may comprise an amino acid sequence at least 95% identical to SEQ ID NO: 16 or SEQ ID NO: 17. The functional variant of CRX may comprise an amino acid sequence at least 96% identical to SEQ ID NO: 16 or SEQ ID NO: 17. The functional variant of CRX may comprise an amino acid sequence at least 97% identical to SEQ ID NO: 16 or SEQ ID NO: 17. The functional variant of CRX may comprise an amino acid sequence at least 98% identical to SEQ ID NO: 16 or SEQ ID NO: 17. The functional variant of CRX may comprise an amino acid sequence at least 99% identical to SEQ ID NO: 16 or SEQ ID NO: 17. SEQ ID NO: 16 and SEQ ID NO: 17 share 287 identical amino acids out of 299 and thus are at least 96% identical to one another. The nucleic acid sequence may comprise any nucleic acid sequence encoding a functional variant of CRX. Therefore, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 70% identical to SEQ ID NO: 16 or SEQ ID NO: 17. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 90% identical to SEQ ID NO: 16 or SEQ ID NO: 17. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 96% identical to SEQ ID NO: 16 or SEQ ID NO: 17. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 97% identical to SEQ ID NO: 16 or SEQ ID NO: 17.

[0392] The functional variant of CRX may consist essentially of an amino acid sequence at least 70% identical to SEQ ID NO: 16 or SEQ ID NO: 17. The functional variant of CRX may consist essentially of any amino acid sequence described elsewhere herein as a sequence that the functional variant of CRX may comprise.

[0393] The nucleic acid sequence may comprise any nucleic acid sequence encoding CRX. CRX may comprise an amino acid sequence according to SEQ ID NO: 16 or SEQ ID NO: 17. Therefore, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 16 or SEQ ID NO: 17. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 16. Alternatively, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 17.

[0394] The nucleotide sequence encoding CRX, or a functional variant thereof may comprise a nucleic acid sequence encoding:

[0395] (a) SEQ ID NO: 16,

[0396] (b) SEQ ID NO: 17,

[0397] (c) an amino acid sequence having at least 70% identity to SEQ ID NO: 16 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 16, or

[0398] (d) an amino acid sequence having at least 70% identity to SEQ ID NO: 17 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 17.

[0399] The nucleotide sequence encoding CRX, or a functional variant thereof may consist essentially of a nucleic acid sequence encoding:

[0400] (a) SEQ ID NO: 16,

[0401] (b) SEQ ID NO: 17,

[0402] (c) an amino acid sequence having at least 70% identity to SEQ ID NO: 16 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 16, or

[0403] (d) an amino acid sequence having at least 70% identity to SEQ ID NO: 17 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 17.

[0404] The nucleotide sequence encoding CRX, or a functional variant thereof may consist essentially of any nucleic acid sequence described elsewhere herein as a sequence that may encode CRX or functional variant of CRX. The nucleotide sequence encoding CRX, or a functional variant thereof may comprise a nucleic acid sequence encoding:

[0405] (a) SEQ ID NO: 16,

[0406] (b) SEQ ID NO: 17,

[0407] (c) an amino acid sequence having at least 96% identity to SEQ ID NO: 16 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 16, or

[0408] (d) an amino acid sequence having at least 96% identity to SEQ ID NO: 17 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 17.

[0409] The nucleotide sequence encoding CRX, or a functional variant thereof may comprise:

[0410] (a) SEQ ID NO: 18,

[0411] (b) SEQ ID NO: 19,

[0412] (c) SEQ ID NO: 20, or

[0413] (d) a nucleotide sequence having at least 60% identity to SEQ ID NO: 18 or SEQ ID NO: 20, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by S EQ I D NO: 16, or

[0414] (e) a nucleotide sequence having at least 60% identity to SEQ ID NO: 19, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 17.

[0415] The nucleotide sequence encoding CRX or a functional variant thereof may comprise a nucleic acid sequence having at least 60% identity to SEQ ID NO: 18, SEQ ID NO: 19, or SEQ ID NO: 20. The nucleotide sequence having at least 60% identity to SEQ ID NO: 18, SEQ ID NO: 19, or SEQ ID NO: 20 may have at least 70%, 75%, 80%, 85%, 90% or 95% identity to SEQ ID NO: 18, SEQ ID NO: 19, or SEQ ID NO: 20, respectively. SEQ ID NO: 18 and SEQ ID NO: 19 share 793 identical nucleotides out of 900 and thus are at least 88% identical to one another. SEQ ID NO: 18 and SEQ ID NO: 20 share 568 identical nucleotides out of 900 and therefore have at least 63% sequence identity to each other and encode the same protein sequence. The nonidentical nucleotides may represent silent mutations (i.e. mutations which do not alter the sequence of the encoded amino acid). The non-identical nucleotides may alter the amino acid sequence of the encoded amino acid, for example by one or more conservative amino acid mutation. The non-identical nucleotides may alter the amino acid sequence of the encoded amino acid by up to 20, up to 15, up to 10, up to 9, up to 8, up to 7, up to 6, up to 5, up to 4, up to 3, up to 2 or up to 1 conservative amino acid mutation.

[0416] The nucleotide sequence encoding CRX, or a functional variant thereof may comprise:

[0417] (a) SEQ ID NO: 18,

[0418] (b) SEQ ID NO: 19,

[0419] (c) SEQ ID NO: 20, or

[0420] (d) a nucleotide sequence having at least 63% identity to SEQ ID NO: 18 or SEQ ID NO: 20, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by S EQ I D NO: 16, or

[0421] (e) a nucleotide sequence having at least 63% identity to SEQ ID NO: 19, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 17.

[0422] The nucleotide sequence encoding CRX, or a functional variant thereof may comprise:

[0423] (a) SEQ ID NO: 18, (b) SEQ ID NO: 19,

[0424] (c) SEQ ID NO: 20, or

[0425] (d) a nucleotide sequence having at least 88% identity to SEQ ID NO: 18 or SEQ ID NO: 20, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by S EQ I D NO: 16, or

[0426] (e) a nucleotide sequence having at least 88% identity to SEQ ID NO: 19, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 17.

[0427] The nucleic acid sequence may encode CRX. The nucleotide sequence encoding CRX may comprise:

[0428] (a) SEQ ID NO: 18,

[0429] (b) SEQ ID NO: 19, or

[0430] (c) SEQ ID NO: 20.

[0431] In an alternative statement of the first aspect, the nucleic acid molecule may encode at least two transcription factors, or functional variants thereof, wherein one transcription factor is CRX and wherein the at least two transcription factors further comprise at least one transcription factor selected from the group consisting of NEUROD1 , FOXJ1 and OTX2.

[0432] In an alternative statement, the transcription factors may comprise:

[0433] (a) CRX and NEURODI;

[0434] (b) CRX and FOXJ1; or

[0435] (c) CRX and OTX2.

[0436] In an alternative statement, the transcription factors may comprise:

[0437] (a) CRX, OTX2 and FOXJ1;

[0438] (b) CRX, FOXJ1 and NEUROD1;

[0439] (c) CRX, FOXJ1, NEUROD1 AND OTX2; or

[0440] (d) CRX, FOXJ1 and one other transcription factor.

[0441] In any of the alternative statements comprising CRX, the at least two transcription factors may further comprise one or more further transcription factor, such as one or more proneural bHLH transcription factor as described herein.

[0442] As used herein, “NRL” refers to Neural retina-specific leucine zipper protein. In humans it is encoded by the NRL gene, also known as D14S46E, NRL-MAF and RP27. The mouse ortholog Nrl is also known as Neural retina-specific leucine zipper protein. In humans, the Ensembl gene ID is ENSG00000129535, such as ENSG00000129535.12. An example of a transcript is the Ensembl transcript ID ENST00000397002, such as ENST00000397002.6 and the UniProt ID is P54845-1, such as P54845-1 v1; codon-optimised and alternatively spliced transcript variants are encompassed. In mice, an Ensembl gene ID is ENSMUSG00000040632. An example of a transcript is the Ensembl transcript ID ENSMUST00000062232, such as ENSMUST00000062232.15 and the UniProt ID is P54846, such as P54846 v1; codon-optimised and alternatively spliced transcript variants are encompassed.

[0443] NRL may refer to the human sequence having the following amino acid sequence, identified as SEQ ID NO: 21 SEQ ID NO: 21

[0444] MALPPSPLAMEYVNDFDLMKFEVKREPSEGRPGPPTASLGSTPYSSVPPSPTFSEPGMVGATEGTRPGLEELYWLATLQQQL

[0445] GAGEALGLSPEEAMELLQGQGPVPVDGPHGYYPGSPEETGAQHVQLAERFSDAALVSMSVRELNRQLRGCGRDEALRLKQ

[0446] RRRTLKNRGYAQACRSKRLQQRRGLEAERARLAAQLDALRAEVARLARERDLYKARCDRLTSSGPGSGDPSHLFL

[0447] NRL may refer to the mouse sequence having the following amino acid sequence, identified as SEQ ID NO: 22

[0448] SEQ ID NO: 22

[0449] MAFPPSPLAMEYVNDFDLMKFEIKREPSEGRSGVPTASLGSTPYSSVPPSPTFSEPGMVGGGEAPRPGLEELYWLATLQQQL

[0450] GSDEVLGLSPDEAVELLQNQGPVSMEGPLGYYSGSPGETGAQHVQLPERFSDAALVSMSVRELNRQLRGCGRDEALRLKQR RRTLKNRGYAQACRSKRLQQRRGLEAERARLAAQLDALRAEVARLARERDLYKARCDRLTSGGPGSDDHTHLFL

[0451] NRL may be encoded by the following human coding sequence, identified as SEQ ID NO: 23

[0452] SEQ ID NO: 23

[0453] ATGGCCCTGCCCCCCAGCCCCCTGGCCATGGAATATGTCAATGACTTTGACTTGATGAAGTTTGAGGTAAAGCGGGAACC

[0454] CTCTGAGGGCCGACCTGGCCCCCCTACAGCCTCACTGGGCTCCACACCTTACAGCTCAGTGCCTCCTTCACCCACCTTC

[0455] AGTGAACCAGGCATGGTGGGGGCAACCGAGGGCACCCGGCCAGGCCTGGAGGAGCTGTACTGGCTGGCTACCCTGCA

[0456] GCAGCAGCTGGGGGCTGGGGAGGCATTGGGGCTGAGTCCTGAAGAGGCCATGGAGCTGCTGCAGGGTCAGGGCCCAG

[0457] TCCCTGTTGATGGGCCCCATGGCTACTACCCAGGGAGCCCAGAGGAGACAGGAGCCCAGCACGTCCAGCTGGCAGAGC

[0458] GGTTTTCCGACGCGGCGCTGGTCTCGATGTCTGTGCGGGAGCTAAACCGGCAGCTGCGGGGCTGCGGGCGCGACGAG

[0459] GCGCTGCGGCTGAAGCAGAGGCGCCGCACGCTGAAGAACCGCGGCTACGCGCAGGCCTGTCGCTCCAAGCGGCTGCA

[0460] GCAGCGGCGCGGGCTGGAGGCCGAGCGCGCCCGCCTGGCCGCCCAGCTGGACGCGCTGCGGGCCGAGGTGGCCCG

[0461] CCTGGCCCGGGAGCGCGATCTCTACAAGGCTCGCTGTGACCGGCTAACCTCGAGCGGCCCCGGGTCCGGGGACCCCT CCCACCTCTTCCTCTGA

[0462] NRL may be encoded by the following mouse coding sequence, identified as SEQ ID NO: 24

[0463] SEQ ID NO: 24

[0464] ATGGCTTTCCCTCCCAGTCCCTTGGCTATGGAATATGTTAATGACTTTGATTTGATGAAGTTCGAAATAAAGCGGGAGCCTT

[0465] CTGAGGGCCGATCTGGAGTCCCCACAGCCTCGTTGGGCTCCACACCATACAGCTCGGTGCCTCCTTCACCCACCTTCAG

[0466] TGAGCCAGGCATGGTGGGTGGTGGCGAGGCCCCTAGGCCAGGCCTGGAGGAGCTATATTGGCTGGCCACCCTGCAGCA

[0467] GCAGCTGGGGTCGGATGAGGTTCTCGGGCTGAGTCCCGACGAAGCTGTGGAGCTGCTGCAGAACCAGGGTCCTGTCTC

[0468] TATGGAAGGGCCTCTTGGCTACTATTCAGGGAGCCCGGGAGAGACAGGAGCCCAGCATGTCCAGCTGCCCGAGAGATTT

[0469] TCGGACGCCGCGCTGGTCTCGATGTCTGTGCGCGAGTTGAACCGGCAGCTGCGGGGCTGCGGGCGCGACGAGGCTCT

[0470] GCGGCTGAAGCAGAGGCGCCGCACGCTCAAGAACCGCGGCTACGCTCAGGCTTGTCGCTCCAAGCGGCTGCAACAGC

[0471] GGCGCGGGCTGGAGGCAGAGCGCGCTCGCCTGGCCGCCCAGCTGGATGCCCTGCGGGCCGAGGTGGCACGCCTGGC

[0472] TCGCGAGCGCGACCTCTATAAGGCCCGCTGTGACCGGCTGACCTCCGGCGGCCCTGGGTCCGACGACCACACACACCT CTTCCTCTGA NRL may be encoded by the following codon optimised human sequence, identified as SEQ ID NO: 25

[0473] SEQ ID NO: 25

[0474] ATGGCTTTGCCACCTTCTCCTTTGGCAATGGAGTACGTGAACGATTTCGATCTGATGAAATTCGAAGTGAAAAGAGAGCCG AGCGAAGGTCGTCCAGGGCCACCCACCGCATCCTTGGGATCAACCCCATATTCAAGTGTCCCACCCAGTCCTACATTTTC CGAGCCCGGTATGGTTGGAGCTACTGAAGGAACACGTCCCGGACTCGAAGAACTTTATTGGCTTGCGACGCTCCAACAA CAATTGGGTGCAGGCGAAGCGCTCGGACTCTCTCCCGAGGAAGCAATGGAACTTCTCCAAGGCCAAGGACCCGTACCC GTCGACGGCCCACACGGGTATTATCCGGGCTCCCCCGAAGAAACCGGGGCACAACATGTTCAACTCGCTGAAAGATTCA GCGATGCTGCTCTTGTGAGCATGAGTGTACGAGAACTGAATAGGCAACTTCGCGGATGTGGCAGAGATGAAGCCCTGCG CTTGAAACAACGAAGACGTACTCTCAAGAATAGAGGATATGCACAGGCTTGCAGAAGTAAACGACTTCAACAAAGGCGGG GTCTCGAAGCGGAACGGGCTAGACTCGCTGCTCAACTTGATGCTCTTCGAGCTGAAGTTGCTAGACTCGCGCGTGAAAG GGACCTGTATAAAGCGCGGTGCGATCGCCTGACAAGCTCTGGGCCGGGAAGCGGTGATCCTTCACATCTGTTTCTGTAA

[0475] The functional variant of NRL may comprise an amino acid sequence at least 70% identical to SEQ ID NO: 21 or SEQ ID NO: 22. The functional variant of NRL may comprise an amino acid sequence at least 80% identical to SEQ ID NO: 21 or SEQ ID NO: 22. The functional variant of NRL may comprise an amino acid sequence at least 85% identical to SEQ ID NO: 21 or SEQ ID NO: 22. The functional variant of NRL may comprise an amino acid sequence at least 90% identical to SEQ ID NO: 21 or SEQ ID NO: 22. The functional variant of NRL may comprise an amino acid sequence at least 95% identical to SEQ ID NO: 21 or SEQ ID NO: 22. The functional variant of NRL may comprise an amino acid sequence at least 96% identical to SEQ ID NO: 21 or SEQ ID NO: 22. The functional variant of NRL may comprise an amino acid sequence at least 97% identical to SEQ ID NO: 21 or SEQ ID NO: 22. The functional variant of NRL may comprise an amino acid sequence at least 98% identical to SEQ ID NO: 21 or SEQ ID NO: 22. The functional variant of NRL may comprise an amino acid sequence at least 99% identical to SEQ ID NO: 21 or SEQ ID NO: 22. SEQ ID NO: 21 and SEQ ID NO: 22 share 212 identical amino acids out of 237 and thus are at least 89% identical to one another. The nucleic acid sequence may comprise any nucleic acid sequence encoding a functional variant of NRL. Therefore, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 70% identical to SEQ ID NO: 21 or SEQ ID NO: 22. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 90% identical to SEQ ID NO: 21 or SEQ ID NO: 22. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 89% identical to SEQ ID NO: 21 or SEQ ID NO: 22. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 90% identical to SEQ ID NO: 21 or SEQ ID NO: 22.

[0476] The functional variant of NRL may consist essentially of an amino acid sequence at least 70% identical to SEQ ID NO: 21 or SEQ ID NO: 22. The functional variant of NRL may consist essentially of any amino acid sequence described elsewhere herein as a sequence that the functional variant of NRL may comprise.

[0477] The nucleic acid sequence may comprise any nucleic acid sequence encoding NRL. NRL may comprise an amino acid sequence according to SEQ ID NO: 21 or SEQ ID NO: 22. Therefore, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 21 or SEQ ID NO: 22. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 21. Alternatively, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 22.

[0478] The nucleotide sequence encoding N RL, or a functional variant thereof may comprise a nucleic acid sequence encoding:

[0479] (a) SEQ ID NO: 21,

[0480] (b) SEQ ID NO: 22,

[0481] (c) an amino acid sequence having at least 70% identity to SEQ ID NO: 21 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 21 , or

[0482] (d) an amino acid sequence having at least 70% identity to SEQ ID NO: 22 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 22.

[0483] The nucleotide sequence encoding NRL, or a functional variant thereof may consist essentially of a nucleic acid sequence encoding:

[0484] (a) SEQ ID NO: 21,

[0485] (b) SEQ ID NO: 22,

[0486] (c) an amino acid sequence having at least 70% identity to SEQ ID NO: 21 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 21 , or

[0487] (d) an amino acid sequence having at least 70% identity to SEQ ID NO: 22 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 22.

[0488] The nucleotide sequence encoding NRL, or a functional variant thereof may consist essentially of any nucleic acid sequence described elsewhere herein as a sequence that may encode NRL or functional variant of NRL.

[0489] The nucleotide sequence encoding NRL, or a functional variant thereof may comprise a nucleic acid sequence encoding:

[0490] (a) SEQ ID NO: 21,

[0491] (b) SEQ ID NO: 22,

[0492] (c) an amino acid sequence having at least 89% identity to SEQ ID NO: 21 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 21 , or

[0493] (d) an amino acid sequence having at least 89% identity to SEQ ID NO: 22 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 22.

[0494] The nucleotide sequence encoding NRL, or a functional variant thereof may comprise:

[0495] (a) SEQ ID NO: 23,

[0496] (b) SEQ ID NO: 24,

[0497] (c) SEQ ID NO: 25, or

[0498] (d) a nucleotide sequence having at least 60% identity to SEQ ID NO: 23 or SEQ ID NO: 25, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 21, or

[0499] (e) a nucleotide sequence having at least 60% identity to SEQ ID NO: 24, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 22. The nucleotide sequence encoding NRL or a functional variant thereof may comprise a nucleic acid sequence having at least 60% identity to SEQ ID NO: 23, SEQ ID NO: 24, or SEQ ID NO: 25. The nucleotide sequence having at least 60% identity to SEQ ID NO: 23, SEQ ID NO: 24, or SEQ ID NO: 25 may have at least 70%, 75%, 80%, 85%, 90% or 95% identity to SEQ ID NO: 23, SEQ ID NO: 24, or SEQ ID NO: 25, respectively. SEQ ID NO: 23 and SEQ ID NO: 24 share 615 identical nucleotides out of 714 and thus are at least 86% identical to one another. SEQ ID NO: 23 and SEQ ID NO: 25 share 421 identical nucleotides out of 714 and therefore have at least 58% sequence identity to each other and encode the same protein sequence. The nonidentical nucleotides may represent silent mutations (i.e. mutations which do not alter the sequence of the encoded amino acid). The non-identical nucleotides may alter the amino acid sequence of the encoded amino acid, for example by one or more conservative amino acid mutation. The non-identical nucleotides may alter the amino acid sequence of the encoded amino acid by up to 20, up to 15, up to 10, up to 9, up to 8, up to 7, up to 6, up to 5, up to 4, up to 3, up to 2 or up to 1 conservative amino acid mutation.

[0500] The nucleotide sequence encoding NRL, or a functional variant thereof may comprise:

[0501] (a) SEQ ID NO: 23,

[0502] (b) SEQ ID NO: 24,

[0503] (c) SEQ ID NO: 25, or

[0504] (d) a nucleotide sequence having at least 58% identity to SEQ ID NO: 23 or SEQ ID NO: 25, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 21, or

[0505] (e) a nucleotide sequence having at least 58% identity to SEQ ID NO: 24, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 22.

[0506] The nucleotide sequence encoding NRL, or a functional variant thereof may comprise:

[0507] (a) SEQ ID NO: 23,

[0508] (b) SEQ ID NO: 24,

[0509] (c) SEQ ID NO: 25, or

[0510] (d) a nucleotide sequence having at least 86% identity to SEQ ID NO: 23 or SEQ ID NO: 25, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 21, or

[0511] (e) a nucleotide sequence having at least 86% identity to SEQ ID NO: 24, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 22.

[0512] The nucleic acid sequence may encode NRL. The nucleotide sequence encoding NRL may comprise:

[0513] (a) SEQ ID NO: 23,

[0514] (b) SEQ ID NO: 24, or

[0515] (c) SEQ ID NO: 25.

[0516] In an alternative statement of the first aspect, the nucleic acid molecule may encode at least two transcription factors, or functional variants thereof, wherein one transcription factor is NRL and wherein the at least two transcription factors further comprise at least one transcription factor selected from the group consisting of NEUROD1 , FOXJ1 and OTX2.

[0517] In an alternative statement, the transcription factors may comprise: (a) NRL and NEUR0D1;

[0518] (b) NRL and F0XJ1; or

[0519] (c) NRL and 0TX2.

[0520] In an alternative statement, the transcription factors may comprise:

[0521] (a) NRL, FOXJ1 and NEUROD1;

[0522] (b) NRL, OTX2 and FOXJ1; or

[0523] (c) NRL, OTX2 and NEUROD1 .

[0524] In any of the alternative statements comprising NRL, the at least two transcription factors may further comprise CRX and / or one or more further transcription factor, such as one or more proneural bHLH transcription factor as described herein.

[0525] As used herein, “ONECUT1” refers to One Cut Homeobox 1. In humans it is encoded by the 0NECUT1 gene, also known as HNF-6, HNF6A, One Cut Domain Family Member 1, Hepatocyte Nuclear Factor 6, and Hepatocyte Nuclear Factor 6 Alpha. The mouse ortholog Onecutl is also known as One Cut Homeobox 1. In humans. In humans, the Ensembl gene ID is ENSG00000169856, such as ENSG00000169856.9. An example of a transcript is the Ensembl transcript ID ENST00000305901, such as ENST00000305901.7 and the UniProt ID is Q9UBC0, such as Q9UBC0v1; codon-optimised and alternatively spliced transcript variants are encompassed. In mice, an Ensembl gene ID is ENSMUSG00000043013. An example of a transcript is the Ensembl transcript ID ENSMUST00000056006, such as ENSMUST00000056006.11 and the UniProt ID is 008755, such as 008755 v1; codon-optimised and alternatively spliced transcript variants are encompassed.

[0526] 0NECUT1 may refer to the human sequence having the following amino acid sequence, identified as SEQ ID NO: 26.

[0527] SEQ ID NO: 26

[0528] MNAQLTMEAIGELHGVSHEPVPAPADLLGGSPHARSSVAHRGSHLPPAHPRSMGMASLLDGGSGGGDYHHHHRAPEHSLAG PLHPTMTMACETPPGMSMPTTYTTLTPLQPLPPISTVSDKFPHHHHHHHHHHHPHHHQRLAGNVSGSFTLMRDERGLASMN NLYTPYHKDVAGMGQSLSPLSSSGLGSIHNSQQGLPHYAHPGAAMPTDKMLTPNGFEAHHPAMLGRHGEQHLTPTSAGMVPI NGLPPHHPHAHLNAQGHGQLLGTAREPNPSVTGAQVSNGSNSGQMEEINTKEVAQRITTELKRYSIPQAIFAQRVLCRSQGTL SDLLRNPKPWSKLKSGRETFRRMWKWLQEPEFQRMSALRLAACKRKEQEHGKDRGNTPKKPRLVFTDVQRRTLHAIFKENK RPSKELQITISQQLGLELSTVSNFFMNARRRSLDKWQDEGSSNSGNSSSSSSTCTKA

[0529] 0NECUT1 may refer to the mouse sequence having the following amino acid sequence, identified as SEQ ID NO: 27.

[0530] SEQ ID NO: 27

[0531] MNAQLTMEAIGELHGVSHEPVPAPADLLGGSPHARSSVGHRGSHLPPAHPRSMGMASLLDGGSGGSDYHHHHRAPEHSLAG PLHPTMTMACETPPGMSMPTTYTTLTPLQPLPPISTVSDKFPHHHHHHHHHHHPHHHQRLAGNVSGSFTLMRDERGLASMN NLYTPYHKDVAGMGQSLSPLSGSGLGSIHNSQQGLPHYAHPGAAMPTDKMLTPNGFEAHHPAMLGRHGEQHLTPTSAGMVPI NGLPPHHPHAHLNAQGHGQLLGTAREPNPSVTGAQVSNGSNSGQMEEINTKEVAQRITTELKRYSIPQAIFAQRVLCRSQGTL SDLLRNPKPWSKLKSGRETFRRMWKWLQEPEFQRMSALRLAACKRKEQEHGKDRGNTPKKPRLVFTDVQRRTLHAIFKENK RPSKELQITISQQLGLELSTVSNFFMNARRRSLDKWQDEGGSNSGSSSSSSSTCTKA 0NECUT1 may be encoded by the following human coding sequence, identified as SEQ ID NO: 28

[0532] SEQ ID NO: 28

[0533] ATGAACGCGCAGCTGACCATGGAAGCGATCGGCGAGCTGCACGGGGTGAGCCATGAGCCGGTGCCCGCCCCTGCCGA

[0534] CCTGCTGGGCGGCAGCCCCCACGCGCGCAGCTCCGTGGCGCACCGCGGCAGCCACCTGCCCCCCGCGCACCCGCGC

[0535] TCCATGGGCATGGCGTCCCTGCTGGACGGCGGCAGCGGCGGCGGAGATTACCACCACCACCACCGGGCCCCTGAGCA

[0536] CAGCCTGGCCGGCCCCCTGCATCCCACCATGACCATGGCCTGCGAGACTCCCCCAGGTATGAGCATGCCCACCACCTAC

[0537] ACCACCTTGACCCCTCTGCAGCCGCTGCCTCCCATCTCCACAGTCTCGGACAAGTTCCCCCACCATCACCACCACCACC

[0538] ATCACCACCACCACCCGCACCACCACCAGCGCCTGGCGGGCAACGTGAGCGGTAGCTTCACGCTCATGCGGGATGAGC

[0539] GCGGGCTGGCCTCCATGAATAACCTCTATACCCCCTACCACAAGGACGTGGCCGGCATGGGCCAGAGCCTCTCGCCCCT

[0540] CTCCAGCTCCGGTCTGGGCAGCATCCACAACTCCCAGCAAGGGCTCCCCCACTATGCCCACCCGGGGGCCGCCATGCC

[0541] CACCGACAAGATGCTCACCCCCAACGGCTTCGAAGCCCACCACCCGGCCATGCTCGGCCGCCACGGGGAGCAGCACCT

[0542] CACGCCCACCTCGGCCGGCATGGTGCCCATCAACGGCCTTCCTCCGCACCATCCCCACGCCCACCTGAACGCCCAGGG

[0543] CCACGGGCAACTCCTGGGCACAGCCCGGGAGCCCAACCCTTCGGTGACCGGCGCGCAGGTCAGCAATGGAAGTAATTC

[0544] AGGGCAGATGGAAGAGATCAATACCAAAGAGGTGGCGCAGCGTATCACCACCGAGCTCAAGCGCTACAGCATCCCACAG

[0545] GCCATCTTCGCGCAGAGGGTGCTCTGCCGCTCCCAGGGGACCCTCTCGGACCTGCTGCGCAACCCCAAACCCTGGAGC

[0546] AAACTCAAATCCGGCCGGGAGACCTTCCGGAGGATGTGGAAGTGGCTGCAGGAGCCGGAGTTCCAGCGCATGTCCGCG

[0547] CTCCGCTTAGCAGCATGCAAAAGGAAAGAACAAGAACATGGGAAGGATAGAGGCAACACACCCAAAAAGCCCAGGTTGG

[0548] TCTTCACAGATGTCCAGCGTCGAACTCTACATGCAATATTCAAGGAAAATAAGCGTCCATCCAAAGAATTGCAAATCACCAT

[0549] TTCCCAGCAGCTGGGGTTGGAGCTGAGCACTGTCAGCAACTTCTTCATGAACGCAAGAAGGAGGAGTCTGGACAAGTGG

[0550] CAGGACGAGGGCAGCTCCAATTCAGGCAACTCATCTTCTTCATCAAGCACTTGTACCAAAGCATGA

[0551] ONECUT1 may be encoded by the following mouse coding sequence, identified as SEQ ID NO: 29

[0552] SEQ ID NO: 29

[0553] ATGAACGCACAGCTGACCATGGAGGCGATCGGCGAGCTGCACGGGGTGAGCCATGAGCCGGTGCCCGCCCCTGCTGAC

[0554] CTGCTGGGCGGCAGCCCTCACGCGCGCAGCTCCGTGGGACACCGCGGCAGCCACCTGCCTCCCGCGCACCCGCGTTC

[0555] CATGGGCATGGCGTCCCTGCTGGACGGCGGCAGCGGAGGCAGCGATTACCACCACCACCACCGCGCCCCTGAGCACA

[0556] GCTTGGCTGGCCCCCTGCACCCCACCATGACCATGGCCTGTGAAACTCCCCCAGGTATGAGCATGCCCACCACCTACAC

[0557] TACCTTAACCCCTCTGCAGCCGCTGCCGCCCATCTCCACCGTGTCCGACAAGTTCCCTCACCATCATCACCACCACCATC

[0558] ACCACCACCACCCACACCACCACCAGCGCCTGGCGGGCAACGTGAGCGGTAGTTTCACACTTATGCGGGATGAGCGCG

[0559] GGCTGGCCTCTATGAATAACCTCTATACCCCCTACCACAAGGACGTGGCTGGCATGGGCCAGAGCCTCTCGCCCCTCTCT

[0560] GGCTCCGGTCTGGGCAGCATTCACAACTCCCAGCAAGGACTTCCCCACTATGCTCATCCCGGCGCGGCTATGCCCACCG

[0561] ACAAGATGCTCACCCCAAATGGCTTTGAAGCCCACCACCCTGCCATGCTCGGTCGCCACGGGGAGCAGCACCTCACGCC

[0562] CACCTCGGCCGGCATGGTACCCATCAACGGCCTTCCTCCGCACCATCCTCATGCCCACCTGAATGCCCAGGGCCACGGA

[0563] CAGCTCCTGGGCACAGCCCGAGAGCCCAACCCTTCGGTGACCGGCGCGCAGGTCAGCAATGGAAGTAATTCAGGGCAG

[0564] ATGGAAGAGATCAATACCAAAGAGGTGGCGCAGCGTATCACCACCGAGCTCAAACGTTACAGCATCCCACAGGCCATCTT

[0565] CGCGCAGAGGGTGCTCTGCCGTTCCCAGGGGACCCTTTCGGACCTGCTGCGAAACCCCAAGCCCTGGAGCAAACTCAA

[0566] GTCGGGTCGGGAGACCTTCCGGAGGATGTGGAAGTGGCTGCAGGAGCCGGAGTTCCAGCGCATGTCGGCGCTCCGCTT AGCAGCCTGCAAACGGAAAGAGCAAGAACACGGGAAGGACAGAGGCAACACCCCCAAAAAGCCCAGGCTGGTCTTCAC AGACGTCCAACGTCGAACTCTACATGCAATATTCAAGGAAAATAAGCGTCCGTCCAAAGAATTACAAATCACCATCTCCCAG CAGCTGGGGTTGGAGCTGAGCACTGTCAGCAACTTCTTCATGAATGCCAGGAGGAGGAGTCTGGACAAGTGGCAGGAC GAGGGCGGCTCCAACTCAGGCAGTTCATCGTCCTCATCGAGCACTTGTACCAAAGCATGA

[0567] 0NECUT1 may be encoded by the following codon optimised human sequence, identified as SEQ ID NO: 20

[0568] SEQ ID NO: 30

[0569] ATGAATGCTCAATTGACTATGGAAGCAATTGGGGAACTTCATGGTGTCTCCCACGAACCCGTTCCTGCTCCGGCTGATTTG TTAGGTGGGTCACCGCATGCCCGATCAAGCGTCGCTCATAGGGGTAGTCATCTCCCACCTGCCCATCCAAGGAGTATGGG TATGGCAAGTTTGTTGGATGGCGGTTCCGGCGGTGGGGACTATCATCATCATCATCGTGCACCCGAACATAGTTTAGCTGG ACCTTTACACCCAACTATGACTATGGCTTGTGAAACCCCACCCGGAATGTCCATGCCAACAACGTATACTACTTTAACTCCG CTCCAACCTCTCCCGCCTATTTCTACCGTATCCGATAAATTTCCACATCACCATCATCATCATCACCATCATCATCATCCCCAT CATCATCAACGACTTGCCGGTAATGTATCCGGGTCATTTACTTTAATGCGCGACGAACGTGGCCTCGCAAGCATGAACAAT TTGTACACGCCATATCATAAAGATGTCGCTGGTATGGGGCAATCACTGAGCCCTCTGAGTTCCAGTGGGTTAGGAAGTATT CATAATAGTCAACAGGGACTTCCTCATTACGCTCATCCTGGAGCAGCTATGCCAACGGATAAAATGCTGACTCCTAATGGAT TTGAGGCACATCATCCTGCAATGCTTGGACGACATGGCGAACAACATCTGACACCTACTTCAGCAGGTATGGTTCCAATTA ATGGATTGCCACCACATCACCCGCATGCACATCTTAATGCACAAGGACATGGCCAGCTGCTCGGGACCGCTAGGGAACCA AATCCCAGCGTTACAGGGGCTCAAGTGAGTAACGGCTCCAACAGTGGACAAATGGAAGAAATTAACACGAAGGAAGTAGC ACAAAGGATAACGACAGAACTGAAAAGGTATAGTATTCCCCAAGCTATTTTCGCCCAACGGGTTCTTTGTAGGAGTCAAGG AACATTGAGTGATTTACTCAGAAATCCTAAGCCGTGGTCCAAGCTGAAGAGTGGTAGGGAAACATTTCGACGCATGTGGAA ATGGCTTCAAGAACCCGAATTTCAAAGGATGTCAGCACTGCGGCTGGCTGCCTGTAAGCGAAAGGAGCAGGAGCACGGC AAAGACCGCGGGAATACCCCTAAGAAACCAAGACTTGTTTTCACTGACGTTCAAAGGAGAACACTTCACGCCATCTTTAAA

[0570] GAGAACAAAAGACCCTCAAAGGAGCTCCAGATAACGATCAGTCAACAACTCGGTCTGGAATTGTCCACGGTGTCCAATTT CTTTATGAATGCCCGTCGCCGGAGCCTCGATAAATGGCAAGATGAAGGTTCAAGTAACTCTGGAAATAGCAGTTCCAGCAG CTCAACATGCACTAAGGCTTAG

[0571] The functional variant of ONECUT1 may comprise an amino acid sequence at least 70% identical to SEQ ID NO: 26 or SEQ ID NO: 27. The functional variant of ONECUT1 may comprise an amino acid sequence at least 80% identical to SEQ ID NO: 26 or SEQ ID NO: 27. The functional variant of ON ECUT1 may comprise an amino acid sequence at least 85% identical to SEQ ID NO: 26 or SEQ ID NO: 27. The functional variant of ONECUT1 may comprise an amino acid sequence at least 90% identical to SEQ ID NO: 26 or SEQ ID NO: 27. The functional variant of ONECUT1 may comprise an amino acid sequence at least 95% identical to SEQ ID NO: 26 or SEQ ID NO: 27. The functional variant of ONECUT1 may comprise an amino acid sequence at least 96% identical to SEQ ID NO: 26 or SEQ ID NO: 27. The functional variant of ONECUT1 may comprise an amino acid sequence at least 97% identical to SEQ ID NO: 26 or SEQ ID NO: 27. The functional variant of ONECUT1 may comprise an amino acid sequence at least 98% identical to SEQ ID NO: 26 or SEQ ID NO: 27. The functional variant of ONECUT1 may comprise an amino acid sequence at least 99% identical to SEQ ID NO: 26 or SEQ ID NO: 27. SEQ ID NO: 26 and SEQ ID NO: 27 share 460 identical amino acids out of 465 and thus are at least 98% identical to one another. The nucleic acid sequence may comprise any nucleic acid sequence encoding a functional variant of ON ECUT1. Therefore, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 70% identical to SEQ ID NO: 26 or SEQ ID NO: 27. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 90% identical to SEQ ID NO: 26 or SEQ ID NO: 27. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 98% identical to SEQ ID NO: 26 or SEQ ID NO: 27. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 99% identical to SEQ ID NO: 26 orSEQ ID NO: 27.

[0572] The functional variant of ONECUT1 may consist essentially of an amino acid sequence at least 70% identical to SEQ ID NO: 26 or SEQ ID NO: 27. The functional variant of ONECUT1 may consist essentially of any amino acid sequence described elsewhere herein as a sequence that the functional variant of ONECUT1 may comprise.

[0573] The nucleic acid sequence may comprise any nucleic acid sequence encoding ONECUT 1. ONECUT 1 may comprise an amino acid sequence according to SEQ ID NO: 26 or SEQ ID NO: 27. Therefore, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 26 or SEQ ID NO: 27. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 26. Alternatively, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 27.

[0574] The nucleotide sequence encoding ONECUT 1 , or a functional variant thereof may comprise a nucleic acid sequence encoding:

[0575] (a) SEQ ID NO: 26,

[0576] (b) SEQ ID NO: 27,

[0577] (c) an amino acid sequence having at least 70% identity to SEQ ID NO: 26 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 26, or

[0578] (d) an amino acid sequence having at least 70% identity to SEQ ID NO: 27 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 27.

[0579] The nucleotide sequence encoding ONECUT 1 , or a functional variant thereof may consist essentially of a nucleic acid sequence encoding:

[0580] (a) SEQ ID NO: 26,

[0581] (b) SEQ ID NO: 27,

[0582] (c) an amino acid sequence having at least 70% identity to SEQ ID NO: 26 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 26, or

[0583] (d) an amino acid sequence having at least 70% identity to SEQ ID NO: 27 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 27.

[0584] The nucleotide sequence encoding ONECUT1, or a functional variant thereof may consist essentially of any nucleic acid sequence described elsewhere herein as a sequence that may encode ONECUT1 or functional variant of ONECUT1.

[0585] The nucleotide sequence encoding ONECUT 1 , or a functional variant thereof may comprise a nucleic acid sequence encoding:

[0586] (a) SEQ ID NO: 26,

[0587] (b) SEQ ID NO: 27, (c) an amino acid sequence having at least 98% identity to SEQ ID NO: 26 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 26, or

[0588] (d) an amino acid sequence having at least 98% identity to SEQ ID NO: 27 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 27.

[0589] The nucleotide sequence encoding ONECUT 1 , or a functional variant thereof may comprise:

[0590] (a) SEQ ID NO: 28,

[0591] (b) SEQ ID NO: 29,

[0592] (c) SEQ ID NO: 30, or

[0593] (d) a nucleotide sequence having at least 60% identity to SEQ ID NO: 28 or SEQ ID NO: 30, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 26, or

[0594] (e) a nucleotide sequence having at least 60% identity to SEQ ID NO: 29, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 27.

[0595] The nucleotide sequence encoding ONECUT1 or a functional variant thereof may comprise a nucleic acid sequence having at least 60% identity to SEQ ID NO: 28, SEQ ID NO: 29, or SEQ ID NO: 30. The nucleotide sequence having at least 60% identity to SEQ ID NO: 28, SEQ ID NO: 29, or SEQ ID NO: 30 may have at least 70%, 75%, 80%, 85%, 90% or 95% identity to SEQ ID NO: 28, SEQ ID NO: 29, or SEQ ID NO: 30, respectively. SEQ ID NO: 28 and SEQ ID NO: 29 share 1312 identical nucleotides out of 1398 and thus are at least 93% identical to one another. SEQ ID NO: 28 and SEQ ID NO: 30 share 863 identical nucleotides out of 1398 and therefore have at least 61% sequence identity to each other and encode the same protein sequence. The non-identical nucleotides may represent silent mutations (i.e. mutations which do not alter the sequence of the encoded amino acid). The non-identical nucleotides may alterthe amino acid sequence of the encoded amino acid, for example by one or more conservative amino acid mutation. The non-identical nucleotides may alter the amino acid sequence of the encoded amino acid by up to 20, up to 15, up to 10, up to 9, up to 8, up to 7, up to 6, up to 5, up to 4, up to 3, up to 2 or up to 1 conservative amino acid mutation.

[0596] The nucleotide sequence encoding ONECUT 1 , or a functional variant thereof may comprise:

[0597] (a) SEQ ID NO: 28,

[0598] (b) SEQ ID NO: 29,

[0599] (c) SEQ ID NO: 30, or

[0600] (d) a nucleotide sequence having at least 61% identity to SEQ ID NO: 28 or SEQ ID NO: 30, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 26, or

[0601] (e) a nucleotide sequence having at least 61% identity to SEQ ID NO: 29, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 27.

[0602] The nucleotide sequence encoding ONECUT 1 , or a functional variant thereof may comprise:

[0603] (a) SEQ ID NO: 28,

[0604] (b) SEQ ID NO: 29,

[0605] (c) SEQ ID NO: 30, or (d) a nucleotide sequence having at least 93% identity to SEQ ID NO: 28 or SEQ ID NO: 30, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 26, or

[0606] (e) a nucleotide sequence having at least 93% identity to SEQ ID NO: 29, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 27.

[0607] The nucleic acid sequence may encode ONECUT1. The nucleotide sequence encoding ONECUT1 may comprise:

[0608] (a) SEQ ID NO: 28,

[0609] (b) SEQ ID NO: 29, or

[0610] (c) SEQ ID NO: 30.

[0611] In an alternative statement of the first aspect, the nucleic acid molecule may encode at least two transcription factors, or functional variants thereof, wherein one transcription factor is ONECUT1 and wherein the at least two transcription factors further comprise at least one transcription factor selected from the group consisting of NEUROD1, FOXJ1 and OTX2.

[0612] In an alternative statement, the transcription factors may comprise:

[0613] (a) ONECUT1 and NEUROD1;

[0614] (b) ONECUT1 and FOXJ1; or

[0615] (c) ONECUT1 and OTX2.

[0616] In an alternative statement, the transcription factors may comprise:

[0617] (a) ONECUT1, FOXJ1 and NEUROD1;

[0618] (b) ONECUT1, OTX2 and FOXJ1; or

[0619] (c) ONECUT1, OTX2 and NEUROD1.

[0620] In any of the alternative statements comprising ONECUT1, the at least two transcription factors may further comprise CRX and / or one or more further transcription factor, such as one or more proneural bHLH transcription factor as described herein.

[0621] As used herein, “MEF2C” refers to Myocyte-Specific Enhancer Factor 2C. In humans it is encoded by the MEF2C gene, also known as MADS Box Transcription Enhancer Factor 2, Polypeptide C 3, C5DELq14.3, DEL5q14.3 and NEDHSIL. The mouse ortholog Mef2c isalso known as Myocyte-Specific Enhancer Factor 2C. In humans, the Ensembl gene ID is ENSG00000081189, such as ENSG00000081189.15. An example of a transcript is the Ensembl transcript ID ENST00000636998, such as ENST00000636998.1 and the UniProt ID is Q06413-3, such as Q06413-3 v1; codon-optimised and alternatively spliced transcript variants are encompassed. In mice, an Ensembl gene ID is ENSMUSG00000005583. An example of a transcript is the Ensembl transcript ID ENSMUST00000197681 , such as ENSMUST00000197681.5 and the UniProt ID is Q8CFN5-3, such as Q8CFN5-3 v2; codon-optimised and alternatively spliced transcript variants are encompassed.

[0622] MEF2C may refer to the human sequence having the following amino acid sequence, identified as SEQ ID NO: 31.

[0623] SEQ ID NO: 31 MGRKKIQITRIMDERNRQVTFTKRKFGLMKKAYELSVLCDCEIALIIFNSTNKLFQYASTDMDKVLLKYTEYNEPHESRTNSDIVE

[0624] TLRKKGLNGCDSPDPDADDSVGHSPESEDKYRKINEDIDLMISRQRLCAVPPPNFEMPVSIPVSSHNSLVYSNPVSSLGNPNLL

[0625] PLAHPSLQRNSMSPGVTHRPPSAGNTGGLMGGDLTSGAGTSAGNGYGNPRNSPGLLVSPGNLNKNMQAKSPPPMNLGMNN

[0626] RKPDLRVLIPPGSKNTMPSVSEDVDLLLNQRINNSQSAQSLATPWSVATPTLPGQGMGGYPSAISTTYGTEYSLSSADLSSLS

[0627] GFNTASALHLGSVTGWQQQHLHNMPPSALSQLGDRTTTPSRYPQHTRHEAGRSPVDSLSSCSSSYDGSDREDHRNEFHSPI

[0628] GLTRPSPDERESPSVKRMRLSEGWAT

[0629] MEF2C may refer to the mouse sequence having the following amino acid sequence, identified as SEQ ID NO: 32

[0630] SEQ ID NO: 32

[0631] MGRKKIQITRIMDERNRQVTFTKRKFGLMKKAYELSVLCDCEIALIIFNSTNKLFQYASTDMDKVLLKYTEYNEPHESRTNSDIVE

[0632] TLRKKGLNGCDSPDPDADDSVGHSPESEDKYRKINEDIDLMISRQRLCAVPPPSFEMPVTIPVSSHNSLVYSNPVSTLGNPNLL

[0633] PLAHPSLQRNSMSPGVTHRPPSAGNTGGLMGGDLTSGAGTSAGNGYGNPRNSPGLLVSPGNLNKNIQAKSPPPMNLGMNN

[0634] RKPDLRVLIPPGSKNTMPSVSEDVDLLLNQRINNSQSAQSLATPWSVATPTLPGQGMGGYPSAISTTYGTEYSLSSADLSSLS

[0635] GFNTASALHLGSVTGWQQQHLHNMPPSALSQLGDRTTTPSRYPQHTTRHEAGRSPVDSLSSCSSSYDGSDREDHRNEFHSP

[0636] IGLTRPSPDERESPSVKRMRLSEGWAT

[0637] MEF2C may be encoded by the following human coding sequence, identified as SEQ ID NO: 33

[0638] SEQ ID NO: 33

[0639] ATGGGGAGAAAAAAGATTCAGATTACGAGGATTATGGATGAACGTAACAGACAGGTGACATTTACAAAGAGGAAATTTGGG

[0640] TTGATGAAGAAGGCTTATGAGCTGAGCGTGCTGTGTGACTGTGAGATTGCGCTGATCATCTTCAACAGCACCAACAAGCT

[0641] GTTCCAGTATGCCAGCACCGACATGGACAAAGTGCTTCTCAAGTACACGGAGTACAACGAGCCGCATGAGAGCCGGACA

[0642] AACTCAGACATCGTGGAGACGTTGAGAAAGAAGGGCCTTAATGGCTGTGACAGCCCAGACCCCGATGCGGACGATTCCG

[0643] TAGGTCACAGCCCTGAGTCTGAGGACAAGTACAGGAAAATTAACGAAGATATTGATCTAATGATCAGCAGGCAAAGATTGT

[0644] GTGCTGTTCCACCTCCCAACTTCGAGATGCCAGTCTCCATCCCAGTGTCCAGCCACAACAGTTTGGTGTACAGCAACCCT

[0645] GTCAGCTCACTGGGAAACCCCAACCTATTGCCACTGGCTCACCCTTCTCTGCAGAGGAATAGTATGTCTCCTGGTGTAACA

[0646] CATCGACCTCCAAGTGCAGGTAACACAGGTGGTCTGATGGGTGGAGACCTCACGTCTGGTGCAGGCACCAGTGCAGGG

[0647] AACGGGTATGGCAATCCCCGAAACTCACCAGGTCTGCTGGTCTCACCTGGTAACTTGAACAAGAATATGCAAGCAAAATCT

[0648] CCTCCCCCAATGAATTTAGGAATGAATAACCGTAAACCAGATCTCCGAGTTCTTATTCCACCAGGCAGCAAGAATACGATGC

[0649] CATCAGTGTCTGAGGATGTCGACCTGCTTTTGAATCAAAGGATAAATAACTCCCAGTCGGCTCAGTCATTGGCTACCCCAG

[0650] TGGTTTCCGTAGCAACTCCTACTTTACCAGGACAAGGAATGGGAGGATATCCATCAGCCATTTCAACAACATATGGTACCGA

[0651] GTACTCTCTGAGTAGTGCAGACCTGTCATCTCTGTCTGGGTTTAACACCGCCAGCGCTCTTCACCTTGGTTCAGTAACTGG

[0652] CTGGCAACAGCAACACCTACATAACATGCCACCATCTGCCCTCAGTCAGTTGGGAGACCGTACCACCACCCCTTCGAGAT

[0653] ACCCACAACACACGCGCCACGAGGCGGGGAGATCTCCTGTTGACAGCTTGAGCAGCTGTAGCAGTTCGTACGACGGGA

[0654] GCGACCGAGAGGATCACCGGAACGAATTCCACTCCCCCATTGGACTCACCAGACCTTCGCCGGACGAAAGGGAAAGTCC

[0655] CTCAGTCAAGCGCATGCGACTTTCTGAAGGATGGGCAACATGA

[0656] MEF2C may be encoded by the following mouse coding sequence, identified as SEQ ID NO: 34 SEQ ID NO: 34

[0657] ATGGGGAGAAAAAAGATTCAGATTACGAGGATAATGGATGAGCGTAACAGACAGGTGACTTTTACGAAGAGGAAATTTGGA

[0658] TTGATGAAGAAGGCTTATGAGCTGAGCGTGCTGTGCGACTGTGAGATTGCACTGATCATCTTCAACAGCACCAACAAGCT

[0659] GTTCCAGTACGCCAGCACTGACATGGATAAGGTGTTGCTCAAGTACACCGAGTACAACGAGCCGCACGAGAGCCGGACA

[0660] AACTCAGACATTGTGGAGACATTGAGAAAGAAGGGCCTCAATGGCTGTGACAGCCCAGATCCCGATGCAGACGATTCAGT

[0661] AGGTCACAGCCCTGAGTCTGAGGACAAGTACAGGAAAATTAACGAAGATATTGATCTAATGATCAGCAGGCAAAGATTGTG

[0662] TGCTGTTCCACCTCCCAGCTTTGAGATGCCAGTTACCATCCCAGTGTCCAGCCATAACAGTTTGGTGTACAGCAATCCTGT

[0663] CAGCACACTGGGAAACCCCAATCTTCTGCCACTGGCCCACCCGTCTCTGCAGAGGAATAGTATGTCTCCTGGTGTAACAC

[0664] ATAGACCTCCAAGTGCAGGTAACACAGGCGGTCTGATGGGCGGAGATCTGACATCCGGTGCAGGCACCAGCGCAGGGA

[0665] ATGGATACGGCAACCCCCGGAACTCACCAGGCCTGCTGGTCTCACCTGGTAACCTGAACAAGAATATACAAGCCAAATCT

[0666] CCTCCCCCTATGAATCTAGGAATGAATAATCGTAAGCCAGATCTCCGCGTTCTTATCCCACCTGGCAGCAAGAACACGATG

[0667] CCATCAGTGTCTGAGGATGTGGATCTGCTGTTGAATCAAAGGATAAATAACTCCCAGTCGGCTCAGTCATTGGCTACCCCG

[0668] GTGGTTTCCGTAGCAACTCCTACTTTACCAGGACAAGGAATGGGAGGATATCCATCAGCCATTTCAACAACATATGGTACTG

[0669] AGTACTCTCTGAGTAGCGCAGATCTGTCATCTCTGTCTGGCTTCAACACTGCCAGTGCGCTCCACCTCGGCTCTGTAACT

[0670] GGCTGGCAGCAGCAGCACCTACATAACATGCCGCCATCTGCCCTCAGTCAGTTGGGAGACCGTACCACCACCCCTTCGA

[0671] GATACCCACAACACACCACGCGCCACGAGGCGGGGAGGTCTCCTGTTGACAGCTTGAGCAGCTGTAGCAGTTCCTACGA

[0672] TGGGAGCGACCGAGAGGATCACCGGAACGAATTCCACTCCCCCATTGGACTCACCAGACCTTCGCCGGACGAAAGGGA

[0673] AAGTCCTTCAGTCAAGCGCATGCGACTCTCTGAAGGATGGGCAACATGA

[0674] MEF2C may be encoded by the following codon optimised human sequence, identified as SEQ ID NO: 35

[0675] SEQ ID NO: 35

[0676] ATGGGAAGAAAGAAAATCCAAATAACCAGAATCATGGACGAGCGGAATAGGCAAGTTACCTTCACGAAACGGAAGTTCGG

[0677] ACTGATGAAGAAGGCCTACGAACTCAGTGTCTTGTGCGATTGCGAGATCGCCCTTATTATCTTTAATTCTACAAACAAACTC

[0678] TTCCAATACGCTTCCACTGATATGGATAAGGTGTTGCTGAAGTACACCGAGTATAATGAACCACACGAAAGTCGTACCAATT

[0679] CTGATATTGTAGAAACCCTCAGGAAGAAAGGACTCAACGGGTGCGATAGTCCTGATCCGGACGCTGATGACTCTGTTGGG

[0680] CATTCTCCCGAATCAGAAGATAAATATAGAAAGATCAATGAGGACATCGACCTGATGATTTCCCGGCAGAGGCTCTGCGCG

[0681] GTCCCGCCCCCTAATTTTGAAATGCCCGTGAGTATTCCTGTCTCTAGTCATAATAGCCTGGTCTATTCCAATCCAGTGTCAA

[0682] GCCTTGGGAATCCAAATCTGCTGCCTCTCGCCCATCCCTCATTGCAACGGAACTCAATGAGTCCCGGCGTCACCCACAGA

[0683] CCGCCATCCGCCGGAAATACTGGCGGCCTTATGGGCGGTGATCTGACATCAGGCGCTGGGACTTCAGCGGGAAATGGAT

[0684] ACGGAAACCCACGCAATAGTCCGGGCTTGCTTGTGTCTCCAGGAAATCTTAATAAGAACATGCAGGCTAAGAGTCCACCA

[0685] CCTATGAACCTGGGCATGAACAATAGGAAGCCCGACTTGAGGGTGCTCATCCCACCCGGTTCTAAGAACACCATGCCTTC

[0686] CGTTTCAGAAGACGTGGATCTCTTGCTCAACCAGCGAATCAACAATTCTCAAAGCGCCCAATCTCTTGCAACGCCTGTAGT

[0687] CTCTGTTGCTACACCCACACTGCCTGGGCAGGGGATGGGCGGCTACCCTAGCGCTATCTCCACTACGTACGGCACTGAAT

[0688] ATTCCCTTAGCAGCGCCGATCTCAGCAGTTTGAGCGGCTTCAATACAGCTTCCGCGCTGCATCTGGGGTCTGTTACTGGT

[0689] TGGCAGCAACAGCATTTGCACAATATGCCGCCTAGCGCGCTTAGCCAACTCGGGGATCGGACTACAACACCCTCTCGCTA

[0690] TCCGCAGCATACTCGGCATGAAGCAGGACGATCCCCCGTGGATTCACTGTCTAGTTGCTCCTCTTCCTATGATGGCAGTG

[0691] ATAGGGAAGACCATCGTAATGAGTTTCATAGTCCAATCGGCCTGACACGGCCATCACCTGATGAGCGCGAGTCTCCTTCTG

[0692] TGAAACGGATGCGGCTGTCAGAGGGGTGGGCTACCTAA The functional variant of MEF2C may comprise an amino acid sequence at least 70% identical to SEQ ID NO: 31 or SEQ ID NO: 32. The functional variant of MEF2C may comprise an amino acid sequence at least 80% identical to SEQ ID NO: 31 or SEQ ID NO: 32. The functional variant of MEF2C may comprise an amino acid sequence at least 85% identical to SEQ ID NO: 31 or SEQ ID NO: 32. The functional variant of MEF2C may comprise an amino acid sequence at least 90% identical to SEQ ID NO: 31 or SEQ ID NO: 32. The functional variant of MEF2C may comprise an amino acid sequence at least 95% identical to SEQ ID NO: 31 or SEQ ID NO: 32. The functional variant of MEF2C may comprise an amino acid sequence at least 96% identical to SEQ ID NO: 31 or SEQ ID NO: 32. The functional variant of MEF2C may comprise an amino acid sequence at least 97% identical to SEQ ID NO: 31 or SEQ ID NO: 32. The functional variant of MEF2C may comprise an amino acid sequence at least 98% identical to SEQ ID NO: 31 or SEQ ID NO: 32. The functional variant of MEF2C may comprise an amino acid sequence at least 99% identical to SEQ ID NO: 31 or SEQ ID NO: 32. SEQ ID NO: 31 and SEQ ID NO: 32 share 437 identical amino acids out of 442 and thus are at least 98% identical to one another. The nucleic acid sequence may comprise any nucleic acid sequence encoding a functional variant of MEF2C. Therefore, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 70% identical to SEQ ID NO: 31 or SEQ ID NO: 32. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 90% identical to SEQ ID NO: 31 or SEQ ID NO: 32. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 98% identical to SEQ ID NO: 31 or SEQ ID NO: 32. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 99% identical to SEQ ID NO: 31 or SEQ ID NO: 32.

[0693] The functional variant of MEF2C may consist essentially of an amino acid sequence at least 70% identical to SEQ ID NO: 31 or SEQ ID NO: 32. The functional variant of MEF2C may consist essentially of any amino acid sequence described elsewhere herein as a sequence that the functional variant of MEF2C may comprise.

[0694] The nucleic acid sequence may comprise any nucleic acid sequence encoding MEF2C. MEF2C may comprise an amino acid sequence according to SEQ ID NO: 31 or SEQ ID NO: 32. Therefore, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 31 or SEQ ID NO: 32. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 31. Alternatively, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 32.

[0695] The nucleotide sequence encoding MEF2C, or a functional variant thereof may comprise a nucleic acid sequence encoding:

[0696] (a) SEQ ID NO: 31,

[0697] (b) SEQ ID NO: 32,

[0698] (c) an amino acid sequence having at least 70% identity to SEQ ID NO: 31 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 31 , or

[0699] (d) an amino acid sequence having at least 70% identity to SEQ ID NO: 32 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 32.

[0700] The nucleotide sequence encoding MEF2C, or a functional variant thereof may consist essentially of a nucleic acid sequence encoding:

[0701] (a) SEQ ID NO: 31, (b) SEQ ID NO: 32,

[0702] (c) an amino acid sequence having at least 70% identity to SEQ ID NO: 31 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 31 , or

[0703] (d) an amino acid sequence having at least 70% identity to SEQ ID NO: 32 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 32.

[0704] The nucleotide sequence encoding MEF2C, or a functional variant thereof may consist essentially of any nucleic acid sequence described elsewhere herein as a sequence that may encode MEF2C or functional variant of MEF2C.

[0705] The nucleotide sequence encoding MEF2C, or a functional variant thereof may comprise a nucleic acid sequence encoding:

[0706] (a) SEQ ID NO: 31,

[0707] (b) SEQ ID NO: 32,

[0708] (c) an amino acid sequence having at least 98% identity to SEQ ID NO: 31 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 31 , or

[0709] (d) an amino acid sequence having at least 98% identity to SEQ ID NO: 32 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 32.

[0710] The nucleotide sequence encoding MEF2C, or a functional variant thereof may comprise:

[0711] (a) SEQ ID NO: 33,

[0712] (b) SEQ ID NO: 34,

[0713] (c) SEQ ID NO: 35, or

[0714] (d) a nucleotide sequence having at least 60% identity to SEQ ID NO: 33 or SEQ ID NO: 35, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 31 , or

[0715] (e) a nucleotide sequence having at least 60% identity to SEQ ID NO: 34, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 32.

[0716] The nucleotide sequence encoding MEF2C or a functional variant thereof may comprise a nucleic acid sequence having at least 60% identity to SEQ ID NO: 33, SEQ ID NO: 34, or SEQ ID NO: 35. The nucleotide sequence having at least 60% identity to SEQ ID NO: 33, SEQ ID NO: 34, or SEQ ID NO: 35 may have at least 70%, 75%, 80%, 85%, 90% or 95% identity to SEQ ID NO: 33, SEQ ID NO: 34, or SEQ ID NO: 35, respectively. SEQ ID NO: 33 and SEQ ID NO: 34 share 1244 identical nucleotides out of 1329 and thus are at least 93% identical to one another. SEQ ID NO: 33 and SEQ ID NO: 35 share 859 identical nucleotides out of 1326 and therefore have at least 64% sequence identity to each other and encode the same protein sequence. The non-identical nucleotides may represent silent mutations (i.e. mutations which do not alter the sequence of the encoded amino acid). The non-identical nucleotides may alterthe amino acid sequence of the encoded amino acid, for example by one or more conservative amino acid mutation. The non-identical nucleotides may alter the amino acid sequence of the encoded amino acid by up to 20, up to 15, up to 10, up to 9, up to 8, up to 7, up to 6, up to 5, up to 4, up to 3, up to 2 or up to 1 conservative amino acid mutation.

[0717] The nucleotide sequence encoding MEF2C, or a functional variant thereof may comprise:

[0718] (a) SEQ ID NO: 33, (b) SEQ ID NO: 34,

[0719] (c) SEQ ID NO: 35, or

[0720] (d) a nucleotide sequence having at least 64% identity to SEQ ID NO: 33 or SEQ ID NO: 35, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 31 , or

[0721] (e) a nucleotide sequence having at least 64% identity to SEQ ID NO: 34, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 32.

[0722] The nucleotide sequence encoding MEF2C, or a functional variant thereof may comprise:

[0723] (a) SEQ ID NO: 33,

[0724] (b) SEQ ID NO: 34,

[0725] (c) SEQ ID NO: 35, or

[0726] (d) a nucleotide sequence having at least 93% identity to SEQ ID NO: 33 or SEQ ID NO: 35, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 31 , or

[0727] (e) a nucleotide sequence having at least 93% identity to SEQ ID NO: 34, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 32.

[0728] The nucleic acid sequence may encode MEF2C. The nucleotide sequence encoding MEF2C may comprise:

[0729] (a) SEQ ID NO: 33,

[0730] (b) SEQ ID NO: 34, or

[0731] (c) SEQ ID NO: 35.

[0732] In an alternative statement of the first aspect, the nucleic acid molecule may encode at least two transcription factors, or functional variants thereof, wherein one transcription factor is MEF2C and wherein the at least two transcription factors further comprise at least one transcription factor selected from the group consisting of NEUROD1 , FOXJ1 and OTX2.

[0733] In an alternative statement, the transcription factors may comprise:

[0734] (a) MEF2C and NEURODI;

[0735] (b) MEF2C and FOXJ1; or

[0736] (c) MEF2C and OTX2.

[0737] In an alternative statement, the transcription factors may comprise:

[0738] (a) MEF2C, FOXJ1 and NEURODI;

[0739] (b)MEF2C, OTX2 and FOXJ1; or

[0740] (c) MEF2C, OTX2 and NEURODI.

[0741] In any of the alternative statements comprising MEF2C, the at least two transcription factors may further comprise CRX and / or one or more further transcription factor, such as one or more proneural bHLH transcription factor as described herein.

[0742] As used herein, “RAX” refers to Retina and Anterior Neural Fold Homeobox. In humans it is encoded by the RAX gene, also known as RX, Retinal Homeobox Protein Rx, RAX1, Retina and Anterior Neural Fold Homeobox Protein, MCOPS16 and MC0P3. The mouse ortholog Rax is also known as Retina and Anterior Neural Fold Homeobox. In humans, the Ensembl gene ID is ENSG00000134438, such as ENSG00000134438.9. An example of a transcript is the Ensembl transcript ID ENST00000334889, such as ENST00000334889.3 and the UniProt ID is Q9Y2V3-1 , such as Q9Y2V3-1 v2; codon-optimised and alternatively spliced transcript variants are encompassed. In mice, an Ensembl gene ID is ENSMUSG00000024518. An example of a transcript is the Ensembl transcript ID ENSMUST00000025396, such as ENSMUST00000025396.5 and the UniProt ID is 035602, such as 035602 v2; codon-optimised and alternatively spliced transcript variants are encompassed.

[0743] RAX may refer to the human sequence having the following amino acid sequence, identified as SEQ ID NO: 36.

[0744] SEQ ID NO: 36

[0745] MHLPGCAPAMADGSFSLAGHLLRSPGGSTSRLHSIEAILGFTKDDGILGTFPAERGARGAKERDRRLGARPACPKAPEEGSEP SPPPAPAPAPEYEAPRPYCPKEPG EARPS PGLPVGPATGEAKLSEEEQPKKKHRRNRTTFTTYQLHELERAFEKSHYPDVYSR EELAGKVNLPEVRVQVWFQNRRAKWRRQEKLEVSSMKLQDSPLLSFSRSPPSATLSPLGAGPGSGGGPAGGALPLESWLGP PLPGGGATALQSLPGFGPPAQSLPASYTPPPPPPPFLNSPPLGPGLQPLAPPPPSYPCGPGFGDKFPLDEADPRNSSIAALRLK AKEHIQAIGKPWQAL

[0746] RAX may refer to the mouse sequence having the following amino acid sequence, identified as SEQ ID NO: 37

[0747] SEQ ID NO: 37

[0748] MHLPGCAPAMADGSFSLAGHLLRSPGGSTSRLHSIEAILGFTKEDGILDTFPAERSSRSSKERDPRLGAQPACPKAPAGGSES SPPAAPGFVPEYEATRPCYPKEQGEARPSPGLSVGPAAGDSKLSEEEPPKKKHRRNRTTFTTYQLHELERAFEKSHYPDVYS REELAGKVNLPEVRVQVWFQNRRAKWRRQEKLEVSSMKLQDSPLLSFSRSPPSSALAPLGTGPGSGSGPPGSALPLEPWLG PPLPGGGATALQSLPGFGPPGQGLPASYTPPPPFLNSAPLGPGLQQLGPPPAYPCAPAFGDKFSLEEAYPRNSSIAALRLKAKE HIQAIGKPWQAL

[0749] RAX may be encoded by the following human coding sequence, identified as SEQ ID NO: 38

[0750] SEQ ID NO: 38

[0751] ATGCACCTGCCGGGCTGCGCGCCAGCCATGGCCGACGGGAGCTTCTCGCTTGCCGGCCACCTGCTCCGCAGCCCGGG CGGGAGCACCTCGCGACTTCACAGCATCGAGGCCATCCTGGGGTTTACCAAGGACGACGGGATCCTCGGCACCTTCCC GGCGGAGCGGGGCGCCCGGGGCGCGAAGGAGCGGGATAGGAGGCTGGGCGCGCGGCCCGCCTGCCCCAAGGCGCC CGAGGAAGGCTCCGAGCCCTCCCCGCCGCCAGCCCCGGCGCCCGCCCCCGAGTACGAAGCCCCTCGACCCTACTGCC CCAAGGAGCCCGGGGAGGCACGGCCGAGCCCAGGGCTGCCCGTCGGGCCAGCCACCGGCGAAGCGAAACTGTCAGA

[0752] GGAGGAACAGCCCAAGAAAAAGCATCGGCGGAACCGCACGACTTTCACCACGTACCAGCTGCATGAGCTGGAGCGCGC GTTCGAGAAGTCCCACTACCCGGACGTGTACAGCCGCGAGGAGCTGGCCGGCAAGGTCAACCTACCAGAGGTCCGGGT CCAGGTGTGGTTCCAGAACCGACGGGCTAAGTGGCGGCGGCAGGAGAAGCTGGAAGTGTCCTCCATGAAGCTGCAGGA CTCGCCCCTCCTCTCCTTCAGCCGCTCCCCGCCCTCCGCGACGCTGTCGCCCCTCGGGGCGGGCCCGGGCAGCGGTG GCGGGCCGGCTGGGGGCGCGCTGCCGCTGGAGTCCTGGCTCGGGCCGCCGCTGCCGGGCGGGGGCGCCACGGCGC TGCAGAGCCTGCCGGGCTTCGGGCCGCCGGCGCAGAGCCTGCCTGCCAGCTACACGCCACCGCCGCCGCCTCCGCCC TTCCTGAACTCCCCGCCGTTGGGCCCCGGCCTGCAACCTCTCGCGCCGCCGCCGCCCTCCTACCCGTGCGGGCCCGG CTTCGGGGACAAGTTCCCGCTGGACGAGGCGGACCCGCGCAACAGCAGCATCGCGGCGCTGCGTCTGAAAGCCAAGG AGCACATCCAGGCCATCGGGAAGCCGTGGCAGGCCCTCTAG

[0753] RAX may be encoded by the following mouse coding sequence, identified as SEQ ID NO: 39

[0754] SEQ ID NO: 39

[0755] ATGCACCTGCCGGGCTGCGCGCCAGCCATGGCGGACGGGAGCTTCTCGCTCGCTGGCCACCTGCTCCGCAGCCCGGG

[0756] CGGGAGCACGTCGCGTTTGCACAGCATCGAAGCCATCCTGGGCTTTACCAAGGAAGACGGCATCCTAGACACCTTTCCT

[0757] GCAGAGAGGAGCTCCAGGAGCTCGAAAGAGCGGGATCCCAGGCTGGGCGCGCAGCCTGCCTGCCCCAAGGCGCCAGC

[0758] CGGAGGCTCCGAGTCTTCCCCACCAGCAGCCCCGGGATTCGTCCCGGAGTACGAAGCTACTAGGCCCTGCTACCCCAAG

[0759] GAGCAAGGAGAAGCACGTCCGAGCCCAGGACTCTCGGTTGGGCCAGCAGCAGGCGACTCGAAGCTGTCGGAGGAGGA

[0760] ACCTCCCAAGAAGAAGCATCGACGCAACCGCACGACGTTCACCACTTACCAACTGCACGAGCTGGAGCGCGCCTTCGAG

[0761] AAGTCCCACTACCCCGACGTGTACAGCCGCGAAGAGCTGGCCGGCAAGGTTAACCTACCCGAGGTTCGGGTCCAGGTAT GGTTCCAGAACCGACGGGCTAAGTGGAGGCGCCAGGAGAAACTGGAAGTGTCGTCCATGAAGCTGCAGGATTCTCCCCT

[0762] CCTCTCCTTCAGCCGCTCCCCGCCTTCCTCGGCACTGGCCCCGCTGGGAACCGGCCCGGGCAGCGGGAGCGGACCTC

[0763] CGGGGAGCGCCCTGCCGCTGGAGCCGTGGCTTGGGCCACCGCTGCCCGGAGGAGGCGCCACAGCGCTGCAGAGCCT

[0764] GCCGGGATTCGGGCCGCCGGGGCAGGGTCTCCCGGCCAGCTACACGCCACCACCGCCCTTCCTGAACTCCGCGCCCC

[0765] TGGGTCCAGGTCTGCAGCAGCTCGGGCCACCGCCCGCGTACCCCTGCGCGCCGGCATTCGGGGACAAGTTCTCGCTG

[0766] GAAGAGGCGTACCCGCGCAACAGCAGCATCGCCGCTCTGCGCCTGAAGGCCAAAGAGCACATCCAGGCCATCGGAAAG CCCTGGCAAGCCCTCTAG

[0767] RAX may be encoded by the following codon optimised human sequence, identified as SEQ ID NO: 40

[0768] SEQ ID NO: 40

[0769] ATGCATCTCCCCGGTTGTGCTCCTGCTATGGCTGATGGTTCATTTAGTCTCGCTGGACATCTTCTGCGAAGTCCCGGCGG

[0770] CTCAACTAGCAGGTTGCATTCCATAGAAGCAATACTTGGTTTCACAAAAGATGATGGAATACTGGGTACGTTTCCAGCCGAA

[0771] CGTGGGGCCCGAGGTGCTAAAGAACGCGACCGAAGACTTGGAGCAAGGCCTGCGTGTCCGAAAGCACCGGAAGAGGG

[0772] GTCTGAACCATCTCCTCCTCCTGCGCCCGCCCCAGCTCCAGAATATGAGGCTCCAAGACCTTATTGTCCTAAAGAACCTG

[0773] GAGAAGCCCGTCCTTCACCCGGTTTGCCTGTGGGCCCCGCAACAGGAGAGGCTAAACTTAGCGAAGAAGAGCAACCAAA

[0774] GAAGAAACACAGAAGGAATAGGACAACATTTACGACCTATCAACTTCACGAATTGGAACGGGCTTTTGAGAAAAGCCATTA

[0775] TCCAGATGTATATAGTCGGGAAGAACTTGCTGGGAAAGTAAATCTTCCCGAAGTAAGAGTGCAAGTCTGGTTTCAAAATAGA

[0776] CGCGCCAAATGGCGCCGACAAGAGAAATTGGAAGTCAGCTCTATGAAATTGCAAGATAGTCCTCTGCTGTCATTTTCCCGG

[0777] AGCCCACCTAGCGCAACACTCAGTCCGCTTGGAGCCGGACCAGGATCTGGTGGTGGACCTGCAGGCGGGGCCTTGCCA

[0778] CTCGAATCTTGGCTTGGACCACCACTCCCAGGTGGTGGAGCTACCGCTTTGCAATCTTTGCCCGGATTTGGTCCCCCTGC

[0779] CCAATCCTTGCCAGCATCATATACCCCGCCCCCTCCTCCACCACCTTTTCTCAATTCACCCCCACTGGGACCAGGTCTTCA GCCACTGGCTCCACCACCCCCGTCTTATCCATGTGGTCCAGGTTTTGGAGATAAATTTCCCCTCGATGAAGCCGATCCTCG

[0780] GAATTCTTCCATTGCTGCTCTCCGGCTCAAGGCAAAAGAACATATTCAAGCAATTGGTAAACCTTGGCAAGCACTGTAA

[0781] The functional variant of RAX may comprise an amino acid sequence at least 70% identical to SEQ ID NO: 36 or SEQ ID NO: 37. The functional variant of RAX may comprise an amino acid sequence at least 80% identical to SEQ ID NO: 36 or SEQ ID NO: 37. The functional variant of RAX may comprise an amino acid sequence at least 85% identical to SEQ ID NO: 36 or SEQ ID NO: 37. The functional variant of RAX may comprise an amino acid sequence at least 90% identical to SEQ ID NO: 36 or SEQ ID NO: 37. The functional variant of RAX may comprise an amino acid sequence at least 95% identical to SEQ ID NO: 36 or SEQ ID NO: 37. The functional variant of RAX may comprise an amino acid sequence at least 96% identical to SEQ ID NO: 36 or SEQ ID NO: 37. The functional variant of RAX may comprise an amino acid sequence at least 97% identical to SEQ ID NO: 36 or SEQ ID NO: 37. The functional variant of RAX may comprise an amino acid sequence at least 98% identical to SEQ ID NO: 36 or SEQ ID NO: 37. The functional variant of RAX may comprise an amino acid sequence at least 99% identical to SEQ ID NO: 36 or SEQ ID NO: 37. SEQ ID NO: 36 and SEQ ID NO: 37 share 299 identical amino acids out of 346 and thus are at least 86% identical to one another. The nucleic acid sequence may comprise any nucleic acid sequence encoding a functional variant of RAX. Therefore, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 70% identical to SEQ ID NO: 36 or SEQ ID NO: 37. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 90% identical to SEQ ID NO: 36 or SEQ ID NO: 37. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 86% identical to SEQ ID NO: 36 or SEQ ID NO: 37. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 87% identical to SEQ ID NO: 36 or SEQ ID NO: 37.

[0782] The functional variant of RAX may consist essentially of an amino acid sequence at least 70% identical to SEQ ID NO: 36 or SEQ ID NO: 37. The functional variant of RAX may consist essentially of any amino acid sequence described elsewhere herein as a sequence that the functional variant of RAX may comprise.

[0783] The nucleic acid sequence may comprise any nucleic acid sequence encoding RAX. RAX may comprise an amino acid sequence according to SEQ ID NO: 36 or SEQ ID NO: 37. Therefore, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 36 or SEQ ID NO: 37. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 36. Alternatively, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 37.

[0784] The nucleotide sequence encoding RAX, or a functional variant thereof may comprise a nucleic acid sequence encoding:

[0785] (a) SEQ ID NO: 36,

[0786] (b) SEQ ID NO: 37,

[0787] (c) an amino acid sequence having at least 70% identity to SEQ ID NO: 36 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 36, or

[0788] (d) an amino acid sequence having at least 70% identity to SEQ ID NO: 37 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 37.

[0789] The nucleotide sequence encoding RAX, or a functional variant thereof may consist essentially of a nucleic acid sequence encoding:

[0790] (a) SEQ ID NO: 36,

[0791] (b) SEQ ID NO: 37,

[0792] (c) an amino acid sequence having at least 70% identity to SEQ ID NO: 36 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 36, or (d) an amino acid sequence having at least 70% identity to SEQ ID NO: 37 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 37.

[0793] The nucleotide sequence encoding RAX, or a functional variant thereof may consist essentially of any nucleic acid sequence described elsewhere herein as a sequence that may encode RAX or functional variant of RAX.

[0794] The nucleotide sequence encoding RAX, or a functional variant thereof may comprise a nucleic acid sequence encoding:

[0795] (a) SEQ ID NO: 36,

[0796] (b) SEQ ID NO: 37,

[0797] (c) an amino acid sequence having at least 86% identity to SEQ ID NO: 36 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 36, or

[0798] (d) an amino acid sequence having at least 86% identity to SEQ ID NO: 37 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 37.

[0799] The nucleotide sequence encoding RAX, or a functional variant thereof may comprise:

[0800] (a) SEQ ID NO: 38,

[0801] (b) SEQ ID NO: 39,

[0802] (c) SEQ ID NO: 40, or

[0803] (d) a nucleotide sequence having at least 60% identity to SEQ ID NO: 38 or SEQ ID NO: 40, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 36, or

[0804] (e) a nucleotide sequence having at least 60% identity to SEQ ID NO: 39, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 37.

[0805] The nucleotide sequence encoding RAX or a functional variant thereof may comprise a nucleic acid sequence having at least 60% identity to SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40. The nucleotide sequence having at least 60% identity to SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40 may have at least 70%, 75%, 80%, 85%, 90% or 95% identity to SEQ ID NO: 38, SEQ ID NO: 39, or SEQ ID NO: 40, respectively. SEQ ID NO: 38 and SEQ ID NO: 39 share 878 identical nucleotides out of 1041 and thus are at least 84% identical to one another. SEQ ID NO: 38 and SEQ ID NO: 40 share 671 identical nucleotides out of 1041 and therefore have at least 64% sequence identity to each other and encode the same protein sequence. The non-identical nucleotides may represent silent mutations (i.e. mutations which do not alter the sequence of the encoded amino acid). The non-identical nucleotides may alterthe amino acid sequence of the encoded amino acid, for example by one or more conservative amino acid mutation. The non-identical nucleotides may alter the amino acid sequence of the encoded amino acid by up to 20, up to 15, up to 10, up to 9, up to 8, up to 7, up to 6, up to 5, up to 4, up to 3, up to 2 or up to 1 conservative amino acid mutation.

[0806] The nucleotide sequence encoding RAX, or a functional variant thereof may comprise:

[0807] (a) SEQ ID NO: 38,

[0808] (b) SEQ ID NO: 39,

[0809] (c) SEQ ID NO: 40, or (d) a nucleotide sequence having at least 64% identity to SEQ ID NO: 38 or SEQ ID NO: 40, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 36, or

[0810] (e) a nucleotide sequence having at least 64% identity to SEQ ID NO: 39, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 37.

[0811] The nucleotide sequence encoding RAX, or a functional variant thereof may comprise:

[0812] (a) SEQ ID NO: 38,

[0813] (b) SEQ ID NO: 39,

[0814] (c) SEQ ID NO: 40, or

[0815] (d) a nucleotide sequence having at least 84% identity to SEQ ID NO: 38 or SEQ ID NO: 40, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 36, or

[0816] (e) a nucleotide sequence having at least 84% identity to SEQ ID NO: 39, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 37.

[0817] The nucleic acid sequence may encode RAX. The nucleotide sequence encoding RAX may comprise:

[0818] (a) SEQ ID NO: 38,

[0819] (b) SEQ ID NO: 39, or

[0820] (c) SEQ ID NO: 40.

[0821] In an alternative statement of the first aspect, the nucleic acid molecule may encode at least two transcription factors, or functional variants thereof, wherein one transcription factor is RAX and wherein the at least two transcription factors further comprise at least one transcription factor selected from the group consisting of NEUROD1 , FOXJ1 and OTX2.

[0822] In an alternative statement, the transcription factors may comprise:

[0823] (a) RAX and NEUROD1;

[0824] (b) RAX and FOXJ1; or

[0825] (c) RAX and OTX2.

[0826] In an alternative statement, the transcription factors may comprise:

[0827] (a) RAX, FOXJ1 and NEUROD1;

[0828] (b) RAX, OTX2 and FOXJ1; or

[0829] (c) RAX, OTX2 and NEUROD1.

[0830] In any of the alternative statements comprising RAX, the at least two transcription factors may further comprise CRX and / or one or more further transcription factor, such as one or more proneural bHLH transcription factor as described herein.

[0831] As used herein, “NEUROG2” refers to neurogenin 2. In humans it is encoded by the NEUROG2 gene, also known as BHLHa8, NGN2, Math4A, Atoh4 and Ngn-2. The mouse ortholog Neurog2 is also known as neurogenin 2. In humans, the Ensembl gene ID is ENSG00000178403, such as ENSG00000178403.4. An example of a transcript is the Ensembl transcript ID ENST00000313341, such as ENST00000313341.4 and the UniProt ID is Q9H2A3, such as Q9H2A3 v2; codon-optimised and alternatively spliced transcript variants are encompassed. In mice, an Ensembl gene ID is ENSMUSG00000027967. An example of a transcript is the Ensembl transcript ID ENSMUST00000029587, such as ENSMUST00000029587.9 and the UniProt ID is Q6GTH9, such as Q6GTH9 v1 ; codon-optimised and alternatively spliced transcript variants are encompassed.

[0832] NEUROG2 may refer to the human sequence having the following amino acid sequence, identified as SEQ ID NO: 41

[0833] SEQ ID NO: 41

[0834] MFVKSETLELKEEEDVLVLLGSASPALAALTPLSSSADEEEEEEPGASGGARRQRGAEAGQGARGGVAAGAEGCRPARLLGL VHDCKRRPSRARAVSRGAKTAETVQRIKKTRRLKANNRERNRMHNLNAALDALREVLPTFPEDAKLTKIETLRFAHNYIWALTE TLRLADHCGGGGGGLPGALFSEAVLLSPGGASAALSSSGDSPSPASTWSCTNSPAPSSSVSSNSTSPYSCTLSPASPAGSDM DYWQPPPPDKHRYAPHLPIARDCI

[0835] NEUROG2 may refer to the mouse sequence having the following amino acid sequence, identified as SEQ ID NO: 42

[0836] SEQ ID NO: 42

[0837] MFVKSETLELKEEEEVLMLLGSASPASATLTPMSSSADEEEDEELRRPGSARGQRGAEAGQGVQGSPASGAGGCRPGRLLG LMHECKRRPSRSRAVSRGAKTAETVQRIKKTRRLKANNRERNRMHNLNAALDALREVLPTFPEDAKLTKIETLRFAHNYIWALT ETLRLADHCAGAGGLQGALFTEAVLLSPGAALGASGDSPSPPSSWSCTNSPASSSNSTSPYSCTLSPASPGSDVDYWQPPPP EKHRYAPHLPLARDCI

[0838] NEUROG2 may be encoded by the following human coding sequence, identified as SEQ ID NO: 43

[0839] SEQ ID NO: 43

[0840] ATGTTCGTCAAATCCGAGACCTTGGAGTTGAAGGAGGAAGAGGACGTGTTAGTGCTGCTCGGATCGGCCTCCCCCGCCT TGGCGGCCCTGACCCCGCTGTCATCCAGCGCCGACGAAGAAGAGGAGGAGGAGCCGGGCGCGTCAGGCGGGGCGCG TCGGCAGCGCGGGGCTGAGGCCGGGCAGGGGGCGCGGGGCGGCGTGGCTGCGGGTGCGGAGGGCTGCCGGCCCGC ACGGCTGCTGGGTCTGGTACACGATTGCAAACGGCGCCCTTCCCGGGCGCGGGCCGTCTCCCGAGGCGCCAAGACGG CCGAGACGGTGCAGCGCATCAAGAAGACCCGTAGACTGAAGGCCAACAACCGCGAGCGAAACCGCATGCACAACCTCA ACGCGGCACTGGACGCGCTGCGCGAGGTGCTCCCCACGTTCCCCGAGGACGCCAAGCTCACCAAGATCGAGACCCTG CGCTTCGCCCACAACTACATCTGGGCACTCACCGAGACCCTGCGCCTGGCGGATCACTGCGGGGGCGGCGGCGGGGG CCTGCCGGGGGCGCTCTTCTCCGAGGCAGTGTTGCTGAGCCCGGGAGGAGCCAGCGCCGCCCTGAGCAGCAGCGGAG ACAGCCCCTCGCCCGCCTCCACGTGGAGTTGCACCAACAGCCCCGCGCCGTCCTCCTCCGTGTCCTCCAATTCCACCTC CCCCTACAGCTGCACTTTATCGCCCGCCAGCCCGGCCGGGTCAGACATGGACTATTGGCAGCCCCCACCTCCCGACAAG CACCGCTATGCACCTCACCTCCCCATAGCCAGGGATTGTATCTAG

[0841] NEUROG2 may be encoded by the following mouse coding sequence, identified as SEQ ID NO: 44

[0842] SEQ ID NO: 44

[0843] ATGTTCGTCAAATCTGAGACTCTGGAGTTGAAGGAGGAAGAGGAGGTACTGATGCTGCTGGGCTCGGCTTCCCCGGCCT CGGCGACCCTGACCCCGATGTCCTCCAGCGCGGACGAGGAGGAGGACGAGGAGCTGCGCCGGCCGGGCTCCGCGCG TGGGCAGCGTGGAGCGGAAGCCGGGCAGGGGGTGCAGGGCAGTCCGGCGTCGGGTGCCGGGGGTTGCCGGCCAGG GCGGCTGCTGGGCCTGATGCACGAGTGCAAGCGTCGCCCGTCGCGCTCACGGGCCGTCTCCCGAGGTGCCAAGACGG CGGAGACGGTGCAGCGCATCAAGAAGACCCGCAGGCTCAAGGCCAACAACCGCGAGCGCAACCGCATGCACAACCTAA ACGCCGCGCTGGACGCGCTGCGCGAGGTGCTGCCCACCTTCCCCGAGGATGCCAAGCTCACGAAGATCGAGACGCTGC GCTTCGCCCACAATTACATCTGGGCGCTCACCGAGACTCTGCGCCTGGCGGACCACTGCGCCGGCGCCGGTGGCCTCC AGGGGGCGCTCTTCACGGAGGCGGTGCTCCTGAGCCCGGGAGCTGCGCTCGGCGCCAGCGGGGACAGCCCTTCTCCA CCTTCCTCCTGGAGCTGCACCAACAGCCCGGCGTCATCCTCCAACTCCACGTCCCCATACAGCTGCACTTTATCGCCCGC TAGCCCCGGGTCAGACGTGGACTACTGGCAGCCCCCACCTCCGGAGAAGCATCGTTATGCGCCTCACCTGCCCCTCGCC AGGGACTGTATCTAG

[0844] NEUR0G2 may be encoded by the following codon optimised human sequence, identified as SEQ ID NO: 45

[0845] SEQ ID NO: 45

[0846] ATGTTTGTGAAGTCTGAAACACTGGAACTCAAAGAAGAGGAAGATGTTCTGGTCCTTCTGGGGAGCGCGTCTCCTGCGCT GGCCGCTCTCACTCCTCTCAGCTCATCTGCAGATGAGGAAGAAGAAGAAGAACCTGGGGCCAGCGGTGGCGCACGGAG ACAAAGAGGAGCCGAAGCTGGCCAAGGAGCTCGCGGTGGGGTTGCAGCCGGAGCTGAAGGTTGTCGTCCTGCCAGAC TTCTCGGCCTCGTCCATGACTGTAAGAGACGGCCATCTAGGGCCAGGGCTGTGAGCCGGGGCGCAAAGACAGCTGAAA CCGTTCAAAGGATAAAGAAAACGAGGCGCCTCAAAGCAAATAATCGAGAAAGGAATCGGATGCATAATCTTAATGCTGCTTT GGATGCTTTGAGGGAAGTCCTGCCTACTTTTCCTGAAGATGCGAAACTGACCAAAATAGAAACGCTCAGATTTGCACATAA TTATATATGGGCCCTGACTGAAACACTCCGGCTCGCCGACCATTGTGGCGGTGGTGGAGGAGGTTTGCCAGGAGCACTG TTTAGTGAAGCTGTTCTGCTTAGTCCCGGCGGGGCTTCAGCGGCACTCTCCTCTTCAGGGGATTCACCGTCCCCAGCTTC AACTTGGTCTTGTACGAATTCTCCGGCTCCTAGCAGTAGCGTTAGTAGCAACTCTACAAGCCCATATTCTTGTACGCTGTCT CCGGCGTCACCAGCTGGAAGCGATATGGATTACTGGCAACCGCCCCCACCAGATAAACATAGGTACGCTCCCCATTTGCC GATCGCTCGCGACTGCATTTAA

[0847] The functional variant of NEUROG2 may comprise an amino acid sequence at least 70% identical to SEQ ID NO: 41 or SEQ ID NO: 42. The functional variant of NEUROG2 may comprise an amino acid sequence at least 80% identical to SEQ ID NO: 41 or SEQ ID NO: 42. The functional variant of NEUROG2 may comprise an amino acid sequence at least 85% identical to SEQ ID NO: 41 or SEQ ID NO: 42. The functional variant of NEUROG2 may comprise an amino acid sequence at least 90% identical to SEQ ID NO: 41 or SEQ ID NO: 42. The functional variant of NEUROG2 may comprise an amino acid sequence at least 95% identical to SEQ ID NO: 41 or SEQ ID NO: 42. The functional variant of NEUROG2 may comprise an amino acid sequence at least 96% identical to SEQ ID NO: 41 or SEQ ID NO: 42. The functional variant of NEUROG2 may comprise an amino acid sequence at least 97% identical to SEQ ID NO: 41 or SEQ ID NO: 42. The functional variant of NEUROG2 may comprise an amino acid sequence at least 98% identical to SEQ ID NO: 41 or SEQ ID NO: 42. The functional variant of NEUROG2 may comprise an amino acid sequence at least 99% identical to SEQ ID NO: 41 or SEQ ID NO: 42. SEQ ID NO: 41 and SEQ ID NO: 42 share 227 identical amino acids out of 272 and thus are at least 83% identical to one another. The nucleic acid sequence may comprise any nucleic acid sequence encoding a functional variant of NEUROG2. Therefore, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 70% identical to SEQ ID NO: 41 or SEQ ID NO: 42. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 90% identical to SEQ ID NO: 41 or SEQ ID NO: 42. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 83% identical to SEQ ID NO: 41 or SEQ ID NO: 42. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 84% identical to SEQ ID NO: 41 or SEQ ID NO: 42.

[0848] The functional variant of NEUROG2 may consist essentially of an amino acid sequence at least 70% identical to SEQ ID NO: 41 or SEQ ID NO: 42. The functional variant of NEUROG2 may consist essentially of any amino acid sequence described elsewhere herein as a sequence that the functional variant of NEUROG2 may comprise.

[0849] The nucleic acid sequence may comprise any nucleic acid sequence encoding NEUROG2. NEUROG2 may comprise an amino acid sequence according to SEQ ID NO: 41 or SEQ ID NO: 42. Therefore, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 41 or SEQ ID NO: 42. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 41. Alternatively, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 42.

[0850] The nucleotide sequence encoding NEUROG2, or a functional variant thereof may comprise a nucleic acid sequence encoding:

[0851] (a) SEQ ID NO: 41,

[0852] (b) SEQ ID NO: 42,

[0853] (c) an amino acid sequence having at least 70% identity to SEQ ID NO: 41 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 41 , or

[0854] (d) an amino acid sequence having at least 70% identity to SEQ ID NO: 42 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 42.

[0855] The nucleotide sequence encoding NEUROG2, or a functional variant thereof may consist essentially of a nucleic acid sequence encoding:

[0856] (a) SEQ ID NO: 41,

[0857] (b) SEQ ID NO: 42,

[0858] (c) an amino acid sequence having at least 70% identity to SEQ ID NO: 41 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 41 , or

[0859] (d) an amino acid sequence having at least 70% identity to SEQ ID NO: 42 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 42.

[0860] The nucleotide sequence encoding NEUROG2, or a functional variant thereof may consist essentially of any nucleic acid sequence described elsewhere herein as a sequence that may encode NEUROG2 or functional variant of NEUROG2.

[0861] The nucleotide sequence encoding NEUROG2, or a functional variant thereof may comprise a nucleic acid sequence encoding:

[0862] (a) SEQ ID NO: 41,

[0863] (b) SEQ ID NO: 42,

[0864] (c) an amino acid sequence having at least 83% identity to SEQ ID NO: 41 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 41 , or (d) an amino acid sequence having at least 83% identity to SEQ ID NO: 42 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 42.

[0865] The nucleotide sequence encoding NEUROG2, or a functional variant thereof may comprise:

[0866] (a) SEQ ID NO: 43,

[0867] (b) SEQ ID NO: 44,

[0868] (c) SEQ ID NO: 45, or

[0869] (d) a nucleotide sequence having at least 60% identity to SEQ ID NO: 43 or SEQ ID NO: 45, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 41 , or

[0870] (e) a nucleotide sequence having at least 60% identity to SEQ ID NO: 44, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 42.

[0871] The nucleotide sequence encoding NEUROG2 or a functional variant thereof may comprise a nucleic acid sequence having at least 60% identity to SEQ ID NO: 43, SEQ ID NO: 44, or SEQ ID NO: 45. The nucleotide sequence having at least 60% identity to SEQ ID NO: 43, SEQ ID NO: 44, or SEQ ID NO: 45 may have at least 70%, 75%, 80%, 85%, 90% or 95% identity to SEQ ID NO: 43, SEQ ID NO: 44, or SEQ ID NO: 45, respectively. SEQ ID NO: 43 and SEQ ID NO: 44 share 672 identical nucleotides out of 819 and thus are at least 82% identical to one another. SEQ ID NO: 43 and SEQ ID NO: 45 share 504 identical nucleotides out of 819 and therefore have at least 61% sequence identity to each other and encode the same protein sequence. The nonidentical nucleotides may represent silent mutations (i.e. mutations which do not alter the sequence of the encoded amino acid). The non-identical nucleotides may alter the amino acid sequence of the encoded amino acid, for example by one or more conservative amino acid mutation. The non-identical nucleotides may alter the amino acid sequence of the encoded amino acid by up to 20, up to 15, up to 10, up to 9, up to 8, up to 7, up to 6, up to 5, up to 4, up to 3, up to 2 or up to 1 conservative amino acid mutation.

[0872] The nucleotide sequence encoding NEUROG2, or a functional variant thereof may comprise:

[0873] (a) SEQ ID NO: 43,

[0874] (b) SEQ ID NO: 44,

[0875] (c) SEQ ID NO: 45, or

[0876] (d) a nucleotide sequence having at least 61% identity to SEQ ID NO: 43 or SEQ ID NO: 45, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 41 , or

[0877] (e) a nucleotide sequence having at least 61% identity to SEQ ID NO: 44, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 42.

[0878] The nucleotide sequence encoding NEUROG2, or a functional variant thereof may comprise:

[0879] (a) SEQ ID NO: 43,

[0880] (b) SEQ ID NO: 44,

[0881] (c) SEQ ID NO: 45, or

[0882] (d) a nucleotide sequence having at least 82% identity to SEQ ID NO: 43 or SEQ ID NO: 45, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 41 , or (e) a nucleotide sequence having at least 82% identity to SEQ ID NO: 44, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 42.

[0883] The nucleic acid sequence may encode NEUROG2. The nucleotide sequence encoding NEUROG2 may comprise:

[0884] (a) SEQ ID NO: 43,

[0885] (b) SEQ ID NO: 44, or

[0886] (c) SEQ ID NO: 45.

[0887] In an alternative statement of the first aspect, the nucleic acid molecule may encode at least two transcription factors, or functional variants thereof, wherein one transcription factor is NEUROG2 and wherein the at least two transcription factors further comprise at least one transcription factor selected from the group consisting of NEUROD1, FOXJ1 and OTX2.

[0888] In an alternative statement, the transcription factors may comprise:

[0889] (a) NEUROG2 and NEURODI;

[0890] (b) NEUROG2 and FOXJ1; or

[0891] (c) NEUROG2 and OTX2.

[0892] In an alternative statement, the transcription factors may comprise:

[0893] (a) NEUROG2, FOXJ1 and NEUROD1;

[0894] (b) NEUROG2, OTX2 and FOXJ1; or

[0895] (c) NEUROG2, OTX2 and NEUROD1.

[0896] In any of the alternative statements comprising NEUROG2, the at least two transcription factors may further comprise CRX and / or one or more further transcription factor, such as one or more proneural bHLH transcription factor as described herein.

[0897] As used herein, “ASCL1” refers to Achaete-Scute Family BHLH Transcription Factor 1. In humans it is encoded by the ASCL1 gene, also known as HASH1, BHLHa46, ASH1, Class A Basic Helix-Loop-Helix Protein 46, Achaete-Scute Homolog 1, and ASH-1. The mouse ortholog Ascii is also known as Achaete-Scute Family BHLH Transcription Factor 1. In humans, the Ensembl gene ID is ENSG00000139352, such as ENSG00000139352.4. An example of a transcript is the Ensembl transcript ID ENST00000266744, ENST00000266744.4 and the UniProt ID is P50553, such as P50553 v2; codon-optimised and alternatively spliced transcript variants are encompassed. In mice, an Ensembl gene ID is ENSMUSG00000020052. An example of a transcript is the Ensembl transcript ID ENSMUST00000020243, such as ENSMUST00000020243.10 and the UniProt ID is Q02067, such as Q02067 v2; codon-optimised and alternatively spliced transcript variants are encompassed.

[0898] ASCL1 may refer to the human sequence having the following amino acid sequence, identified as SEQ ID NO: 46

[0899] SEQ ID NO: 46

[0900] MESSAKMESGGAGQQPQPQPQQPFLPPAACFFATAAAAAAAAAAAAAQSAQQQQQQQQQQQQAPQLRPAADGQPSGGGH KSAPKQVKRQRSSSPELMRCKRRLNFSGFGYSLPQQQPAAVARRNERERNRVKLVNLGFATLREHVPNGAANKKMSKVETLR SAVEYIRALQQLLDEHDAVSAAFQAGVLSPTISPNYSNDLNSMAGSPVSSYSSDEGSYDPLSPEEQELLDFTNWF ASCL1 may refer to the mouse sequence having the following amino acid sequence, identified as SEQ ID NO: 47

[0901] SEQ ID NO: 47

[0902] MESSGKMESGAGQQPQPPQPFLPPAACFFATAAAAAAAAAAAAQSAQQQQPQAPPQQAPQLSPVADSQPSGGGHKSAAKQ

[0903] VKRQRSSSPELMRCKRRLNFSGFGYSLPQQQPAAVARRNERERNRVKLVNLGFATLREHVPNGAANKKMSKVETLRSAVEYI

[0904] RALQQLLDEHDAVSAAFQAGVLSPTISPNYSNDLNSMAGSPVSSYSSDEGSYDPLSPEEQELLDFTNWF

[0905] ASCL1 may be encoded by the following human coding sequence, identified as SEQ ID NO: 48

[0906] SEQ ID NO: 48

[0907] ATGGAAAGCTCTGCCAAGATGGAGAGCGGCGGCGCCGGCCAGCAGCCCCAGCCGCAGCCCCAGCAGCCCTTCCTGCC

[0908] GCCCGCAGCCTGTTTCTTTGCCACGGCCGCAGCCGCGGCGGCCGCAGCCGCCGCAGCGGCAGCGCAGAGCGCGCAG

[0909] CAGCAGCAGCAGCAGCAGCAGCAGCAGCAGCAGGCGCCGCAGCTGAGACCGGCGGCCGACGGCCAGCCCTCAGGGG

[0910] GCGGTCACAAGTCAGCGCCCAAGCAAGTCAAGCGACAGCGCTCGTCTTCGCCCGAACTGATGCGCTGCAAACGCCGGC

[0911] TCAACTTCAGCGGCTTTGGCTACAGCCTGCCGCAGCAGCAGCCGGCCGCCGTGGCGCGCCGCAACGAGCGCGAGCGC

[0912] AACCGCGTCAAGTTGGTCAACCTGGGCTTTGCCACCCTTCGGGAGCACGTCCCCAACGGCGCGGCCAACAAGAAGATG

[0913] AGTAAGGTGGAGACACTGCGCTCGGCGGTCGAGTACATCCGCGCGCTGCAGCAGCTGCTGGACGAGCATGACGCGGTG

[0914] AGCGCCGCCTTCCAGGCAGGCGTCCTGTCGCCCACCATCTCCCCCAACTACTCCAACGACTTGAACTCCATGGCCGGCT

[0915] CGCCGGTCTCATCCTACTCGTCGGACGAGGGCTCTTACGACCCGCTCAGCCCCGAGGAGCAGGAGCTTCTCGACTTCAC

[0916] CAACTGGTTCTGA

[0917] ASCL1 may be encoded by the following mouse coding sequence, identified as SEQ ID NO: 49

[0918] SEQ ID NO: 49

[0919] ATGGAGAGCTCTGGCAAGATGGAGAGTGGAGCCGGCCAGCAGCCGCAGCCCCCGCAGCCCTTCCTGCCTCCCGCAGC

[0920] CTGCTTCTTTGCGACCGCGGCGGCGGCGGCAGCGGCGGCGGCCGCGGCAGCTCAGAGCGCGCAGCAGCAACAGCCG

[0921] CAGGCGCCGCCGCAGCAGGCGCCGCAGCTGAGCCCGGTGGCCGACAGCCAGCCCTCAGGGGGCGGTCACAAGTCAG

[0922] CGGCCAAGCAGGTCAAGCGCCAGCGCTCGTCCTCTCCGGAACTGATGCGCTGCAAACGCCGGCTCAACTTCAGCGGCT

[0923] TCGGCTACAGCCTGCCACAGCAGCAGCCGGCCGCCGTGGCGCGCCGCAACGAGCGCGAGCGCAACCGGGTCAAGTTG

[0924] GTCAACCTGGGTTTTGCCACCCTCCGGGAGCATGTCCCCAACGGCGCGGCCAACAAGAAGATGAGCAAGGTGGAGACG

[0925] CTGCGCTCGGCGGTCGAGTACATCCGCGCGCTGCAGCAGCTGCTGGACGAGCACGACGCGGTGAGCGCTGCCTTTCAG

[0926] GCGGGCGTCCTGTCGCCCACCATCTCCCCCAACTACTCCAACGACTTGAACTCTATGGCGGGTTCTCCGGTCTCGTCCTA

[0927] CTCCTCCGACGAGGGATCCTACGACCCTCTTAGCCCAGAGGAACAAGAGCTGCTGGACTTTACCAACTGGTTCTGA

[0928] ASCL1 may be encoded by the following codon optimised human sequence, identified as SEQ ID NO: 50

[0929] SEQ ID NO: 50

[0930] ATGGAGAGCTCAGCTAAAATGGAAAGCGGCGGTGCTGGTCAACAACCGCAACCACAACCGCAACAACCGTTTCTTCCAC

[0931] CTGCCGCATGCTTCTTTGCGACTGCTGCCGCTGCTGCTGCAGCTGCGGCTGCTGCCGCCGCCCAATCCGCACAACAGC AGCAACAACAGCAACAGCAACAGCAACAAGCACCCCAACTCCGTCCAGCTGCAGATGGTCAACCAAGTGGAGGAGGGC ATAAATCTGCTCCTAAACAGGTGAAACGGCAACGATCATCCTCTCCGGAGTTGATGCGTTGTAAGCGGCGACTTAATTTTA GTGGGTTCGGGTATTCACTCCCTCAACAACAACCAGCTGCTGTCGCCCGGCGGAATGAACGTGAACGGAATAGGGTAAA ACTGGTAAATCTTGGTTTCGCGACTCTGCGAGAACATGTTCCGAATGGGGCCGCTAATAAGAAAATGTCTAAAGTTGAAAC CTTGCGGAGTGCCGTTGAATATATTCGGGCATTGCAACAACTCCTTGATGAACACGATGCAGTCTCCGCTGCGTTTCAAGC TGGTGTGCTCTCCCCTACTATATCTCCTAATTATAGCAATGATCTCAATTCAATGGCGGGAAGCCCAGTTAGTAGTTATTCAA GTGATGAAGGTTCCTATGATCCCCTTTCACCGGAAGAACAAGAACTCCTGGATTTTACTAATTGGTTTTGA

[0932] The functional variant of ASCL1 may comprise an amino acid sequence at least 70% identical to SEQ ID NO: 46 or SEQ ID NO: 47. The functional variant of ASCL1 may comprise an amino acid sequence at least 80% identical to SEQ ID NO: 46 or SEQ ID NO: 47. The functional variant of ASCL1 may comprise an amino acid sequence at least 85% identical to SEQ ID NO: 46 or SEQ ID NO: 47. The functional variant of ASCL1 may comprise an amino acid sequence at least 90% identical to SEQ ID NO: 46 or SEQ ID NO: 47. The functional variant of ASCL1 may comprise an amino acid sequence at least 95% identical to SEQ ID NO: 46 or SEQ ID NO: 47. The functional variant of ASCL1 may comprise an amino acid sequence at least 96% identical to SEQ ID NO: 46 or SEQ ID NO: 47. The functional variant of ASCL1 may comprise an amino acid sequence at least 97% identical to SEQ ID NO: 46 or SEQ ID NO: 47. The functional variant of ASCL1 may comprise an amino acid sequence at least 98% identical to SEQ ID NO: 46 or SEQ ID NO: 47. The functional variant of ASCL1 may comprise an amino acid sequence at least 99% identical to SEQ ID NO: 46 or SEQ ID NO: 47. SEQ ID NO: 46 and SEQ ID NO: 47 share 161 identical amino acids out of 236 and thus are at least 68% identical to one another. The nucleic acid sequence may comprise any nucleic acid sequence encoding a functional variant of ASCL1. Therefore, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 70% identical to SEQ ID NO: 46 or SEQ ID NO: 47. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 90% identical to SEQ ID NO: 46 or SEQ ID NO: 47. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 68% identical to SEQ ID NO: 46 or SEQ ID NO: 47. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 69% identical to SEQ ID NO: 46 or SEQ ID NO: 47.

[0933] The functional variant of ASCL1 may consist essentially of an amino acid sequence at least 70% identical to SEQ ID NO: 46 or SEQ ID NO: 47. The functional variant of ASCL1 may consist essentially of any amino acid sequence described elsewhere herein as a sequence that the functional variant of ASCL1 may comprise.

[0934] The nucleic acid sequence may comprise any nucleic acid sequence encoding ASCL1. ASCL1 may comprise an amino acid sequence according to SEQ ID NO: 46 or SEQ ID NO: 47. Therefore, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 46 or SEQ ID NO: 47. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 46. Alternatively, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 47.

[0935] The nucleotide sequence encoding ASCL1, or a functional variant thereof may comprise a nucleic acid sequence encoding:

[0936] (a) SEQ ID NO: 46,

[0937] (b) SEQ ID NO: 47, (c) an amino acid sequence having at least 70% identity to SEQ ID NO: 46 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 46, or

[0938] (d) an amino acid sequence having at least 70% identity to SEQ ID NO: 47 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 47.

[0939] The nucleotide sequence encoding ASCL1, or a functional variant thereof may consist essentially of a nucleic acid sequence encoding:

[0940] (a) SEQ ID NO: 46,

[0941] (b) SEQ ID NO: 47,

[0942] (c) an amino acid sequence having at least 70% identity to SEQ ID NO: 46 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 46, or

[0943] (d) an amino acid sequence having at least 70% identity to SEQ ID NO: 47 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 47.

[0944] The nucleotide sequence encoding ASCL1 , or a functional variant thereof may consist essentially of any nucleic acid sequence described elsewhere herein as a sequence that may encode ASCL1 or functional variant of ASCL1.

[0945] The nucleotide sequence encoding ASCL1, or a functional variant thereof may comprise a nucleic acid sequence encoding:

[0946] (a) SEQ ID NO: 46,

[0947] (b) SEQ ID NO: 47,

[0948] (c) an amino acid sequence having at least 68% identity to SEQ ID NO: 46 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 46, or

[0949] (d) an amino acid sequence having at least 68% identity to SEQ ID NO: 47 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 47.

[0950] The nucleotide sequence encoding ASCL1 , or a functional variant thereof may comprise:

[0951] (a) SEQ ID NO: 48,

[0952] (b) SEQ ID NO: 49,

[0953] (c) SEQ ID NO: 50, or

[0954] (d) a nucleotide sequence having at least 60% identity to SEQ ID NO: 48 or SEQ ID NO: 50, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 46, or

[0955] (e) a nucleotide sequence having at least 60% identity to SEQ ID NO: 49, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 47.

[0956] The nucleotide sequence encoding ASCL1 or a functional variant thereof may comprise a nucleic acid sequence having at least 60% identity to SEQ ID NO: 48, SEQ ID NO: 49, or SEQ ID NO: 50. The nucleotide sequence having at least 60% identity to SEQ ID NO: 48, SEQ ID NO: 49, or SEQ ID NO: 50 may have at least 70%, 75%, 80%, 85%, 90% or 95% identity to SEQ ID NO: 48, SEQ ID NO: 49, or SEQ ID NO: 50, respectively. SEQ ID NO: 48 and SEQ ID NO: 49 share 636 identical nucleotides out of 711 and thus are at least 89% identical to one another. SEQ ID NO: 48 and SEQ ID NO: 50 share 469 identical nucleotides out of 711 and therefore have at least 65% sequence identity to each other and encode the same protein sequence. The non- identical nucleotides may represent silent mutations (i.e. mutations which do not alter the sequence of the encoded amino acid). The non-identical nucleotides may alter the amino acid sequence of the encoded amino acid, for example by one or more conservative amino acid mutation. The non-identical nucleotides may alter the amino acid sequence of the encoded amino acid by up to 20, up to 15, up to 10, up to 9, up to 8, up to 7, up to 6, up to 5, up to 4, up to 3, up to 2 or up to 1 conservative amino acid mutation.

[0957] The nucleotide sequence encoding ASCL1 , or a functional variant thereof may comprise:

[0958] (a) SEQ ID NO: 48,

[0959] (b) SEQ ID NO: 49,

[0960] (c) SEQ ID NO: 50, or

[0961] (d) a nucleotide sequence having at least 65% identity to SEQ ID NO: 48 or SEQ ID NO: 50, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 46, or

[0962] (e) a nucleotide sequence having at least 65% identity to SEQ ID NO: 49, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 47.

[0963] The nucleotide sequence encoding ASCL1 , or a functional variant thereof may comprise:

[0964] (a) SEQ ID NO: 48,

[0965] (b) SEQ ID NO: 49,

[0966] (c) SEQ ID NO: 50, or

[0967] (d) a nucleotide sequence having at least 89% identity to SEQ ID NO: 48 or SEQ ID NO: 50, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 46, or

[0968] (e) a nucleotide sequence having at least 89% identity to SEQ ID NO: 49, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 47.

[0969] The nucleic acid sequence may encode ASCL1. The nucleotide sequence encoding ASCL1 may comprise:

[0970] (a) SEQ ID NO: 48,

[0971] (b) SEQ ID NO: 49, or

[0972] (c) SEQ ID NO: 50.

[0973] In an alternative statement of the first aspect, the nucleic acid molecule may encode at least two transcription factors, or functional variants thereof, wherein one transcription factor is ASCL1 and wherein the at least two transcription factors further comprise at least one transcription factor selected from the group consisting of NEUROD1 , FOXJ1 and OTX2.

[0974] In an alternative statement, the transcription factors may comprise:

[0975] (a)ASCL1 and NEURODI;

[0976] (b) ASCL1 and FOXJ1; or

[0977] (c) ASCL1 and OTX2.

[0978] In an alternative statement, the transcription factors may comprise:

[0979] (a) ASCL1, FOXJ1 and NEUROD1; (b) ASCL1 , 0TX2 and FOXJ1; or

[0980] (c) ASCL1 , 0TX2 and NEUR0D1.

[0981] In any of the alternative statements comprising ASCL1 , the at least two transcription factors may further comprise CRX and / or one or more further transcription factor, such as one or more proneural bHLH transcription factor as described herein.

[0982] As used herein, “MESP2” refers to Mesoderm Posterior BHLH Transcription Factor 2. In humans it is encoded by the MESP2 gene, also known as BHLHc6, SCDO2 and Mesoderm Posterior Basic Helix-Loop-Helix Transcription Factor 2. The mouse ortholog Mesp2 is also known as Mesoderm Posterior BHLH Transcription Factor 2. In humans, the Ensembl gene ID is ENSG00000188095, such as ENSG00000188095.6. An example of a transcript is the Ensembl transcript ID ENST00000560219, such as ENST00000560219.2 and the UniProt ID is H0YKZ5, such as H0YKZ5 v1 ; codon-optimised and alternatively spliced transcript variants are encompassed. In mice, an Ensembl gene ID is ENSMUSG00000030543. An example of a transcript is the Ensembl transcript ID ENSMUST00000107394, such as ENSMUST00000107394.3 and the UniProt ID is A6H5V4, such as A6H5V4 v1; codon-optimised and alternatively spliced transcript variants are encompassed.

[0983] MESP2 may refer to the human sequence having the following amino acid sequence, identified as SEQ ID NO: 51

[0984] SEQ ID NO: 51

[0985] MSHHARPNCMGLSVSPEPCLSLGAPSLLPHPSCQRLQPQTPGRCWSHSAEWPNSEDQGPGAAFQLSEASPPQSSGLRFS GCPELWQEDLEGARLGIFY

[0986] MESP2 may refer to the mouse sequence having the following amino acid sequence, identified as SEQ ID NO: 52

[0987] SEQ ID NO: 52

[0988] MAQSPPPQSLQGLDHVWFSQGWGWAQQSDSTSPASSSDSSGSCPCYATRRPSQPAGPARSTRTTQATAPRRTRPAPAGGQ RQSASEREKLRMRTLARALQELRRFLPPSVAPAGQSLTKIETLRLAIRYIGHLSALLGLSEDSLRRRRRRSADAAFSHRCPQCP DGGSPSQAQMLGPSLGSAMSSGVSWGCPPACPGPLISPENLGNRISNVDPWVTPPYCPQIQSPLHQSLERAADSSPWAPPQ ACPGMQMSPEPRNKTGHWTQSTEPAELTKVYQSLSVSPEPCLSLGSPLLLPRPSCQRLQPQPQPQPQWGCWGHDAEVLST SEDQGSSPALQLPVASPTPSSGLQLSGCPELWQEDLEGPPLNIFY

[0989] MESP2 may be encoded by the following human coding sequence, identified as SEQ ID NO: 53

[0990] SEQ ID NO: 53

[0991] ATGAGCCACCACGCCCGGCCAAATTGTATGGGTCTCTCTGTGTCTCCAGAGCCCTGTCTGTCGCTGGGAGCTCCATCTCT CCTGCCCCACCCATCATGCCAGAGACTGCAGCCTCAGACCCCCGGGAGGTGCTGGAGCCACAGTGCAGAGGTGGTGCC CAACTCAGAGGACCAGGGACCGGGCGCCGCCTTCCAGCTCAGTGAAGCAAGCCCTCCCCAGAGCTCAGGCCTGCGGTT CAGTGGCTGCCCTGAACTTTGGCAAGAAGATCTGGAGGGGGCCCGCCTGGGCATCTTCTACTAA

[0992] MESP2 may be encoded by the following mouse coding sequence, identified as SEQ ID NO: 54 SEQ ID NO: 54

[0993] ATGGCCCAGTCGCCTCCTCCTCAGAGCCTCCAGGGTCTCGACCACTGGGTCTTCTCCCAGGGCTGGGGCTGGGCTCAG CAATCGGACTCCACGTCTCCGGCCTCGTCCTCAGATTCGTCCGGTTCCTGCCCTTGCTACGCCACCCGTCGGCCCTCGC AGCCCGCCGGCCCGGCCCGTAGCACGCGCACTACCCAGGCGACGGCGCCCCGACGAACGCGCCCAGCGCCCGCAGG CGGACAGCGGCAGAGCGCCAGCGAGCGCGAGAAGCTGCGCATGCGCACACTCGCCCGCGCGCTGCAAGAACTGCGCC GCTTCCTGCCGCCGTCGGTGGCACCTGCAGGCCAGAGCCTGACCAAGATCGAGACGCTGCGCCTGGCCATCCGCTACA TCGGCCACCTGTCAGCCCTGCTGGGCCTCAGCGAGGACAGTCTGCGGCGCAGGCGCCGACGGAGTGCGGACGCGGC GTTCTCTCACCGATGCCCTCAATGCCCCGACGGTGGCAGCCCCTCACAGGCTCAGATGCTTGGTCCTAGCCTGGGATCA GCCATGAGTAGTGGGGTGTCCTGGGGGTGCCCGCCTGCTTGTCCTGGACCTCTGATCTCACCTGAAAACCTTGGGAACA GGATCTCCAACGTGGATCCCTGGGTGACACCTCCTTATTGTCCCCAAATACAGTCACCCTTACACCAGTCCCTAGAAAGAG CCGCTGACTCCTCTCCCTGGGCACCACCTCAAGCATGTCCTGGCATGCAGATGTCCCCAGAGCCTAGGAACAAGACTGG ACACTGGACACAATCCACTGAACCTGCAGAGCTGACTAAAGTGTATCAGAGTCTTTCTGTGTCTCCAGAACCCTGCCTGT CCCTGGGAAGCCCACTTCTCCTGCCCCGCCCATCATGCCAGAGACTACAGCCTCAGCCTCAGCCTCAGCCTCAGTGGGG CTGCTGGGGCCACGATGCAGAGGTGCTCTCCACCTCTGAGGATCAGGGTTCCAGCCCTGCCCTCCAGCTTCCTGTGGC CAGCCCCACCCCCAGCTCAGGCCTGCAGCTCAGTGGCTGTCCTGAACTTTGGCAGGAAGACCTGGAAGGACCCCCACT GAATATTTTCTACTAA

[0994] MESP2 may be encoded by the following codon optimised human sequence, identified as SEQ ID NO: 55

[0995] SEQ ID NO: 55

[0996] ATGTCACATCATGCGAGACCGAACTGCATGGGACTGAGTGTCTCACCTGAACCGTGCCTCAGTCTTGGCGCACCTTCCCT GCTTCCACATCCGTCTTGTCAACGGCTCCAACCCCAAACTCCTGGTCGGTGTTGGAGTCATTCTGCTGAAGTTGTACCAA ATTCCGAAGATCAAGGGCCTGGTGCAGCTTTTCAACTGAGCGAGGCCTCTCCCCCACAATCTTCTGGATTAAGGTTTTCTG GGTGTCCCGAGCTGTGGCAAGAGGACCTCGAAGGAGCGCGACTCGGTATATTTTATTGA

[0997] The functional variant of MESP2 may comprise an amino acid sequence at least 70% identical to SEQ ID NO: 51 or SEQ ID NO: 52. The functional variant of MESP2 may comprise an amino acid sequence at least 80% identical to SEQ ID NO: 51 or SEQ ID NO: 52. The functional variant of MESP2 may comprise an amino acid sequence at least 85% identical to SEQ ID NO: 51 or SEQ ID NO: 52. The functional variant of MESP2 may comprise an amino acid sequence at least 90% identical to SEQ ID NO: 51 or SEQ ID NO: 52. The functional variant of MESP2 may comprise an amino acid sequence at least 95% identical to SEQ ID NO: 51 or SEQ ID NO: 52. The functional variant of MESP2 may comprise an amino acid sequence at least 96% identical to SEQ ID NO: 51 or SEQ ID NO: 52. The functional variant of MESP2 may comprise an amino acid sequence at least 97% identical to SEQ ID NO: 51 or SEQ ID NO: 52. The functional variant of MESP2 may comprise an amino acid sequence at least 98% identical to SEQ ID NO: 51 or SEQ ID NO: 52. The functional variant of MESP2 may comprise an amino acid sequence at least 99% identical to SEQ ID NO: 51 or SEQ ID NO: 52. SEQ ID NO: 51 and SEQ ID NO: 52 share 63 identical amino acids out of 92 and thus are at least 68% identical to one another. The nucleic acid sequence may comprise any nucleic acid sequence encoding a functional variant of MESP2. Therefore, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 70% identical to SEQ ID NO: 51 or SEQ ID NO: 52. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 90% identical to SEQ ID NO: 51 or SEQ ID NO: 52. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 68% identical to SEQ ID NO: 51 or SEQ ID NO: 52. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 69% identical to SEQ ID NO: 51 or SEQ ID NO: 52.

[0998] The functional variant of MESP2 may consist essentially of an amino acid sequence at least 70% identical to SEQ ID NO: 51 or SEQ ID NO: 52. The functional variant of MESP2 may consist essentially of any amino acid sequence described elsewhere herein as a sequence that the functional variant of MESP2 may comprise.

[0999] The nucleic acid sequence may comprise any nucleic acid sequence encoding MESP2. MESP2 may comprise an amino acid sequence according to SEQ ID NO: 51 or SEQ ID NO: 52. Therefore, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 51 or SEQ ID NO: 52. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 51. Alternatively, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 52.

[1000] The nucleotide sequence encoding MESP2, or a functional variant thereof may comprise a nucleic acid sequence encoding:

[1001] (a) SEQ ID NO: 51,

[1002] (b) SEQ ID NO: 52,

[1003] (c) an amino acid sequence having at least 70% identity to SEQ ID NO: 51 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 51 , or

[1004] (d) an amino acid sequence having at least 70% identity to SEQ ID NO: 52 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 52.

[1005] The nucleotide sequence encoding MESP2, or a functional variant thereof may consist essentially of a nucleic acid sequence encoding:

[1006] (a) SEQ ID NO: 51,

[1007] (b) SEQ ID NO: 52,

[1008] (c) an amino acid sequence having at least 70% identity to SEQ ID NO: 51 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 51 , or

[1009] (d) an amino acid sequence having at least 70% identity to SEQ ID NO: 52 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 52.

[1010] The nucleotide sequence encoding MESP2, or a functional variant thereof may consist essentially of any nucleic acid sequence described elsewhere herein as a sequence that may encode MESP2 or functional variant of MESP2.

[1011] The nucleotide sequence encoding MESP2, or a functional variant thereof may comprise a nucleic acid sequence encoding:

[1012] (a) SEQ ID NO: 51,

[1013] (b) SEQ ID NO: 52,

[1014] (c) an amino acid sequence having at least 68% identity to SEQ ID NO: 51 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 51 , or (d) an amino acid sequence having at least 68% identity to SEQ ID NO: 52 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 52.

[1015] The nucleotide sequence encoding MESP2, or a functional variant thereof may comprise:

[1016] (a) SEQ ID NO: 53,

[1017] (b) SEQ ID NO: 54,

[1018] (c) SEQ ID NO: 55, or

[1019] (d) a nucleotide sequence having at least 60% identity to SEQ ID NO: 53 or SEQ ID NO: 55, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 51 , or

[1020] (e) a nucleotide sequence having at least 60% identity to SEQ ID NO: 54, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 52.

[1021] The nucleotide sequence encoding MESP2 or a functional variant thereof may comprise a nucleic acid sequence having at least 60% identity to SEQ ID NO: 53, SEQ ID NO: 54, or SEQ ID NO: 55. The nucleotide sequence having at least 60% identity to SEQ ID NO: 53, SEQ ID NO: 54, or SEQ ID NO: 55 may have at least 70%, 75%, 80%, 85%, 90% or 95% identity to SEQ ID NO: 53, SEQ ID NO: 54, or SEQ ID NO: 55, respectively. SEQ ID NO: 53 and SEQ ID NO: 54 share 222 identical nucleotides out of 294 and thus are at least 75% identical to one another. S EQ I D NO: 53 and S EQ I D NO: 55 share 179 identical nucleotides out of 278 and therefore have at least 64% sequence identity to each other and encode the same protein sequence. The nonidentical nucleotides may represent silent mutations (i.e. mutations which do not alter the sequence of the encoded amino acid). The non-identical nucleotides may alter the amino acid sequence of the encoded amino acid, for example by one or more conservative amino acid mutation. The non-identical nucleotides may alter the amino acid sequence of the encoded amino acid by up to 20, up to 15, up to 10, up to 9, up to 8, up to 7, up to 6, up to 5, up to 4, up to 3, up to 2 or up to 1 conservative amino acid mutation.

[1022] The nucleotide sequence encoding MESP2, or a functional variant thereof may comprise:

[1023] (a) SEQ ID NO: 53,

[1024] (b) SEQ ID NO: 54,

[1025] (c) SEQ ID NO: 55, or

[1026] (d) a nucleotide sequence having at least 64% identity to SEQ ID NO: 53 or SEQ ID NO: 55, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 51 , or

[1027] (e) a nucleotide sequence having at least 64% identity to SEQ ID NO: 54, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 52.

[1028] The nucleotide sequence encoding MESP2, or a functional variant thereof may comprise:

[1029] (a) SEQ ID NO: 53,

[1030] (b) SEQ ID NO: 54,

[1031] (c) SEQ ID NO: 55, or

[1032] (d) a nucleotide sequence having at least 75% identity to SEQ ID NO: 53 or SEQ ID NO: 55, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 51 , or (e) a nucleotide sequence having at least 75% identity to SEQ ID NO: 54, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 52.

[1033] The nucleic acid sequence may encode MESP2. The nucleotide sequence encoding MESP2 may comprise:

[1034] (a) SEQ ID NO: 53,

[1035] (b) SEQ ID NO: 54, or

[1036] (c) SEQ ID NO: 55.

[1037] In an alternative statement of the first aspect, the nucleic acid molecule may encode at least two transcription factors, or functional variants thereof, wherein one transcription factor is MESP2 and wherein the at least two transcription factors further comprise at least one transcription factor selected from the group consisting of NEUROD1 , FOXJ1 and OTX2.

[1038] In an alternative statement, the transcription factors may comprise:

[1039] (a) MESP2 and NEURODI;

[1040] (b) MESP2 and FOXJ1; or

[1041] (c) MESP2 and OTX2.

[1042] In an alternative statement, the transcription factors may comprise:

[1043] (a) MESP2, FOXJ1 and NEURODI;

[1044] (b) MESP2, OTX2 and FOXJ1; or

[1045] (c) MESP2, OTX2 and NEURODI.

[1046] In any of the alternative statements comprising MESP2, the at least two transcription factors may further comprise CRX and / or one or more further transcription factor, such as one or more proneural bHLH transcription factor as described herein.

[1047] As used herein, “RAX2” refers to Retina and Anterior Neural Fold Homeobox 2. In humans it is encoded by the RAX2 gene, also known as CORD11, ARMD6, RAXL1 and Retina and Anterior Neural Fold Homeobox-Like Protein 1. In humans, the Ensembl gene I D is E NSG00000173976, such as ENSG00000173976.16. An example of a transcript is the Ensembl transcript ID ENST00000555633, such as ENST00000555633.3 and the UniProt ID is Q96IS3, such as Q96IS3 v1 ; codon-optimised and alternatively spliced transcript variants are encompassed.

[1048] RAX2 may refer to the human sequence having the following amino acid sequence, identified as SEQ ID NO: 56

[1049] SEQ ID NO: 56

[1050] MFLSPGEGPATEGGGLGPGEEAPKKKHRRNRTTFTTYQLHQLERAFEASHYPDVYSREELAAKVHLPEVRVQVWFQNRRAK WRRQERLESGSGAVAAPRLPEAPALPFARPPAMSLPLEPWLGPGPPAVPGLPRLLGPGPGLQASFGPHAFAPTFADGFALEEA SLRLLAKEHAQALDRAWPPA

[1051] RAX2 may be encoded by the following human coding sequence, identified as SEQ ID NO: 57

[1052] SEQ ID NO: 57 ATGTTCCTGAGCCCGGGCGAGGGGCCGGCAACCGAGGGTGGGGGTCTGGGGCCGGGCGAGGAGGCCCCCAAGAAGA AGCACCGGAGGAACCGCACCACCTTCACCACCTACCAGCTGCACCAGCTGGAGCGGGCGTTCGAGGCCTCTCACTACC CGGATGTGTACAGCCGTGAGGAGCTGGCAGCCAAGGTGCACCTACCTGAGGTGCGCGTGCAGGTGTGGTTCCAGAACC GCCGGGCCAAGTGGCGCCGCCAGGAGCGGCTGGAGTCAGGCTCGGGTGCCGTGGCAGCTCCGAGACTCCCCGAGGC CCCAGCGCTGCCGTTCGCCCGCCCCCCGGCCATGTCGCTGCCCCTGGAGCCCTGGTTGGGCCCCGGACCGCCGGCCG TGCCAGGCCTCCCCCGCCTCCTGGGCCCGGGCCCGGGGCTGCAAGCGTCCTTCGGGCCTCATGCCTTTGCTCCCACCT TCGCAGATGGCTTCGCCCTGGAGGAGGCGTCCCTGCGGCTGCTGGCCAAGGAACATGCACAGGCTCTGGACAGGGCCT GGCCGCCAGCCTGA

[1053] RAX2 may be encoded by the following codon optimised human sequence, identified as SEQ ID NO: 58

[1054] SEQ ID NO: 58

[1055] ATGTTTCTCTCCCCAGGGGAAGGACCAGCTACAGAAGGCGGCGGGCTTGGCCCTGGTGAAGAAGCTCCGAAGAAGAAA CATCGTCGCAATCGAACGACTTTTACTACATATCAACTTCATCAATTGGAAAGAGCATTTGAGGCTTCCCATTATCCTGACGT CTATAGTCGCGAAGAATTGGCCGCTAAAGTCCATCTCCCCGAAGTAAGAGTCCAAGTATGGTTTCAAAATAGGCGTGCTAA ATGGCGTAGGCAAGAAAGACTTGAAAGTGGATCAGGGGCAGTCGCGGCCCCCAGACTGCCTGAAGCTCCCGCCTTGCC ATTTGCTAGGCCCCCTGCAATGAGTTTGCCACTTGAACCTTGGTTAGGACCAGGACCCCCTGCGGTTCCCGGACTGCCTA GGTTACTTGGACCCGGACCCGGACTCCAGGCTTCTTTTGGACCCCACGCTTTCGCCCCTACATTTGCCGACGGGTTTGCT TTGGAAGAAGCCAGCCTCAGGTTGTTGGCAAAAGAGCACGCTCAAGCCCTTGATCGGGCTTGGCCACCCGCTTAG

[1056] The functional variant of RAX2 may comprise an amino acid sequence at least 70% identical to SEQ ID NO: 56. The functional variant of RAX2 may comprise an amino acid sequence at least 80% identical to SEQ ID NO: 56. The functional variant of RAX2 may comprise an amino acid sequence at least 85% identical to SEQ ID NO: 56. The functional variant of RAX22 may comprise an amino acid sequence at least 90% identical to SEQ ID NO: 56. The functional variant of RAX2 may comprise an amino acid sequence at least 95% identical to SEQ ID NO: 56. The functional variant of RAX2 may comprise an amino acid sequence at least 96% identical to SEQ ID NO: 56. The functional variant of RAX2 may comprise an amino acid sequence at least 97% identical to SEQ ID NO: 56. The functional variant of RAX2 may comprise an amino acid sequence at least 98% identical to SEQ ID NO: 56. The functional variant of RAX2 may comprise an amino acid sequence at least 99% identical to SEQ ID NO: 56. The nucleic acid sequence may comprise any nucleic acid sequence encoding a functional variant of RAX2. Therefore, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 70% identical to SEQ ID NO: 56. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 90% identical to SEQ ID NO: 56. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 95% identical to SEQ ID NO: 56. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 99% identical to SEQ ID NO: 56.

[1057] The functional variant of RAX2 may consist essentially of an amino acid sequence at least 70% identical to SEQ ID NO: 56. The functional variant of RAX2 may consist essentially of any amino acid sequence described elsewhere herein as a sequence that the functional variant of RAX2 may comprise. The nucleic acid sequence may comprise any nucleic acid sequence encoding RAX2. RAX2 may comprise an amino acid sequence according to SEQ ID NO: 56. Therefore, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 56. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 56.

[1058] The nucleotide sequence encoding RAX2, or a functional variant thereof may comprise a nucleic acid sequence encoding:

[1059] (a) SEQ ID NO: 56, or

[1060] (b) an amino acid sequence having at least 70% identity to SEQ ID NO: 56 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 56.

[1061] The nucleotide sequence encoding RAX2, or a functional variant thereof may consist essentially of a nucleic acid sequence encoding:

[1062] (a) SEQ ID NO: 56,

[1063] (b) an amino acid sequence having at least 70% identity to SEQ ID NO: 56 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 56.

[1064] The nucleotide sequence encoding RAX2, or a functional variant thereof may consist essentially of any nucleic acid sequence described elsewhere herein as a sequence that may encode RAX2 or functional variant of RAX2.

[1065] The nucleotide sequence encoding RAX2, or a functional variant thereof may comprise a nucleic acid sequence encoding:

[1066] (a) SEQ ID NO: 56,

[1067] (b) an amino acid sequence having at least 95% identity to SEQ ID NO: 56 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 56.

[1068] The nucleotide sequence encoding RAX2, or a functional variant thereof may comprise:

[1069] (a) SEQ ID NO: 57,

[1070] (b) SEQ ID NO: 58, or

[1071] (c) a nucleotide sequence having at least 60% identity to SEQ ID NO: 57 or SEQ ID NO: 58, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 56.

[1072] The nucleotide sequence encoding RAX2, or a functional variant thereof may comprise a nucleic acid sequence having at least 60% identity to SEQ ID NO: 57, or SEQ ID NO: 58. The nucleotide sequence having at least 60% identity to SEQ ID NO: 57, or SEQ ID NO: 58 may have at least 70%, 75%, 80%, 85%, 90% or95% identity to SEQ ID NO: 57, orSEQ ID NO: 58, respectively. SEQ ID NO: 57 and SEQ ID NO: 58 share 365 identical nucleotides out of 555 and therefore have at least 65% sequence identity to each other and encode the same protein sequence. The non-identical nucleotides may represent silent mutations (i.e. mutations which do not alter the sequence of the encoded amino acid). The non-identical nucleotides may alter the amino acid sequence of the encoded amino acid, for example by one or more conservative amino acid mutation. The non-identical nucleotides may alter the amino acid sequence of the encoded amino acid by up to 20, up to 15, up to 10, up to 9, up to 8, up to 7, up to 6, up to 5, up to 4, up to 3, up to 2 or up to 1 conservative amino acid mutation. The nucleotide sequence encoding RAX2, or a functional variant thereof may comprise:

[1073] (a) SEQ ID NO: 57,

[1074] (b) SEQ ID NO: 58, or

[1075] (c) a nucleotide sequence having at least 65% identity to SEQ ID NO: 57 or SEQ ID NO: 58, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 56.

[1076] The nucleic acid sequence may encode RAX2. The nucleotide sequence encoding RAX2 may comprise:

[1077] (a) SEQ ID NO: 57, or

[1078] (b) SEQ ID NO: 58.

[1079] In an alternative statement of the first aspect, the nucleic acid molecule may encode at least two transcription factors, or functional variants thereof, wherein one transcription factor is RAX2 and wherein the at least two transcription factors further comprise at least one transcription factor selected from the group consisting of NEUROD1 , FOXJ1 and OTX2.

[1080] In an alternative statement, the transcription factors may comprise:

[1081] (a) RAX2 and NEUROD1;

[1082] (b) RAX2 and FOXJ1; or

[1083] (c) RAX2 and OTX2.

[1084] In an alternative statement, the transcription factors may comprise:

[1085] (a) RAX2, FOXJ1 and NEUROD1;

[1086] (b) RAX2, OXT2 and FOXJ1; or

[1087] (c) RAX2, OTX2 and NEURODI.

[1088] In any of the alternative statements comprising RAX2, the at least two transcription factors may further comprise CRX and / or one or more further transcription factor, such as one or more proneural bHLH transcription factor as described herein.

[1089] As used herein, “ATOH7” refers to Atonal BHLH Transcription Factor 7. In humans it is encoded by the AT0H7 gene, also known as BHLHal 3, Math5, Atonal Homolog BHLH Transcription Factor 7, Class A Basic Helix-Loop-Helix Protein 13, Transcription Factor ATOH7 and Protein Atonal Homolog 7. The mouse ortholog Atoh7 is also known as Atonal BHLH Transcription Factor 7. In humans, the Ensembl gene ID is ENSG00000179774, such as ENSG00000179774.8. An example of a transcript is the Ensembl transcript ID ENST00000373673, such as ENST00000373673.5 and the UniProt ID is Q8N100, such as Q8N100 v1; codon-optimised and alternatively spliced transcript variants are encompassed. In mice, an Ensembl gene ID is ENSMUSG00000036816. An example of a transcript is the Ensembl transcript ID ENSMUST00000044059, such as ENSMUST00000044059.5 and the UniProt ID is Q9Z2E5, such as Q9Z2E5 v1; codon-optimised and alternatively spliced transcript variants are encompassed.

[1090] ATOH7 may refer to the human sequence having the following amino acid sequence, identified as SEQ ID NO: 59

[1091] SEQ ID NO: 59 MKSCKPSGPPAGARVAPPCAGGTECAGTCAGAGRLESAARRRLAANARERRRMQGLNTAFDRLRRWPQWGQDKKLSKYE

[1092] TLQMALSYIMALTRILAEAERFGSERDWVGLHCEHFGRDHYLPFPGAKLPGESELYSQRLFGFQPEPFQMAT

[1093] AT0H7 may refer to the mouse sequence having the following amino acid sequence, identified as SEQ ID NO: 60

[1094] SEQ ID NO: 60

[1095] MKSACKPHGPPAGARGAPPCAGAAERAVSCAGPGRLESAARRRLAANARERRRMQGLNTAFDRLRRWPQWGQDKKLSKY

[1096] ETLQMALSYIIALTRILAEAERDVWGLRCEQRGRDHPYLPFPGARLQVDPEPYGQRLFGFQPEPFPMAS

[1097] ATOH7 may be encoded by the following human coding sequence, identified as SEQ ID NO: 61

[1098] SEQ ID NO: 61

[1099] ATGAAGTCCTGCAAGCCCAGCGGCCCGCCGGCGGGAGCGCGCGTTGCACCCCCGTGCGCGGGCGGCACCGAGTGCG

[1100] CGGGCACGTGCGCCGGGGCCGGGCGGCTGGAGAGCGCGGCGCGCAGGCGCCTGGCGGCCAACGCGCGCGAGCGCC

[1101] GCCGCATGCAGGGGCTCAACACTGCCTTCGACCGCTTACGCAGGGTGGTTCCCCAGTGGGGCCAGGATAAAAAGCTGT

[1102] CCAAGTACGAGACCCTGCAGATGGCCCTGAGCTACATCATGGCTCTGACCCGGATCCTGGCCGAGGCCGAGCGATTCGG

[1103] CTCGGAGCGGGACTGGGTGGGTCTCCACTGTGAGCACTTCGGCCGCGACCACTACCTCCCGTTCCCGGGCGCGAAGCT

[1104] GCCGGGCGAGAGCGAGCTGTACAGCCAGAGACTCTTCGGCTTCCAGCCCGAGCCCTTCCAGATGGCCACCTAG

[1105] ATOH7 may be encoded by the following mouse coding sequence, identified as SEQ ID NO: 62

[1106] SEQ ID NO: 62

[1107] ATGAAGTCGGCCTGCAAACCCCACGGCCCTCCGGCGGGAGCTCGCGGCGCGCCCCCGTGCGCGGGCGCAGCCGAGC

[1108] GCGCGGTCTCGTGCGCGGGGCCCGGGCGGCTGGAGAGCGCGGCGCGCAGGCGTCTGGCGGCCAACGCGCGCGAGC

[1109] GGCGCCGCATGCAGGGGCTGAACACGGCGTTCGACCGGCTGCGCAGGGTGGTGCCGCAGTGGGGCCAGGACAAGAA

[1110] GCTGTCCAAGTACGAGACACTGCAGATGGCGCTCAGCTACATCATCGCGCTCACCCGCATCCTAGCCGAAGCCGAGCGG

[1111] GACTGGGTCGGGCTGCGCTGCGAGCAGCGGGGCCGCGATCACCCCTACCTCCCTTTCCCGGGTGCTAGGCTCCAGGTA

[1112] GACCCTGAGCCCTATGGGCAGAGGCTCTTCGGCTTCCAGCCGGAGCCCTTCCCCATGGCCAGCTAA

[1113] ATOH7 may be encoded by the following codon optimised human sequence, identified as SEQ ID NO: 63

[1114] SEQ ID NO: 63

[1115] ATGAAATCATGTAAACCTTCTGGCCCACCTGCAGGCGCACGAGTCGCGCCGCCTTGTGCAGGTGGGACGGAATGTGCAG

[1116] GAACTTGTGCTGGAGCTGGTAGGCTCGAAAGTGCAGCCCGTCGAAGATTGGCTGCTAATGCCAGAGAAAGGCGGCGGAT

[1117] GCAAGGCCTGAATACAGCATTTGATAGATTGAGGCGCGTAGTGCCACAATGGGGTCAAGACAAGAAACTTTCTAAATATGA

[1118] AACATTGCAAATGGCTTTGTCTTATATAATGGCCTTGACTCGAATTTTGGCTGAAGCTGAAAGGTTTGGAAGCGAAAGGGAT

[1119] TGGGTCGGGTTGCATTGCGAACATTTTGGAAGGGATCATTATCTGCCATTTCCTGGGGCAAAATTGCCTGGAGAATCTGAA

[1120] CTCTATAGTCAAAGGCTGTTTGGTTTTCAACCAGAACCATTTCAAATGGCAACTTGA The functional variant of ATOH7 may comprise an amino acid sequence at least 70% identical to SEQ ID NO: 59 or SEQ ID NO: 60. The functional variant of ATOH7 may comprise an amino acid sequence at least 80% identical to SEQ ID NO: 59 or SEQ ID NO: 60. The functional variant of ATOH7 may comprise an amino acid sequence at least 85% identical to SEQ ID NO: 59 or SEQ ID NO: 60. The functional variant of ATOH7 may comprise an amino acid sequence at least 90% identical to SEQ ID NO: 59 or SEQ ID NO: 60. The functional variant ofATOH7 may comprise an amino acid sequence at least 95% identical to SEQ ID NO: 59 or SEQ ID NO: 60. The functional variant of ATOH7 may comprise an amino acid sequence at least 96% identical to SEQ ID NO: 59 or SEQ ID NO: 60. The functional variant of ATOH7 may comprise an amino acid sequence at least 97% identical to SEQ ID NO: 59 or SEQ ID NO: 60. The functional variant of ATOH7 may comprise an amino acid sequence at least 98% identical to SEQ ID NO: 59 or SEQ ID NO: 60. The functional variant of ATOH7 may comprise an amino acid sequence at least 99% identical to SEQ ID NO: 59 or SEQ ID NO: 60. SEQ ID NO: 59 and SEQ ID NO: 60 share 126 identical amino acids out of 152 and thus are at least 82% identical to one another. The nucleic acid sequence may comprise any nucleic acid sequence encoding a functional variant of ATOH7. Therefore, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 70% identical to SEQ ID NO: 59 or SEQ ID NO: 60. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 90% identical to SEQ ID NO: 59 or SEQ ID NO: 60. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 82% identical to SEQ ID NO: 59 or SEQ ID NO: 60. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 83% identical to SEQ ID NO: 59 or SEQ ID NO: 60.

[1121] The functional variant of ATOH7 may consist essentially of an amino acid sequence at least 70% identical to SEQ ID NO: 59 or SEQ ID NO: 60. The functional variant of ATOH7 may consist essentially of any amino acid sequence described elsewhere herein as a sequence that the functional variant of ATOH7 may comprise.

[1122] The nucleic acid sequence may comprise any nucleic acid sequence encoding ATOH7. ATOH7 may comprise an amino acid sequence according to SEQ ID NO: 59 or SEQ ID NO: 60. Therefore, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 59 or SEQ ID NO: 60. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 59. Alternatively, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 60.

[1123] The nucleotide sequence encoding ATOH7, or a functional variant thereof may comprise a nucleic acid sequence encoding:

[1124] (a) SEQ ID NO: 59,

[1125] (b) SEQ ID NO: 60,

[1126] (c) an amino acid sequence having at least 70% identity to SEQ ID NO: 59 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 59, or

[1127] (d) an amino acid sequence having at least 70% identity to SEQ ID NO: 60 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 60.

[1128] The nucleotide sequence encoding ATOH7, or a functional variant thereof may consist essentially of a nucleic acid sequence encoding:

[1129] (a) SEQ ID NO: 59, (b) SEQ ID NO: 60,

[1130] (c) an amino acid sequence having at least 70% identity to SEQ ID NO: 59 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 59, or

[1131] (d) an amino acid sequence having at least 70% identity to SEQ ID NO: 60 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 60.

[1132] The nucleotide sequence encoding ATOH7, or a functional variant thereof may consist essentially of any nucleic acid sequence described elsewhere herein as a sequence that may encode ATOH7 or functional variant of ATOH7.

[1133] The nucleotide sequence encoding ATOH7, or a functional variant thereof may comprise a nucleic acid sequence encoding:

[1134] (a) SEQ ID NO: 59,

[1135] (b) SEQ ID NO: 60,

[1136] (c) an amino acid sequence having at least 82% identity to SEQ ID NO: 59 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 59, or

[1137] (d) an amino acid sequence having at least 82% identity to SEQ ID NO: 60 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 60.

[1138] The nucleotide sequence encoding ATOH7, or a functional variant thereof may comprise:

[1139] (a) SEQ ID NO: 61,

[1140] (b) SEQ ID NO: 62,

[1141] (c) SEQ ID NO: 63, or

[1142] (d) a nucleotide sequence having at least 60% identity to SEQ ID NO: 61 or SEQ ID NO: 63, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 59, or

[1143] (e) a nucleotide sequence having at least 60% identity to SEQ ID NO: 62, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 60.

[1144] The nucleotide sequence encoding ATOH7 or a functional variant thereof may comprise a nucleic acid sequence having at least 60% identity to SEQ ID NO: 61, SEQ ID NO: 62, or SEQ ID NO: 63. The nucleotide sequence having at least 60% identity to SEQ ID NO: 61, SEQ ID NO: 62, or SEQ ID NO: 63 may have at least 70%, 75%, 80%, 85%, 90% or 95% identity to SEQ ID NO: 61 , SEQ ID NO: 62, or SEQ ID NO: 63, respectively. SEQ ID NO: 61 and SEQ ID NO: 62 share 367 identical nucleotides out of 459 and thus are at least 79% identical to one another. SEQ ID NO: 61 and SEQ ID NO: 63 share 394 identical nucleotides out of 459 and therefore have at least 85% sequence identity to each other and encode the same protein sequence. The nonidentical nucleotides may represent silent mutations (i.e. mutations which do not alter the sequence of the encoded amino acid). The non-identical nucleotides may alter the amino acid sequence of the encoded amino acid, for example by one or more conservative amino acid mutation. The non-identical nucleotides may alter the amino acid sequence of the encoded amino acid by up to 20, up to 15, up to 10, up to 9, up to 8, up to 7, up to 6, up to 5, up to 4, up to 3, up to 2 or up to 1 conservative amino acid mutation.

[1145] The nucleotide sequence encoding ATOH7, or a functional variant thereof may comprise:

[1146] (a) SEQ ID NO: 61, (b) SEQ ID NO: 62,

[1147] (c) SEQ ID NO: 63, or

[1148] (d) a nucleotide sequence having at least 85% identity to SEQ ID NO: 61 or SEQ ID NO: 63, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 59, or

[1149] (e) a nucleotide sequence having at least 85% identity to SEQ ID NO: 62, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 60.

[1150] The nucleotide sequence encoding ATOH7, or a functional variant thereof may comprise:

[1151] (a) SEQ ID NO: 61,

[1152] (b) SEQ ID NO: 62,

[1153] (c) SEQ ID NO: 63, or

[1154] (d) a nucleotide sequence having at least 79% identity to SEQ ID NO: 61 or SEQ ID NO: 63, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 59, or

[1155] (e) a nucleotide sequence having at least 79% identity to SEQ ID NO: 62, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 60.

[1156] The nucleic acid sequence may encode ATOH7. The nucleotide sequence encoding ATOH7 may comprise:

[1157] (a) SEQ ID NO: 61,

[1158] (b) SEQ ID NO: 62, or

[1159] (c) SEQ ID NO: 63.

[1160] In an alternative statement of the first aspect, the nucleic acid molecule may encode at least two transcription factors, or functional variants thereof, wherein one transcription factor is ATOH7 and wherein the at least two transcription factors further comprise at least one transcription factor selected from the group consisting of NEUROD1 , FOXJ1 and OTX2.

[1161] In an alternative statement, the transcription factors may comprise:

[1162] (a)ATOH7 and NEUROD1;

[1163] (b)ATOH7 and FOXJ1; or

[1164] (c) ATOH7 and OTX2.

[1165] In an alternative statement, the transcription factors may comprise:

[1166] (a)ATOH7, FOXJ1 and NEUROD1;

[1167] (b) ATOH7, OTX2 and FOXJ1; or

[1168] (c)ATOH7, OTX2 and NEUROD1.

[1169] In any of the alternative statements comprising ATOH7, the at least two transcription factors may further comprise CRX and / or one or more further transcription factor, such as one or more proneural bHLH transcription factor as described herein.

[1170] As used herein, “ATOH1” refers to Atonal BHLH Transcription Factor 1. In humans it is encoded by the AT0H1 gene, also known as BHLHa14, HATH1, MATH-1, Atonal Homolog BHLH Transcription Factor 1, Class A Basic Helix-Loop-Helix Protein 14, Basic Helix-Loop-Helix Family Member A14 and Helix-Loop-Helix Protein HATH-1. The mouse ortholog Atohl is also known as to Atonal BHLH Transcription Factor 1. In humans, the Ensembl gene ID is ENSG00000172238, such as ENSG00000172238.6. An example of a transcript is the Ensembl transcript ID ENST00000306011 , such as ENST00000306011.6 and the UniProt ID is Q92858, such as Q92858 v1 ; codon-optimised and alternatively spliced transcript variants are encompassed. In mice, an Ensembl gene ID is ENSMUSG00000073043. An example of a transcript is the Ensembl transcript ID ENSMUST00000101351 , such as ENSMUST00000101351 .6 and the UniProt ID is P48985, such as P48985 v1 ; codon-optimised and alternatively spliced transcript variants are encompassed.

[1171] ATOH1 may refer to the human sequence having the following amino acid sequence, identified as SEQ ID NO: 64

[1172] SEQ ID NO: 64

[1173] MSRLLHAEEWAEVKELGDHHRQPQPHHLPQPPPPPQPPATLQAREHPVYPPELSLLDSTDPRAWLAPTLQGICTARAAQYLL HSPELGASEAAAPRDEVDGRGELVRRSSGGASSSKSPGPVKVREQLCKLKGGVWDELGCSRQRAPSSKQVNGVQKQRRL AANARERRRMHGLNHAFDQLRNVIPSFNNDKKLSKYETLQMAQIYINALSELLQTPSGGEQPPPPPASCKSDHHHLRTAASYE GGAGNATAAGAQQASGGSQRPTPPGSCRTRFSAPASAGGYSVQLDALHFSTFEDSALTAMMAQKNLSPSLPGSILQPVQEEN SKTSPRSHRSDGEFSPHSHYSDSDEAS

[1174] ATOH1 may refer to the mouse sequence having the following amino acid sequence, identified as SEQ ID NO: 65

[1175] SEQ ID NO: 65

[1176] MSRLLHAEEWAEVKELGDHHRHPQPHHVPPLTPQPPATLQARDLPVYPAELSLLDSTDPRAWLTPTLQGLCTARAAQYLLHSP ELGASEAAAPRDEADSQGELVRRSGCGGLSKSPGPVKVREQLCKLKGGWVDELGCSRQRAPSSKQVNGVQKQRRLAANA RERRRMHGLNHAFDQLRNVIPSFNNDKKLSKYETLQMAQIYINALSELLQTPNVGEQPPPPTASCKNDHHHLRTASSYEGGAG ASAVAGAQPAPGGGPRPTPPGPCRTRFSGPASSGGYSVQLDALHFPAFEDRALTAMMAQKDLSPSLPGGILQPVQEDNSKTS PRSHRSDGEFSPHSHYSDSDEAS

[1177] ATOH1 may be encoded by the following human coding sequence, identified as SEQ ID NO: 66

[1178] SEQ ID NO: 66

[1179] ATGTCCCGCCTGCTGCATGCAGAAGAGTGGGCTGAAGTGAAGGAGTTGGGAGACCACCATCGCCAGCCCCAGCCGCAT CATCTCCCGCAACCGCCGCCGCCGCCGCAGCCACCTGCAACTTTGCAGGCGAGAGAGCATCCCGTCTACCCGCCTGAG CTGTCCCTCCTGGACAGCACCGACCCACGCGCCTGGCTGGCTCCCACTTTGCAGGGCATCTGCACGGCACGCGCCGCC CAGTATTTGCTACATTCCCCGGAGCTGGGTGCCTCAGAGGCCGCTGCGCCCCGGGACGAGGTGGACGGCCGGGGGGA GCTGGTAAGGAGGAGCAGCGGCGGTGCCAGCAGCAGCAAGAGCCCCGGGCCGGTGAAAGTGCGGGAACAGCTGTGCA AGCTGAAAGGCGGGGTGGTGGTAGACGAGCTGGGCTGCAGCCGCCAACGGGCCCCTTCCAGCAAACAGGTGAATGGG GTGCAGAAGCAGAGACGGCTAGCAGCCAACGCCAGGGAGCGGCGCAGGATGCATGGGCTGAACCACGCCTTCGACCA GCTGCGCAATGTTATCCCGTCGTTCAACAACGACAAGAAGCTGTCCAAATATGAGACCCTGCAGATGGCCCAAATCTACAT CAACGCCTTGTCCGAGCTGCTACAAACGCCCAGCGGAGGGGAACAGCCACCGCCGCCTCCAGCCTCCTGCAAAAGCGA CCACCACCACCTTCGCACCGCGGCCTCCTATGAAGGGGGCGCGGGCAACGCGACCGCAGCTGGGGCTCAGCAGGCTT CCGGAGGGAGCCAGCGGCCGACCCCGCCCGGGAGTTGCCGGACTCGCTTCTCAGCCCCAGCTTCTGCGGGAGGGTAC TCGGTGCAGCTGGACGCTCTGCACTTCTCGACTTTCGAGGACAGCGCCCTGACAGCGATGATGGCGCAAAAGAATTTGT CTCCTTCTCTCCCCGGGAGCATCTTGCAGCCAGTGCAGGAGGAAAACAGCAAAACTTCGCCTCGGTCCCACAGAAGCGA

[1180] CGGGGAATTTTCCCCCCATTCCCATTACAGTGACTCGGATGAGGCAAGTTAG

[1181] AT0H1 may be encoded by the following mouse coding sequence, identified as SEQ ID NO: 67

[1182] SEQ ID NO: 67

[1183] ATGTCCCGCCTGCTGCATGCAGAAGAGTGGGCTGAGGTAAAAGAGTTGGGGGACCACCATCGCCATCCCCAGCCGCACC

[1184] ACGTCCCGCCGCTGACGCCACAGCCACCTGCTACCCTGCAGGCGAGAGACCTTCCCGTCTACCCGGCAGAACTGTCCC

[1185] TCCTGGATAGCACCGACCCACGCGCCTGGCTGACTCCCACTTTGCAGGGCCTCTGCACGGCACGCGCCGCCCAGTATCT

[1186] GCTGCATTCTCCCGAGCTGGGTGCCTCCGAGGCCGCGGCGCCCCGGGACGAGGCTGACAGCCAGGGTGAGCTGGTAA

[1187] GGAGAAGCGGCTGTGGCGGCCTCAGCAAGAGCCCCGGGCCCGTCAAAGTACGGGAACAGCTGTGCAAGCTGAAGGGT

[1188] GGGGTTGTAGTGGACGAGCTTGGCTGCAGCCGCCAGCGAGCCCCTTCCAGCAAACAGGTGAATGGGGTACAGAAGCAA

[1189] AGGAGGCTGGCAGCAAACGCAAGGGAACGGCGCAGGATGCACGGGCTGAACCACGCCTTCGACCAGCTGCGCAACGT

[1190] TATCCCGTCCTTCAACAACGACAAGAAGCTGTCCAAATATGAGACCCTACAGATGGCCCAGATCTACATCAACGCTCTGTC

[1191] GGAGTTGCTGCAGACTCCCAATGTCGGAGAGCAACCGCCGCCGCCCACAGCTTCCTGCAAAAATGACCACCATCACCTT

[1192] CGCACCGCCTCCTCCTATGAAGGAGGTGCGGGCGCCTCTGCGGTAGCTGGGGCTCAGCCAGCCCCGGGAGGGGGCCC

[1193] GAGACCTACCCCGCCCGGGCCTTGCCGGACTCGCTTCTCAGGCCCAGCTTCCTCTGGGGGTTACTCGGTGCAGCTGGA

[1194] CGCTTTGCACTTCCCAGCCTTCGAGGACAGGGCCCTAACAGCGATGATGGCACAGAAGGACCTGTCGCCTTCGCTGCCC

[1195] GGGGGCATCCTGCAGCCTGTACAGGAGGACAACAGCAAAACATCTCCCAGATCCCACAGAAGTGACGGAGAGTTTTCCC

[1196] CCCACTCTCATTACAGTGACTCTGATGAGGCCAGTTAG

[1197] ATOH1 may be encoded by the following codon optimised human sequence, identified as SEQ ID NO: 68

[1198] SEQ ID NO: 68

[1199] ATGAGCCGGCTTCTTCACGCTGAGGAATGGGCCGAGGTTAAAGAACTCGGGGATCATCACAGGCAACCACAACCTCACC

[1200] ACCTGCCACAGCCACCACCACCACCCCAACCACCCGCCACACTCCAAGCCAGGGAACACCCGGTGTATCCACCGGAACT

[1201] TTCACTGCTCGATTCTACAGATCCTAGAGCTTGGCTCGCCCCTACCCTGCAAGGGATTTGTACAGCTCGGGCTGCTCAATA

[1202] CCTGCTGCACTCTCCCGAACTCGGCGCATCTGAAGCAGCCGCCCCTAGGGATGAAGTAGATGGAAGAGGTGAACTTGTG

[1203] CGCAGAAGTTCCGGTGGGGCTTCAAGTTCCAAATCACCAGGCCCCGTAAAGGTAAGAGAGCAACTTTGTAAATTGAAGGG

[1204] TGGCGTAGTAGTGGATGAACTCGGATGTTCACGGCAGAGAGCGCCCTCATCAAAGCAAGTCAACGGAGTTCAGAAACAA

[1205] CGCAGGCTGGCTGCTAATGCTAGAGAACGCCGGCGTATGCACGGACTCAACCATGCTTTCGATCAACTTAGAAACGTGAT

[1206] TCCCAGCTTTAATAATGATAAGAAACTCTCTAAGTACGAAACACTCCAAATGGCGCAGATTTATATTAATGCACTGTCAGAAC

[1207] TCTTACAGACTCCTTCCGGTGGCGAGCAACCGCCACCCCCACCCGCATCATGTAAGTCTGACCATCATCATCTGCGGACA

[1208] GCAGCTTCTTACGAGGGTGGGGCCGGAAATGCCACTGCCGCCGGTGCCCAACAAGCCTCTGGTGGTTCCCAAAGACCA

[1209] ACTCCACCGGGCTCATGTAGAACAAGGTTTAGCGCACCTGCTTCCGCAGGCGGATATAGCGTCCAACTTGATGCGCTCCA

[1210] TTTTAGCACCTTTGAAGATAGTGCACTCACCGCCATGATGGCCCAGAAGAACTTAAGCCCGTCCCTGCCAGGAAGTATTCT

[1211] CCAACCTGTCCAAGAAGAGAATTCCAAGACAAGTCCCCGATCACATAGGAGTGATGGCGAGTTCTCTCCGCACTCACACT

[1212] ATAGCGATAGCGACGAAGCCTCTTGA The functional variant of ATOH1 may comprise an amino acid sequence at least 70% identical to SEQ ID NO: 64 or SEQ ID NO: 65. The functional variant of ATOH1 may comprise an amino acid sequence at least 80% identical to SEQ ID NO: 64 or SEQ ID NO: 65. The functional variant of ATOH1 may comprise an amino acid sequence at least 85% identical to SEQ ID NO: 64 or SEQ ID NO: 65. The functional variant of ATOH1 may comprise an amino acid sequence at least 90% identical to SEQ ID NO: 64 or SEQ ID NO: 65. The functional variant of ATOH1 may comprise an amino acid sequence at least 95% identical to SEQ ID NO: 64 or SEQ ID NO: 65. The functional variant of ATOH1 may comprise an amino acid sequence at least 96% identical to SEQ ID NO: 64 or SEQ ID NO: 65. The functional variant of ATOH1 may comprise an amino acid sequence at least 97% identical to SEQ ID NO: 64 or SEQ ID NO: 65. The functional variant of ATOH1 may comprise an amino acid sequence at least 98% identical to SEQ ID NO: 64 or SEQ ID NO: 65. The functional variant of ATOH1 may comprise an amino acid sequence at least 99% identical to SEQ ID NO: 64 or SEQ ID NO: 65. SEQ ID NO: 64 and SEQ ID NO: 65 share 313 identical amino acids out of 354 and thus are at least 88% identical to one another. The nucleic acid sequence may comprise any nucleic acid sequence encoding a functional variant of ATOH1. Therefore, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 70% identical to SEQ ID NO: 64 or SEQ ID NO: 65. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 90% identical to SEQ ID NO: 64 or SEQ ID NO: 65. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 88% identical to SEQ ID NO: 64 or SEQ ID NO: 65. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 89% identical to SEQ ID NO: 64 or SEQ ID NO: 65.

[1213] The functional variant of ATOH1 may consist essentially of an amino acid sequence at least 70% identical to SEQ ID NO: 64 or SEQ ID NO: 65. The functional variant of ATOH1 may consist essentially of any amino acid sequence described elsewhere herein as a sequence that the functional variant of ATOH1 may comprise.

[1214] The nucleic acid sequence may comprise any nucleic acid sequence encoding ATOH1. ATOH1 may comprise an amino acid sequence according to SEQ ID NO: 64 or SEQ ID NO: 65. Therefore, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 64 or SEQ ID NO: 65. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 64. Alternatively, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 65.

[1215] The nucleotide sequence encoding ATOH1 , or a functional variant thereof may comprise a nucleic acid sequence encoding:

[1216] (a) SEQ ID NO: 64,

[1217] (b) SEQ ID NO: 65,

[1218] (c) an amino acid sequence having at least 70% identity to SEQ ID NO: 64 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 64, or

[1219] (d) an amino acid sequence having at least 70% identity to SEQ ID NO: 65 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 65.

[1220] The nucleotide sequence encoding ATOH1, or a functional variant thereof may consist essentially of a nucleic acid sequence encoding:

[1221] (a) SEQ ID NO: 64, (b) SEQ ID NO: 65,

[1222] (c) an amino acid sequence having at least 70% identity to SEQ ID NO: 64 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 64, or

[1223] (d) an amino acid sequence having at least 70% identity to SEQ ID NO: 65 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 65.

[1224] The nucleotide sequence encoding ATOH1 , or a functional variant thereof may consist essentially of any nucleic acid sequence described elsewhere herein as a sequence that may encode ATOH1 or functional variant of ATOH1.

[1225] The nucleotide sequence encoding ATOH1 , or a functional variant thereof may comprise a nucleic acid sequence encoding:

[1226] (a) SEQ ID NO: 64,

[1227] (b) SEQ ID NO: 65,

[1228] (c) an amino acid sequence having at least 88% identity to SEQ ID NO: 64 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 64, or

[1229] (d) an amino acid sequence having at least 88% identity to SEQ ID NO: 65 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 65.

[1230] The nucleotide sequence encoding ATOH1 , or a functional variant thereof may comprise:

[1231] (a) SEQ ID NO: 66,

[1232] (b) SEQ ID NO: 67,

[1233] (c) SEQ ID NO: 68, or

[1234] (d) a nucleotide sequence having at least 60% identity to SEQ ID NO: 66 or SEQ ID NO: 68, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 64, or

[1235] (e) a nucleotide sequence having at least 60% identity to SEQ ID NO: 67, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 65.

[1236] The nucleotide sequence encoding ATOH1 or a functional variant thereof may comprise a nucleic acid sequence having at least 60% identity to SEQ ID NO: 66, SEQ ID NO: 67, or SEQ ID NO: 68. The nucleotide sequence having at least 60% identity to SEQ ID NO: 66, SEQ ID NO: 67, or SEQ ID NO: 68 may have at least 70%, 75%, 80%, 85%, 90% or 95% identity to SEQ ID NO: 66, SEQ ID NO: 67, or SEQ ID NO: 68, respectively. SEQ ID NO: 66 and SEQ ID NO: 67 share 911 identical nucleotides out of 1065 and thus are at least 85% identical to one another. SEQ ID NO: 66 and SEQ ID NO: 68 share 666 identical nucleotides out of 1065 and therefore have at least 62% sequence identity to each other and encode the same protein sequence. The non-identical nucleotides may represent silent mutations (i.e. mutations which do not alter the sequence of the encoded amino acid). The non-identical nucleotides may alterthe amino acid sequence of the encoded amino acid, for example by one or more conservative amino acid mutation. The non-identical nucleotides may alter the amino acid sequence of the encoded amino acid by up to 20, up to 15, up to 10, up to 9, up to 8, up to 7, up to 6, up to 5, up to 4, up to 3, up to 2 or up to 1 conservative amino acid mutation.

[1237] The nucleotide sequence encoding ATOH1 , or a functional variant thereof may comprise:

[1238] (a) SEQ ID NO: 66, (b) SEQ ID NO: 67,

[1239] (c) SEQ ID NO: 68, or

[1240] (d) a nucleotide sequence having at least 62% identity to SEQ ID NO: 66 or SEQ ID NO: 68, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 64, or

[1241] (e) a nucleotide sequence having at least 62% identity to SEQ ID NO: 67, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 65.

[1242] The nucleotide sequence encoding ATOH1 , or a functional variant thereof may comprise:

[1243] (a) SEQ ID NO: 66,

[1244] (b) SEQ ID NO: 67,

[1245] (c) SEQ ID NO: 68, or

[1246] (d) a nucleotide sequence having at least 85% identity to SEQ ID NO: 66 or SEQ ID NO: 68, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 64, or

[1247] (e) a nucleotide sequence having at least 85% identity to SEQ ID NO: 67, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 65.

[1248] The nucleic acid sequence may encode ATOH1. The nucleotide sequence encoding ATOH1 may comprise:

[1249] (a) SEQ ID NO: 66,

[1250] (b) SEQ ID NO: 67, or

[1251] (c) SEQ ID NO: 68.

[1252] In an alternative statement of the first aspect, the nucleic acid molecule may encode at least two transcription factors, or functional variants thereof, wherein one transcription factor is ATOH1 and wherein the at least two transcription factors further comprise at least one transcription factor selected from the group consisting of NEUROD1 , FOXJ1 and OTX2.

[1253] In an alternative statement, the transcription factors may comprise:

[1254] (a)ATOH1 and NEUROD1;

[1255] (b)ATOH1 and FOXJ1; or

[1256] (c)ATOH1 and OTX2.

[1257] In an alternative statement, the transcription factors may comprise:

[1258] (a)ATOH1, FOXJ1 and NEUROD1;

[1259] (b)ATOH1, OTX2 and FOXJ1; or

[1260] (c)ATOH1, OTX2 and NEUROD1.

[1261] In any of the alternative statements comprising ATOH1 , the at least two transcription factors may further comprise CRX and / or one or more further transcription factor, such as one or more proneural bHLH transcription factor as described herein.

[1262] As used herein, “MEF2D” refers to Myocyte Enhancer Factor 2D. In humans it is encoded by the MEF2D gene, also known as Myocyte-Specific Enhancer Factor 2D and MADS Box Transcription Enhancer Factor 2, Polypeptide D. The mouse ortholog Mef2d is also known as Myocyte Enhancer Factor 2D. In humans, the Ensembl gene ID is ENSG00000116604, such as ENSG00000116604.18. An example of a transcript is the Ensembl transcript ID ENST00000348159, such as ENST00000348159.9 and the UniProt ID is Q14814-1, such as Q14814-1 v1; codon-optimised and alternatively spliced transcript variants are encompassed. In mice, an Ensembl gene ID is ENSMUSG00000001419. An example of a transcript is the Ensembl transcript ID ENSMUST00000001455, such as ENSMUST00000001455.13 and the UniProt ID is Q921S6, such as Q921S6 v1; codon-optimised and alternatively spliced transcript variants are encompassed.

[1263] MEF2D may refer to the human sequence having the following amino acid sequence, identified as SEQ ID NO: 69

[1264] SEQ ID NO: 69

[1265] MGRKKIQIQRITDERNRQVTFTKRKFGLMKKAYELSVLCDCEIALIIFNHSNKLFQYASTDMDKVLLKYTEYNEPHESRTNADIIET LRKKGFNGCDSPEPDGEDSLEQSPLLEDKYRRASEELDGLFRRYGSTVPAPNFAMPVTVPVSNQSSLQFSNPSGSLVTPSLVT SSLTDPRLLSPQQPALQRNSVSPGLPQRPASAGAMLGGDLNSANGACPSPVGNGYVSARASPGLLPVANGNSLNKVIPAKSP PPPTHSTQLGAPSRKPDLRVITSQAGKGLMHHLTEDHLDLNNAQRLGVSQSTHSLTTPWSVATPSLLSQGLPFSSMPTAYNTD YQLTSAELSSLPAFSSPGGLSLGNVTAWQQPQQPQQPQQPQPPQQQPPQPQQPQPQQPQQPQQPPQQQSHLVPVSLSNLI PGSPLPHVGAALTVTTHPHISIKSEPVSPSRERSPAPPPPAVFPAARPEPGDGLSSPAGGSYETGDRDDGRGDFGPTLGLLRPA PEPEAEGSAVKRMRLDTWTLK

[1266] MEF2D may refer to the mouse sequence having the following amino acid sequence, identified as SEQ ID NO: 70

[1267] SEQ ID NO: 70

[1268] MGRKKIQIQRITDERNRQVTFTKRKFGLMKKAYELSVLCDCEIALIIFNHSNKLFQYASTDMDKVLLKYTEYNEPHESRTNADIIET LRKKGFNGCDSPEPDGEDSLEQSPLLEDKYRRASEELDGLFRRYGSSVPAPNFAMPVTVPVSNQSSMQFSNPSSSLVTPSLV TSSLTDPRLLSPQQPALQRNSVSPGLPQRPASAGAMLGGDLNSANGACPSPVGNGYVSARASPGLLPVANGNSLNKVIPAKS PPPPTHNTQLGAPSRKPDLRVITSQGGKGLMHHLNNAQRLGVSQSTHSLTTPWSVATPSLLSQGLPFSSMPTAYNTDYQLPS AELSSLPAFSSPAGLALGNVTAWQQPQPPQQPQPPQPPQSQPQPPQPQPQQPPQQQPHLVPVSLSNLIPGSPLPHVGAALTV TTHPHISIKSEPVSPSRERSPAPPPPAVFPAARPEPGEGLSSPAGGSYETGDRDDGRGDFGPTLGLLRPAPEPEAEGSAVKRM RLDTWTLK

[1269] MEF2D may be encoded by the following human coding sequence, identified as SEQ ID NO: 71

[1270] SEQ ID NO: 71

[1271] ATGGGGAGGAAAAAGATTCAGATCCAGCGAATCACCGACGAGCGGAACCGACAGGTGACTTTCACCAAGCGGAAGTTTG GCCTGATGAAGAAGGCGTATGAGCTGAGCGTGCTATGTGACTGCGAGATCGCACTCATCATCTTCAACCACTCCAACAAG CTGTTCCAGTACGCCAGCACCGACATGGACAAGGTGCTGCTCAAGTACACGGAGTACAATGAGCCACACGAGAGCCGCA CCAACGCCGACATCATCGAGACCCTGAGGAAGAAGGGCTTCAACGGCTGCGACAGCCCCGAGCCCGACGGGGAGGACT CGCTGGAACAGAGCCCCCTGCTGGAGGACAAGTACCGACGCGCCAGCGAGGAGCTCGACGGGCTCTTCCGGCGCTATG GGTCAACTGTCCCGGCCCCCAACTTTGCCATGCCTGTCACGGTGCCCGTGTCCAATCAGAGCTCACTGCAGTTCAGCAA TCCCAGCGGCTCCCTGGTCACCCCTTCCCTGGTGACATCATCCCTCACGGACCCGCGGCTCCTGTCCCCCCAGCAGCCA GCACTACAGAGGAACAGTGTGTCTCCTGGCCTGCCCCAGCGGCCAGCTAGTGCGGGGGCCATGCTGGGGGGTGACCTG AACAGTGCTAACGGAGCCTGCCCCAGCCCTGTTGGGAATGGCTACGTCAGTGCTCGGGCTTCCCCTGGCCTCCTCCCTG

[1272] TGGCCAATGGCAACAGCCTAAACAAGGTCATCCCTGCCAAGTCTCCACCCCCACCTACCCACAGCACCCAGCTTGGAGC

[1273] CCCCAGCCGCAAGCCCGACCTGCGAGTCATCACTTCCCAGGCAGGAAAGGGGTTAATGCATCACTTGACTGAGGACCAT

[1274] TTAGATCTGAACAATGCCCAGCGCCTTGGGGTCTCCCAGTCTACTCATTCGCTCACCACCCCAGTGGTTTCTGTGGCAAC

[1275] GCCGAGTTTACTCAGCCAGGGCCTCCCCTTCTCTTCCATGCCCACTGCCTACAACACAGATTACCAGTTGACCAGTGCAG

[1276] AGCTCTCCTCCTTACCAGCCTTTAGTTCACCTGGGGGGCTGTCGCTAGGCAATGTCACTGCCTGGCAACAGCCACAGCA

[1277] GCCCCAGCAGCCGCAGCAGCCACAGCCTCCACAGCAGCAGCCACCGCAGCCACAGCAGCCACAGCCACAGCAGCCTC

[1278] AGCAGCCGCAACAGCCACCTCAGCAACAGTCCCACCTGGTCCCTGTATCTCTCAGCAACCTCATCCCGGGCAGCCCCCT

[1279] GCCCCACGTGGGTGCTGCCCTCACAGTCACCACCCACCCCCACATCAGCATCAAGTCAGAACCGGTGTCCCCAAGCCGT

[1280] GAGCGCAGCCCTGCGCCTCCCCCTCCAGCTGTGTTCCCAGCTGCCCGCCCTGAGCCTGGCGATGGTCTCAGCAGCCCA

[1281] GCCGGGGGATCCTATGAGACGGGAGACCGGGATGACGGACGGGGGGACTTCGGGCCCACACTGGGCCTGCTGCGCCC

[1282] AGCCCCAGAGCCTGAGGCTGAGGGCTCAGCTGTGAAGAGGATGCGGCTTGATACCTGGACATTAAAGTGA

[1283] MEF2D may be encoded by the following mouse coding sequence, identified as SEQ ID NO: 72

[1284] SEQ ID NO: 72

[1285] ATGGGGAGGAAAAAGATTCAGATCCAGCGAATCACTGATGAACGGAACCGCCAGGTGACCTTCACCAAGCGGAAGTTTG

[1286] GACTGATGAAGAAGGCCTACGAGCTGAGTGTGCTGTGCGACTGCGAGATCGCGCTCATCATCTTCAACCACTCCAACAAG

[1287] CTGTTCCAGTATGCCAGCACCGACATGGACAAGGTGCTGCTCAAGTACACCGAGTACAACGAGCCACACGAGAGCCGCA

[1288] CCAATGCTGACATCATCGAGACCCTGAGGAAGAAGGGTTTCAACGGCTGTGACAGCCCAGAGCCGGATGGGGAGGACT

[1289] CACTGGAGCAGAGCCCCCTGCTGGAGGACAAGTACCGGCGGGCCAGTGAGGAGCTGGATGGGCTCTTCAGGCGCTATG

[1290] GGTCATCTGTTCCGGCCCCCAACTTTGCCATGCCTGTCACAGTGCCCGTGTCCAATCAGAGCTCCATGCAGTTCAGCAAT

[1291] CCAAGTAGCTCTCTGGTCACTCCTTCCCTGGTGACATCATCCCTTACGGACCCACGGCTCCTGTCCCCCCAGCAGCCAG

[1292] CACTACAGAGAAACAGTGTTTCTCCAGGCTTGCCCCAGCGGCCTGCTAGTGCAGGAGCCATGCTGGGTGGAGACCTCAA

[1293] CAGTGCTAATGGAGCCTGCCCCAGCCCCGTTGGGAATGGCTATGTCAGTGCCCGAGCTTCCCCTGGCCTCCTCCCTGTG

[1294] GCCAATGGCAACAGCCTAAACAAAGTCATCCCTGCCAAGTCTCCGCCCCCACCCACCCACAACACCCAGCTTGGAGCCC

[1295] CCAGCCGCAAGCCTGATCTGCGGGTCATCACTTCCCAGGGAGGCAAAGGGTTAATGCATCATTTGAACAATGCCCAGCGC

[1296] CTTGGGGTCTCCCAGTCTACCCACTCGCTCACCACCCCAGTGGTTTCCGTGGCAACACCAAGTTTACTCAGCCAGGGCC

[1297] TCCCCTTCTCCTCCATGCCCACTGCCTACAACACAGATTACCAGCTGCCCAGTGCAGAGCTATCCTCCTTACCAGCCTTCA

[1298] GTTCACCTGCAGGGCTGGCACTAGGCAATGTCACCGCCTGGCAGCAGCCCCAGCCGCCCCAGCAGCCACAACCGCCAC

[1299] AACCGCCACAGTCACAGCCACAGCCACCACAGCCACAGCCACAGCAGCCACCTCAGCAACAGCCCCACTTGGTCCCCG

[1300] TTTCTCTCAGCAACCTCATCCCTGGCAGCCCCTTGCCTCACGTGGGTGCTGCTCTCACAGTCACTACCCACCCCCACATC

[1301] AGCATCAAGTCAGAACCAGTGTCCCCAAGTCGTGAACGCAGCCCTGCACCTCCTCCACCAGCTGTGTTCCCAGCTGCCC

[1302] GCCCTGAGCCTGGCGAAGGTCTCAGCAGCCCAGCTGGAGGATCCTATGAGACCGGGGACCGGGATGATGGACGGGGG

[1303] GACTTTGGGCCCACACTAGGCCTGCTGCGCCCAGCCCCAGAGCCTGAGGCTGAGGGCTCAGCTGTGAAGAGGATGCGG

[1304] CTGGATACTTGGACATTAAAGTGA

[1305] MEF2D may be encoded by the following codon optimised human sequence, identified as SEQ ID NO: 73

[1306] SEQ ID NO: 73 ATGGGAAGAAAGAAAATCCAAATACAAAGAATTACAGATGAACGCAACAGACAAGTTACATTCACCAAAAGGAAGTTCGGT

[1307] TTGATGAAGAAAGCCTACGAACTTTCAGTCCTCTGCGATTGTGAAATAGCCCTGATTATCTTCAATCATAGCAACAAACTGTT CCAATATGCCAGCACAGATATGGATAAAGTACTCCTGAAGTATACAGAATATAACGAACCCCACGAATCACGGACAAATGCT GATATTATTGAAACGCTTCGCAAGAAAGGGTTTAATGGGTGTGATAGTCCTGAACCAGATGGCGAAGATAGCTTGGAGCAA TCCCCATTGCTCGAAGATAAATATCGCAGAGCTTCTGAAGAATTGGATGGACTGTTTAGACGGTACGGCTCCACCGTGCCT GCTCCAAATTTCGCTATGCCAGTTACAGTTCCAGTTTCTAACCAATCAAGCCTGCAATTTTCTAACCCTTCTGGTAGTCTCG TGACACCCTCTCTCGTTACGTCTAGCTTGACAGATCCTAGGCTGTTGTCTCCTCAACAACCTGCCCTGCAACGGAATTCAG TCTCACCGGGACTCCCACAACGTCCCGCAAGCGCAGGAGCGATGCTCGGCGGGGATCTTAATAGCGCGAATGGCGCTTG TCCTTCACCCGTAGGCAACGGGTATGTGTCAGCGCGCGCAAGCCCCGGACTGCTGCCCGTTGCGAACGGTAATTCACTG AACAAAGTGATTCCCGCAAAGAGTCCTCCTCCACCAACACATTCTACACAACTGGGCGCACCTAGTAGAAAACCTGATTTG CGCGTGATTACCTCTCAAGCCGGCAAAGGCCTGATGCACCATCTCACGGAAGATCACCTTGACCTCAATAACGCACAAAG ACTCGGAGTGAGCCAATCCACACACTCCCTGACGACGCCCGTCGTCTCCGTAGCCACCCCATCCCTTTTGTCACAAGGT CTGCCATTTAGCTCTATGCCTACAGCTTATAATACTGACTATCAACTGACGTCCGCTGAACTGAGTTCACTTCCTGCTTTCTC CAGCCCCGGTGGCCTCTCACTTGGGAACGTGACCGCGTGGCAGCAACCTCAACAACCACAACAACCCCAACAACCGCA ACCGCCTCAACAACAACCCCCTCAACCGCAACAACCCCAACCCCAACAACCGCAACAACCCCAGCAACCGCCCCAACAG CAAAGCCATCTTGTTCCAGTGAGTCTGTCCAATCTGATTCCTGGAAGCCCACTCCCTCATGTTGGCGCGGCTCTGACTGT GACTACTCATCCTCATATTTCTATCAAAAGTGAGCCTGTTTCTCCCTCTAGAGAAAGATCTCCCGCTCCGCCCCCACCCGC CGTCTTTCCTGCCGCTAGACCCGAACCAGGGGACGGGCTGTCCTCACCTGCAGGCGGAAGTTACGAAACCGGGGATAG AGACGATGGTAGAGGTGATTTTGGCCCTACTCTTGGACTGCTCCGACCTGCACCGGAACCCGAAGCCGAAGGAAGCGCC GTAAAACGAATGAGACTGGACACATGGACGCTTAAATAA

[1308] The functional variant of MEF2D may comprise an amino acid sequence at least 70% identical to SEQ ID NO: 69 or SEQ ID NO: 70. The functional variant of MEF2D may comprise an amino acid sequence at least 80% identical to SEQ ID NO: 69 or SEQ ID NO: 70. The functional variant of MEF2D may comprise an amino acid sequence at least 85% identical to SEQ ID NO: 69 or SEQ ID NO: 70. The functional variant of MEF2D may comprise an amino acid sequence at least 90% identical to SEQ ID NO: 69 or SEQ ID NO: 70. The functional variant of MEF2D may comprise an amino acid sequence at least 95% identical to SEQ ID NO: 69 or SEQ ID NO: 70. The functional variant of MEF2D may comprise an amino acid sequence at least 96% identical to SEQ ID NO: 69 or SEQ ID NO: 70. The functional variant of MEF2D may comprise an amino acid sequence at least 97% identical to SEQ ID NO: 69 or SEQ ID NO: 70. The functional variant of MEF2D may comprise an amino acid sequence at least 98% identical to SEQ ID NO: 69 or SEQ ID NO: 70. The functional variant of MEF2D may comprise an amino acid sequence at least 99% identical to SEQ ID NO: 69 or SEQ ID NO: 70. SEQ ID NO: 69 and SEQ ID NO: 70 share 493 identical amino acids out of 521 and thus are at least 94% identical to one another. The nucleic acid sequence may comprise any nucleic acid sequence encoding a functional variant of MEF2D. Therefore, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 70% identical to SEQ ID NO: 69 or SEQ ID NO: 70. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 90% identical to SEQ ID NO: 69 or SEQ ID NO: 70. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 94% identical to SEQ ID NO: 69 or SEQ ID NO: 70. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 95% identical to SEQ ID NO: 69 or SEQ ID NO: 70. The functional variant of MEF2D may consist essentially of an amino acid sequence at least 70% identical to SEQ ID NO: 69 or SEQ ID NO: 70. The functional variant of MEF2D may consist essentially of any amino acid sequence described elsewhere herein as a sequence that the functional variant of MEF2D may comprise.

[1309] The nucleic acid sequence may comprise any nucleic acid sequence encoding MEF2D. MEF2D may comprise an amino acid sequence according to SEQ ID NO: 69 or SEQ ID NO: 70. Therefore, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 69 or SEQ ID NO: 70. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 69. Alternatively, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 70.

[1310] The nucleotide sequence encoding MEF2D, or a functional variant thereof may comprise a nucleic acid sequence encoding:

[1311] (a) SEQ ID NO: 69,

[1312] (b) SEQ ID NO: 70,

[1313] (c) an amino acid sequence having at least 70% identity to SEQ ID NO: 69 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 69, or

[1314] (d) an amino acid sequence having at least 70% identity to SEQ ID NO: 70 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 70.

[1315] The nucleotide sequence encoding MEF2D, or a functional variant thereof may consist essentially of a nucleic acid sequence encoding:

[1316] (a) SEQ ID NO: 69,

[1317] (b) SEQ ID NO: 70,

[1318] (c) an amino acid sequence having at least 70% identity to SEQ ID NO: 69 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 69, or

[1319] (d) an amino acid sequence having at least 70% identity to SEQ ID NO: 70 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 70.

[1320] The nucleotide sequence encoding MEF2D, or a functional variant thereof may consist essentially of any nucleic acid sequence described elsewhere herein as a sequence that may encode MEF2D or functional variant of MEF2D.

[1321] The nucleotide sequence encoding MEF2D, or a functional variant thereof may comprise a nucleic acid sequence encoding:

[1322] (a) SEQ ID NO: 69,

[1323] (b) SEQ ID NO: 70,

[1324] (c) an amino acid sequence having at least 94% identity to SEQ ID NO: 69 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 69, or

[1325] (d) an amino acid sequence having at least 94% identity to SEQ ID NO: 70 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 70.

[1326] The nucleotide sequence encoding MEF2D, or a functional variant thereof may comprise:

[1327] (a) SEQ ID NO: 71, (b) SEQ ID NO: 72,

[1328] (c) SEQ ID NO: 73, or

[1329] (d) a nucleotide sequence having at least 60% identity to SEQ ID NO: 71 or SEQ ID NO: 73, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 69, or

[1330] (e) a nucleotide sequence having at least 60% identity to SEQ ID NO: 72, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 70.

[1331] The nucleotide sequence encoding MEF2D or a functional variant thereof may comprise a nucleic acid sequence having at least 60% identity to SEQ ID NO: 71, SEQ ID NO: 72, or SEQ ID NO: 73. The nucleotide sequence having at least 60% identity to SEQ ID NO: 71, SEQ ID NO: 72, or SEQ ID NO: 73 may have at least 70%, 75%, 80%, 85%, 90% or 95% identity to SEQ ID NO: 71 , SEQ ID NO: 72, or SEQ ID NO: 73, respectively. SEQ ID NO: 71 and SEQ ID NO: 72 share 1403 identical nucleotides out of 1566 and thus are at least 89% identical to one another. SEQ ID NO: 71 and SEQ ID NO: 73 share 986 identical nucleotides out of 1566 and therefore have at least 62% sequence identity to each other and encode the same protein sequence. The non-identical nucleotides may represent silent mutations (i.e. mutations which do not alter the sequence of the encoded amino acid). The non-identical nucleotides may alterthe amino acid sequence of the encoded amino acid, for example by one or more conservative amino acid mutation. The non-identical nucleotides may alter the amino acid sequence of the encoded amino acid by up to 20, up to 15, up to 10, up to 9, up to 8, up to 7, up to 6, up to 5, up to 4, up to 3, up to 2 or up to 1 conservative amino acid mutation.

[1332] The nucleotide sequence encoding MEF2D, or a functional variant thereof may comprise:

[1333] (a) SEQ ID NO: 71,

[1334] (b) SEQ ID NO: 72,

[1335] (c) SEQ ID NO: 73, or

[1336] (d) a nucleotide sequence having at least 62% identity to SEQ ID NO: 71 or SEQ ID NO: 73, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 69, or

[1337] (e) a nucleotide sequence having at least 62% identity to SEQ ID NO: 72, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 70.

[1338] The nucleotide sequence encoding MEF2D, or a functional variant thereof may comprise:

[1339] (a) SEQ ID NO: 71,

[1340] (b) SEQ ID NO: 72,

[1341] (c) SEQ ID NO: 73, or

[1342] (d) a nucleotide sequence having at least 89% identity to SEQ ID NO: 71 or SEQ ID NO: 73, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 69, or

[1343] (e) a nucleotide sequence having at least 89% identity to SEQ ID NO: 72, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 70.

[1344] The nucleic acid sequence may encode MEF2D. The nucleotide sequence encoding MEF2D may comprise:

[1345] (a) SEQ ID NO: 71,

[1346] (b) SEQ ID NO: 72, or (c) SEQ ID NO: 73.

[1347] In an alternative statement of the first aspect, the nucleic acid molecule may encode at least two transcription factors, or functional variants thereof, wherein one transcription factor is MEF2D and wherein the at least two transcription factors further comprise at least one transcription factor selected from the group consisting of NEUROD1 , FOXJ1 and OTX2.

[1348] In an alternative statement, the transcription factors may comprise:

[1349] (a) MEF2D and NEUROD1;

[1350] (b) MEF2D and FOXJ1; or

[1351] (c) MEF2D and OTX2.

[1352] In an alternative statement, the transcription factors may comprise:

[1353] (a) MEF2D, FOXJ1 and NEUROD1;

[1354] (b) MEF2D, OTX2 and FOXJ1; or

[1355] (c) MEF2D, OTX2 and NEURODI.

[1356] In any of the alternative statements comprising MEF2D, the at least two transcription factors may further comprise CRX and / or one or more further transcription factor, such as one or more proneural bHLH transcription factor as described herein.

[1357] As used herein, “RXRG” refers to Retinoid X Receptor Gamma. In humans it is encoded by the RXRG gene, also known as NR2B3, Nuclear Receptor Subfamily 2 Group B Members, RXR-Gamma, RXR-gamma, Retinoic Acid Receptor RXR-Gamma, Retinoid X Receptor, Gamma and RXRC. The mouse ortholog Rxrg is also known as Retinoid X Receptor Gamma. In humans, the Ensembl gene ID is ENSG00000143171, such as ENSG00000143171.13. An example of a transcript is the Ensembl transcript ID ENST00000359842, such as ENST00000359842.10 and the UniProt ID is P48443, such as P48443 v1; codon- optimised and alternatively spliced transcript variants are encompassed. In mice, an Ensembl gene ID is ENSMUSG00000015843. An example of a transcript is the Ensembl transcript ID ENSMUST00000015987, such as ENSMUST00000015987.10 and the UniProt ID is P28705, such as P28705 v2; codon-optimised and alternatively spliced transcript variants are encompassed.

[1358] RXRG may refer to the human sequence having the following amino acid sequence, identified as SEQ ID NO: 74

[1359] SEQ ID NO: 74

[1360] MYGNYSHFMKFPAGYGGSPGHTGSTSMSPSAALSTGKPMDSHPSYTDTPVSAPRTLSAVGTPLNALGSPYRVITSAMGPPSG ALAAPPGINLVAPPSSQLNWNSVSSSEDIKPLPGLPGIGNMNYPSTSPGSLVKHICAICGDRSSGKHYGVYSCEGCKGFFKRTI RKDLIYTCRDNKDCLIDKRQRNRCQYCRYQKCLVMGMKREAVQEERQRSRERAESEAECATSGHEDMPVERILEAELAVEPK TESYGDMNMENSTNDPVTNICHAADKQLFTLVEWAKRIPHFSDLTLEDQVILLRAGWNELLIASFSHRSVSVQDGILLATGLHVH RSSAHSAGVGSIFDRVLTELVSKMKDMQMDKSELGCLRAIVLFNPDAKGLSNPSEVETLREKVYATLEAYTKQKYPEQPGRFAK LLLRLPALRSIGLKCLEHLFFFKLIGDTPIDTFLMEMLETPLQIT

[1361] RXRG may refer to the mouse sequence having the following amino acid sequence, identified as SEQ ID NO: 75 SEQ ID NO: 75

[1362] MYGNYSHFMKFPTGFGGSPGHTGSTSMSPSVALPTGKPMDSHPSYTDTPVSAPRTLSAVGTPLNALGSPYRVITSAMGPPSG

[1363] ALAAPPGINLVAPPSSQLNWNSVSSSEDIKPLPGLPGIGNMNYPSTSPGSLVKHICAICGDRSSGKHYGVYSCEGCKGFFKRTI

[1364] RKDLIYTCRDNKDCLIDKRQRNRCQYCRYQKCLVMGMKREAVQEERQRSRERAESEAECASSSHEDMPVERILEAELAVEPK

[1365] TESYGDMNVENSTNDPVTNICHAADKQLFTLVEWAKRIPHFSDLTLEDQVILLRAGWNELLIASFSHRSVSVQDGILLATGLHVH

[1366] RSSAHSAGVGSIFDRVLTELVSKMKDMQMDKSELGCLRAIVLFNPDAKGLSNPSEVETLREKVYATLEAYTKQKYPEQPGRFAK

[1367] LLLRLPALRSIGLKCLEHLFFFKLIGDTPIDSFLMEMLETPLQIT

[1368] RXRG may be encoded by the following human coding sequence, identified as SEQ ID NO: 76

[1369] SEQ ID NO: 76

[1370] ATGTATGGAAATTATTCTCACTTCATGAAGTTTCCCGCAGGCTATGGAGGCTCCCCTGGCCACACTGGCTCTACATCCATGA

[1371] GCCCATCAGCAGCCTTGTCCACAGGGAAGCCAATGGACAGCCACCCCAGCTACACAGATACCCCAGTGAGTGCCCCACG

[1372] GACTCTGAGTGCAGTGGGGACCCCCCTCAATGCCCTGGGCTCTCCATATCGAGTCATCACCTCTGCCATGGGCCCACCC

[1373] TCAGGAGCACTTGCAGCGCCTCCAGGAATCAACTTGGTTGCCCCACCCAGCTCTCAGCTAAATGTGGTCAACAGTGTCAG

[1374] CAGTTCAGAGGACATCAAGCCCTTACCAGGGCTTCCCGGGATTGGAAACATGAACTACCCATCCACCAGCCCCGGATCTC

[1375] TGGTTAAACACATCTGTGCCATCTGTGGAGACAGATCCTCAGGAAAGCACTACGGGGTATACAGTTGTGAAGGCTGCAAA

[1376] GGGTTCTTCAAGAGGACGATAAGGAAGGACCTCATCTACACGTGTCGGGATAATAAAGACTGCCTCATTGACAAGCGTCA

[1377] GCGCAACCGCTGCCAGTACTGTCGCTATCAGAAGTGCCTTGTCATGGGCATGAAGAGGGAAGCTGTGCAAGAAGAAAGA

[1378] CAGAGGAGCCGAGAGCGAGCTGAGAGTGAGGCAGAATGTGCTACCAGTGGTCATGAAGACATGCCTGTGGAGAGGATTC

[1379] TAGAAGCTGAACTTGCTGTTGAACCAAAGACAGAATCCTATGGTGACATGAATATGGAGAACTCGACAAATGACCCTGTTA

[1380] CCAACATATGTCATGCTGCTGACAAGCAGCTTTTCACCCTCGTTGAATGGGCCAAGCGTATTCCCCACTTCTCTGACCTCA

[1381] CCTTGGAGGACCAGGTCATTTTGCTTCGGGCAGGGTGGAATGAATTGCTGATTGCCTCTTTCTCCCACCGCTCAGTTTCC

[1382] GTGCAGGATGGCATCCTTCTGGCCACGGGTTTACATGTCCACCGGAGCAGTGCCCACAGTGCTGGGGTCGGCTCCATCT

[1383] TTGACAGAGTCCTAACTGAGCTGGTTTCCAAAATGAAAGACATGCAGATGGACAAGTCGGAACTGGGATGCCTGCGAGCC

[1384] ATTGTACTCTTTAACCCAGATGCCAAGGGCCTGTCCAACCCCTCTGAGGTGGAGACTCTGCGAGAGAAGGTTTATGCCAC

[1385] CCTTGAGGCCTACACCAAGCAGAAGTATCCGGAACAGCCAGGCAGGTTTGCCAAGCTGCTGCTGCGCCTCCCAGCTCTG

[1386] CGTTCCATTGGCTTGAAATGCCTGGAGCACCTCTTCTTCTTCAAGCTCATCGGGGACACCCCCATTGACACCTTCCTCATG

[1387] GAGATGTTGGAGACCCCGCTGCAGATCACCTGA

[1388] RXRG may be encoded by the following mouse coding sequence, identified as SEQ ID NO: 77

[1389] SEQ ID NO: 77

[1390] ATGTATGGAAATTATTCCCACTTCATGAAGTTTCCCACCGGCTTTGGTGGCTCCCCTGGTCACACTGGCTCGACGTCCATG

[1391] AGCCCTTCAGTAGCCTTGCCCACGGGGAAGCCAATGGACAGCCACCCCAGCTACACAGACACCCCAGTGAGTGCCCCTC

[1392] GGACGCTGAGTGCTGTGGGAACCCCCCTCAATGCTCTTGGCTCTCCGTATAGAGTCATCACTTCTGCCATGGGTCCACCC

[1393] TCAGGAGCACTGGCAGCTCCTCCAGGAATCAACTTGGTGGCTCCACCCAGCTCCCAGCTAAATGTGGTCAACAGTGTCA

[1394] GCAGCTCTGAGGACATCAAGCCCTTACCAGGTCTGCCTGGGATTGGAAATATGAACTACCCATCCACCAGCCCTGGGTCT

[1395] CTGGTGAAACACATCTGTGCCATCTGTGGGGACAGATCCTCAGGGAAGCACTACGGTGTGTACAGCTGTGAAGGTTGCAA

[1396] AGGCTTCTTCAAAAGGACCATCAGGAAAGATCTCATCTACACCTGTCGGGATAACAAAGATTGTCTCATCGACAAGCGCCA GCGCAACCGCTGCCAGTACTGTCGCTACCAGAAGTGCCTGGTCATGGGCATGAAGCGGGAAGCTGTGCAAGAAGAAAG GCAGAGGAGCCGAGAGCGAGCAGAGAGTGAGGCAGAATGTGCCAGTAGTAGCCACGAAGACATGCCCGTGGAGAGGAT TCTAGAAGCCGAACTTGCTGTGGAACCAAAGACAGAATCCTACGGTGACATGAACGTGGAGAACTCAACAAATGACCCTG TTACCAACATATGCCATGCTGCAGATAAGCAACTTTTCACCCTCGTTGAGTGGGCCAAACGCATCCCCCACTTCTCAGATC TCACCTTGGAGGACCAGGTCATTCTACTCCGGGCAGGGTGGAATGAACTGCTCATTGCCTCCTTCTCCCACCGCTCGGTT TCCGTCCAGGATGGCATCCTGCTGGCCACGGGCCTCCACGTGCACAGGAGCAGCGCTCACAGCGCGGGAGTCGGCTC CATCTTCGACAGAGTCCTTACAGAGTTGGTGTCCAAGATGAAAGACATGCAGATGGATAAGTCAGAGCTGGGGTGCCTAC

[1397] GGGCCATCGTGCTGTTTAACCCAGATGCCAAGGGTTTATCCAACCCCTCTGAGGTGGAGACTCTTCGAGAGAAGGTTTAT GCCACCCTGGAGGCCTATACCAAGCAGAAGTATCCGGAACAGCCAGGCAGGTTTGCCAAGCTTCTGCTGCGTCTCCCTG CTCTGCGCTCCATCGGCTTGAAATGCCTGGAACACCTCTTCTTCTTCAAGCTCATTGGAGACACTCCCATCGACAGCTTCC TCATGGAGATGTTGGAGACCCCACTGCAGATCACCTGA

[1398] RXRG may be encoded by the following codon optimised human sequence, identified as SEQ ID NO: 78

[1399] SEQ ID NO: 78

[1400] ATGTACGGCAACTACTCACATTTTATGAAATTCCCAGCCGGATACGGCGGGTCTCCCGGCCATACAGGTAGTACGAGCATG TCCCCCAGCGCGGCGCTGAGCACCGGCAAACCCATGGATTCCCATCCTTCTTATACCGACACGCCTGTCAGCGCTCCCA GAACACTCTCTGCCGTCGGCACGCCTCTGAACGCTCTTGGTAGTCCCTACAGAGTTATTACATCCGCTATGGGACCACCG AGTGGGGCGCTGGCTGCCCCACCCGGCATAAATCTCGTGGCTCCGCCAAGCTCCCAATTGAACGTCGTGAATTCTGTATC TTCTAGTGAAGACATAAAACCTCTTCCTGGCCTGCCGGGTATCGGTAATATGAATTATCCTTCTACGTCCCCTGGTTCACTC GTGAAGCATATTTGCGCTATTTGCGGCGATCGGTCATCTGGGAAACATTATGGAGTCTATTCCTGCGAGGGATGTAAGGGT

[1401] TTCTTTAAACGTACAATCCGTAAAGATCTTATTTATACCTGCAGGGACAACAAGGATTGTCTTATCGACAAAAGGCAACGAAA TCGGTGTCAATATTGCAGATACCAGAAATGTCTCGTGATGGGTATGAAAAGAGAGGCCGTCCAGGAAGAGCGCCAACGGA GTAGAGAAAGGGCGGAATCCGAAGCTGAGTGCGCCACTAGCGGGCACGAGGATATGCCCGTCGAACGTATCCTTGAGGC AGAGCTGGCGGTCGAGCCCAAAACTGAGAGCTACGGGGATATGAACATGGAAAATTCCACTAACGATCCAGTCACTAATAT CTGCCACGCAGCCGATAAACAACTGTTTACATTGGTCGAGTGGGCTAAACGCATACCACATTTTAGTGATCTGACACTTGA AGATCAAGTTATCCTTCTCCGAGCTGGCTGGAACGAGCTTCTCATAGCATCCTTTTCTCATAGATCTGTGTCTGTCCAAGAC

[1402] GGGATTCTCCTCGCAACAGGCCTGCACGTGCATAGGTCCAGCGCGCATAGCGCAGGCGTGGGGAGTATTTTCGATAGGG TGTTGACCGAACTCGTGAGCAAGATGAAGGATATGCAAATGGATAAATCAGAGTTGGGCTGTCTCCGCGCAATAGTGTTGT TCAATCCCGACGCTAAAGGGCTCAGCAATCCTAGTGAAGTCGAAACCTTGAGGGAAAAGGTATACGCTACATTGGAAGCG TATACCAAACAAAAGTACCCCGAGCAACCTGGGCGATTCGCAAAACTTCTTTTGCGGCTGCCTGCCCTGCGGAGTATCGG GCTTAAGTGTTTGGAACATCTGTTCTTCTTTAAACTGATAGGTGATACTCCGATCGACACATTTCTGATGGAAATGCTCGAAA CGCCTCTCCAAATTACATAA

[1403] The functional variant of RXRG may comprise an amino acid sequence at least 70% identical to SEQ ID NO: 74 or SEQ ID NO: 75. The functional variant of RXRG may comprise an amino acid sequence at least 80% identical to SEQ ID NO: 74 or SEQ ID NO: 75. The functional variant of RXRG may comprise an amino acid sequence at least 85% identical to SEQ ID NO: 74 or SEQ ID NO: 75. The functional variant of RXRG may comprise an amino acid sequence at least 90% identical to SEQ ID NO: 74 or SEQ ID NO: 75. The functional variant of RXRG may comprise an amino acid sequence at least 95% identical to SEQ ID NO: 74 or SEQ ID NO: 75. The functional variant of RXRG may comprise an amino acid sequence at least 96% identical to SEQ ID NO: 74 or S EQ ID NO: 75. The functional variant of RXRG may comprise an amino acid sequence at least 97% identical to SEQ ID NO: 74 or SEQ ID NO: 75. The functional variant of RXRG may comprise an amino acid sequence at least 98% identical to SEQ ID NO: 74 or SEQ ID NO: 75. The functional variant of RXRG may comprise an amino acid sequence at least 99% identical to SEQ ID NO: 74 or SEQ ID NO: 75. SEQ ID NO: 74 and SEQ ID NO: 75 share 455 identical amino acids out of 463 and thus are at least 98% identical to one another. The nucleic acid sequence may comprise any nucleic acid sequence encoding a functional variant of RXRG. Therefore, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 70% identical to SEQ ID NO: 74 or SEQ ID NO: 75. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 90% identical to SEQ ID NO: 74 or SEQ ID NO: 75. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 98% identical to SEQ ID NO: 74 or SEQ ID NO: 75. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding an amino acid sequence at least 99% identical to SEQ ID NO: 74 or SEQ ID NO: 75.

[1404] The functional variant of RXRG may consist essentially of an amino acid sequence at least 70% identical to SEQ ID NO: 74 or SEQ ID NO: 75. The functional variant of RXRG may consist essentially of any amino acid sequence described elsewhere herein as a sequence that the functional variant of RXRG may comprise.

[1405] The nucleic acid sequence may comprise any nucleic acid sequence encoding RXRG. RXRG may comprise an amino acid sequence according to SEQ ID NO: 74 or SEQ ID NO: 75. Therefore, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 74 or SEQ ID NO: 75. For example, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 74. Alternatively, the nucleic acid sequence may comprise any nucleic acid sequence encoding SEQ ID NO: 75.

[1406] The nucleotide sequence encoding RXRG, or a functional variant thereof may comprise a nucleic acid sequence encoding:

[1407] (a) SEQ ID NO: 74,

[1408] (b) SEQ ID NO: 75,

[1409] (c) an amino acid sequence having at least 70% identity to SEQ ID NO: 74 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 74, or

[1410] (d) an amino acid sequence having at least 70% identity to SEQ ID NO: 75 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 75.

[1411] The nucleotide sequence encoding RXRG, or a functional variant thereof may consist essentially of a nucleic acid sequence encoding:

[1412] (a) SEQ ID NO: 74,

[1413] (b) SEQ ID NO: 75,

[1414] (c) an amino acid sequence having at least 70% identity to SEQ ID NO: 74 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 74, or

[1415] (d) an amino acid sequence having at least 70% identity to SEQ ID NO: 75 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 75. The nucleotide sequence encoding RXRG, or a functional variant thereof may consist essentially of any nucleic acid sequence described elsewhere herein as a sequence that may encode RXRG or functional variant of RXRG.

[1416] The nucleotide sequence encoding RXRG, or a functional variant thereof may comprise a nucleic acid sequence encoding:

[1417] (a) SEQ ID NO: 74,

[1418] (b) SEQ ID NO: 75,

[1419] (c) an amino acid sequence having at least 98% identity to SEQ ID NO: 74 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 74, or

[1420] (d) an amino acid sequence having at least 98% identity to SEQ ID NO: 75 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 75.

[1421] The nucleotide sequence encoding RXRG, or a functional variant thereof may comprise:

[1422] (a) SEQ ID NO: 76,

[1423] (b) SEQ ID NO: 77,

[1424] (c) SEQ ID NO: 78, or

[1425] (d) a nucleotide sequence having at least 60% identity to SEQ ID NO: 76 or SEQ ID NO: 78, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by S EQ I D NO: 74, or

[1426] (e) a nucleotide sequence having at least 60% identity to SEQ ID NO: 77, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 75.

[1427] The nucleotide sequence encoding RXRG or a functional variant thereof may comprise a nucleic acid sequence having at least 60% identity to SEQ ID NO: 76, SEQ ID NO: 77, or SEQ ID NO: 78. The nucleotide sequence having at least 60% identity to SEQ ID NO: 76, SEQ ID NO: 77, or SEQ ID NO: 78 may have at least 70%, 75%, 80%, 85%, 90% or 95% identity to SEQ ID NO: 76, SEQ ID NO: 77, or SEQ ID NO: 78, respectively. SEQ ID NO: 76 and SEQ ID NO: 77 share 1256 identical nucleotides out of 1392 and thus are at least 90% identical to one another. SEQ ID NO: 76 and SEQ ID NO: 78 share 900 identical nucleotides out of 1392 and therefore have at least 64% sequence identity to each other and encode the same protein sequence. The non-identical nucleotides may represent silent mutations (i.e. mutations which do not alter the sequence of the encoded amino acid). The non-identical nucleotides may alterthe amino acid sequence of the encoded amino acid, for example by one or more conservative amino acid mutation. The non-identical nucleotides may alter the amino acid sequence of the encoded amino acid by up to 20, up to 15, up to 10, up to 9, up to 8, up to 7, up to 6, up to 5, up to 4, up to 3, up to 2 or up to 1 conservative amino acid mutation.

[1428] The nucleotide sequence encoding RXRG, or a functional variant thereof may comprise:

[1429] (a) SEQ ID NO: 76,

[1430] (b) SEQ ID NO: 77,

[1431] (c) SEQ ID NO: 78, or

[1432] (d) a nucleotide sequence having at least 64% identity to SEQ ID NO: 76 or SEQ ID NO: 78, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by S EQ I D NO: 74, or

[1433] (e) a nucleotide sequence having at least 64% identity to SEQ ID NO: 77, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 75. The nucleotide sequence encoding RXRG, or a functional variant thereof may comprise:

[1434] (a) SEQ ID NO: 76,

[1435] (b) SEQ ID NO: 77,

[1436] (c) SEQ ID NO: 78, or

[1437] (d) a nucleotide sequence having at least 90% identity to SEQ ID NO: 76 or SEQ ID NO: 78, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by S EQ I D NO: 74, or

[1438] (e) a nucleotide sequence having at least 90% identity to SEQ ID NO: 77, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 75.

[1439] The nucleic acid sequence may encode RXRG. The nucleotide sequence encoding RXRG may comprise:

[1440] (a) SEQ ID NO: 76,

[1441] (b) SEQ ID NO: 77, or

[1442] (c) SEQ ID NO: 78.

[1443] In an alternative statement of the first aspect, the nucleic acid molecule may encode at least two transcription factors, or functional variants thereof, wherein one transcription factor is RXRG and wherein the at least two transcription factors further comprise at least one transcription factor selected from the group consisting of NEUROD1 , FOXJ1 and OTX2.

[1444] In an alternative statement, the transcription factors may comprise:

[1445] (a) RXRG and NEURODI;

[1446] (b) RXRG and FOXJ1; or

[1447] (c) RXRG and OTX2.

[1448] In an alternative statement, the transcription factors may comprise:

[1449] (a) RXRG, FOXJ1 and NEURODI;

[1450] (b) RXRG, OTX2 and FOXJ1; or

[1451] (c) RXRG, OTX2 and NEURODI

[1452] In any of the alternative statements comprising RXRG, the at least two transcription factors may further comprise CRX and / or one or more further transcription factor, such as one or more proneural bHLH transcription factor as described herein.

[1453] In alternative statements of any aspect of the invention described herein, the transcription factors of the invention may not comprise FOXJ1. The transcription factors may not comprise FOXJ1 or a functional variant thereof. As an example, a transcription factor combination of the invention may comprise NEUROD1, OTX2 and CRX, or functional variants thereof. A transcription factor combination of the invention may consist essentially of NEUROD1 , OTX2 and CRX or functional variants thereof. NEUROD1, OTX2 and CRX and functional variants thereof are described herein. A transcription factor combination of the invention may comprise NEUROD1, OTX2 and CRX, or functional variants thereof and one or more further transcription factor, such as one or more proneural bHLH transcription factor as described herein. In such alternative statements, the nucleic acid molecule, system, vector, composition, product, kit, method, cell, substance or composition for use or method of treatment according to any aspect of the invention may be defined as not comprising, encoding, targeting, introducing, or increasing the expression of FOXJ1, as applicable. The nucleic acid molecule, system, vector, composition, product, kit, method, cell, substance or composition for use or method of treatment according to any aspect of the invention may be defined as not comprising, encoding, targeting, introducing, or increasing the expression of FOXJ1 or a functional variant thereof, as applicable.

[1454] Each of the transcription factor combinations represented above were delivered to experimental systems as detailed in the Examples. Without being bound by theory, they may be associated with surprising technical effects, for example as further described below.

[1455] The data disclosed herein surprisingly indicate that FOXJ1 shifts the gene expression profile of Muller glia towards a photoreceptor gene expression profile more than any other single transcription factor tested. Furthermore, FOXJ1 has a strikingly specific effect to photoreceptors; no significant shift towards a bipolar cell or an RPE gene expression profile is observed. Moreover, the data disclosed herein highlight interactions between FOXJ1 and other transcription factors, suggesting that the use of FOXJ1 may reduce off-target effects driven by less photoreceptor-specific transcription factors. In particular, the data disclosed herein allows a comparison of different transcription factor combinations, with and without FOXJ1. The FOXJ1:OTX2 combination significantly upregulated reprogramming to photoreceptors, with upregulation also observed for OTX2:CRX and NEUROD1:OTX2. Larger transcription factor combinations are also demonstrated to drive reprogramming to photoreceptors, particularly 3 transcription factor combinations of FOXJ1:NEUROD1:OTX2 and NEUROD1:OTX2:CRX, and the 4 transcription factor combination FOXJ1:NEUROD1:OTX2:CRX. Without being bound by theory, the advantageous increase in photoreceptor conversion over other cell types such as bipolar cells or RPE may be driven, at least in part, by FOXJ1 in these combinations. Combinations comprising FOXJ1 may therefore surprisingly increase photoreceptor conversion compared to known combinations without FOXJ1. Delivery or upregulation of FOXJ1, optionally in combination with one or more further transcription factor, may therefore represent an advantageous approach for specifically reprogramming macroglia to photoreceptors and in treatments for retinal disease or degeneration.

[1456] The present inventors have identified and characterised transcription factor combinations that enable the selective and efficient reprogramming of Muller glia and related macroglial cells to photoreceptor cell fates, particularly cone photoreceptors. Through a series of experiments described herein (Examples 1-6), the inventors demonstrated that inclusion of FOXJ1 in transcription factor cocktails produces a striking enhancement of photoreceptor-specific gene expression while substantially limiting or preventing conversion to off-target lineages such as bipolar or retinal pigment epithelial (RPE) cells.

[1457] Combinations comprising FOXJ1 were consistently superior to those lacking it, both in magnitude of photoreceptor gene induction and in lineage specificity. The data disclosed herein demonstrate that FOXJ1 acts as a key determinant of photoreceptor fate, biasing reprogramming outcomes towards cone and rod photoreceptors and away from bipolar and RPE fates. In particular, the present inventors have surprisingly shown that the triple transcription factor combination FOXJ1:NEUROD1:OTX2 and the quadruple transcription factor combination FOXJ1:NEUROD1:OTX2:CRX are particularly effective. According to any aspect of the invention, the transcription factors may preferably comprise or consist of FOXJ1, NEUR0D1 , and 0TX2. Even more preferably, according to any aspect of the invention, the transcription factors may comprise or consist of FOXJ1 , NEUROD1 , OTX2 and CRX.

[1458] Therefore, the nucleic acid molecule of the first aspect may comprise FOXJ1 or functional variants thereof.

[1459] According to any aspect of the invention, the transcription factors may comprise FOXJ1 and at least one further transcription factor. The at least one further transcription factor may be selected from the group consisting of OTX2, NEUROD1, CRX, MEF2C, MESP2, RAX2, NEUROG2, ASCL1, ATOH7, ATOH1, NRL. ONECUT1, RAX, MEF2Dand RXRG or functional variants thereof. The transcription factors may comprise FOXJ1 and at least two further transcription factors. The at least two further transcription factors may be selected from the group consisting ofOTX2, NEUROD1. CRX, MEF2C, MESP2, RAX2, NEUROG2, ASCL1. ATOH7, ATOH1, NRL, ONECUT1, RAX, MEF2D and RXRG or functional variants thereof.

[1460] The transcription factors may comprise FOXJ1 , OTX2 and at least one further transcription factor. It is thought that FOXJ1 and OTX2 have not previously been used together for photoreceptor cell reprogramming. More than one combination comprising FOXJ1 and OTX2 is surprisingly shown herein to upregulate photoreceptor reprogramming while avoiding the generation of RPE or bipolar cells. Combinations comprising FOXJ1 and OTX2 may therefore surprisingly improve photoreceptor reprogramming compared to known transcription factor combinations including OTX2 (OTX2:NRL:CRX). Therefore, the nucleic acid molecule of the first aspect may comprise FOXJ1 and OTX2, or functional variants thereof. The at least one further transcription factor may be selected from the group of NEUROD1 , CRX, MEF2C, MESP2, RAX2, NEUROG2, ASCL1 , ATOH7, ATOH1, NRL, ONECUT1, RAX, MEF2D and RXRG, or functional variants thereof. The transcription factors may comprise FOXJ1 , OTX2 and at least two further transcription factors. The at least two further transcription factors may each be selected from the group of NEUROD1, CRX, MEF2C, MESP2, RAX2, NEUROG2, ASCL1, ATOH7, ATOH1, NRL, ONECUT1, RAX, MEF2D and RXRG, or functional variants thereof.

[1461] The transcription factors may comprise FOXJ1, NEUROD1 and at least one further transcription factor. It is thought that FOXJ1 and NEUROD1 have not previously been used together for photoreceptor cell reprogramming. More than one combination comprising FOXJ1 and NEUROD1 is surprisingly shown herein to upregulate photoreceptor reprogramming while avoiding the generation of RPE or bipolar cells. Combinations comprising FOXJ1 and NEUROD1 may therefore surprisingly improve photoreceptor reprogramming compared to known transcription factor combinations. Therefore, the nucleic acid molecule of the first aspect may comprise FOXJ1 and NEUROD1 , or functional variants thereof. The at least one further transcription factor may be selected from the group of OTX2, CRX, MEF2C, MESP2, RAX2, NEUROG2, ASCL1,ATOH7, ATOH1, NRL, ONECUT1, RAX, MEF2D and RXRG, or functional variants thereof. The transcription factors may comprise FOXJ1, NEUROD1 and at least two further transcription factors. The at least two further transcription factors may each be selected from the group of OTX1 , CRX, MEF2C, MESP2, RAX2, NEUROG2, ASCL1, ATOH7, ATOH1, NRL, ONECUT1, RAX, MEF2D and RXRG.

[1462] The transcription factors may comprise FOXJ1 , CRX and at least one further transcription factor. It is thought that FOXJ1 and CRX have not previously been used together for photoreceptor cell reprogramming. The combination of FOXJ1 and CRX is surprisingly shown here-in to upregulated photoreceptor reprogramming while avoiding the generation of RPE or bipolar cells. Combinations comprising FOXJ1 and CRX may therefore surprisingly improve photoreceptor reprogramming compared to known transcription factor combinations including CRX (OTX2:NRL:CRX). Therefore, the nucleic acid molecule of the first aspect may comprise FOXJ1 and CRX, or functional variants thereof. The at least one further transcription factor may be selected from the group of OTX2, NEUROD1, MEF2C, MESP2, RAX2, NEUROG2, ASCL1, ATOH7, ATOH1, NRL, ONECUT1, RAX, MEF2D and RXRG, or functional variants thereof. The transcription factors may comprise FOXJ1 , CRX and at least two further transcription factors. The at least two further transcription factors may each be selected from the group of OTX1, NEUROD1, MEF2C, MESP2, RAX2, NEUROG2, ASCL1, ATOH7, ATOH1, NRL, ONECUT1, RAX, MEF2D and RXRG.

[1463] The transcription factors may comprise FOXJ1 , NEUROD1 , 0TX2 and at least one further transcription factor. It is thought that FOXJ1, NEUROD1 and OXT2 have not previously been used together for photoreceptor cell reprogramming. More than one combination comprising FOXJ1, NEUROD1 and OTX2 is surprisingly shown herein to upregulated photoreceptor reprogramming while avoiding the generation of RPE or bipolar cells. Combinations comprising FOXJ1, NEUROD1 and OTX2 may therefore surprisingly improve photoreceptor reprogramming compared to known transcription factor combinations including either NEUROD1 or OXT2. Therefore, the nucleic acid molecule of the first aspect may comprise FOXJ1, NEUROD1 and OTX2, or functional variants thereof. The at least one further transcription factor may be selected from the group of CRX, MEF2C, MESP2. RAX2, NEUROG2, ASCL1, ATOH7, ATOH1, NRL, ONECUT1, RAX, MEF2D and RXRG, or functional variants thereof. The transcription factors may comprise FOXJ1 , NEUROD1 , OTX2 and at least two further transcription factors. The at least two further transcription factors may each be selected from the group of CRX, MEF2C, M ESP2 , RAX2, NEU ROG2, ASCL1 , ATOH7.ATOH1, NRL, ONECUT1, RAX, MEF2D and RXRG, or functional variants thereof.

[1464] The transcription factors may comprise FOXJ1 , NEUROD1 , OTX2, CRX and at least one further transcription factor. It is thought that FOXJ1, NEUROD1, OXT2 and CRX have not previously been used together for photoreceptor cell reprogramming. The combination of FOXJ1, NEUROD1, OTX2 and CRX is surprisingly shown herein to upregulated photoreceptor reprogramming while avoiding the generation of RPE or bipolar cells. Combinations comprising FOXJ1, NEUROD1, 0TX2 and CRX may therefore surprisingly improve photoreceptor reprogramming compared to known transcription factor combinations including either NEUROD1, OXT2 or CRX. Therefore, the nucleic acid molecule of the first aspect may comprise FOXJ1, NEUROD1, OTX2 and CRX or functional variants thereof. The at least one further transcription factor may be selected from the group of MEF2C, MESP2. RAX2, NEUROG2, ASCL1, ATOH7, ATOH1, NRL, ONECUT1, RAX, MEF2D and RXRG, or functional variants thereof. The transcription factors may comprise FOXJ1, NEUROD1, OTX2, CRX and at least two further transcription factors. The at least two further transcription factors may each be selected from the group of MEF2C, MESP2, RAX2, NEUROG2, ASCL1.ATOH7, ATOH1, NRL, ONECUT1, RAX, MEF2D and RXRG, or functional variants thereof.

[1465] “Sequence identity” refers to the similarity between amino acid (or nucleotide) sequences. Sequence identity is frequently measured in terms of percentage identity (or similarity or homology); the higher the percentage, the more similar the two sequences are. While there exist a number of methods to measure identity between two polypeptide or two polynucleotide sequences, methods commonly employed to determine identity are codified in computer programs. Preferred computer programs to determine identity between two sequences include, but are not limited to, GCG program package (Devereux, et ai, Nucleic acids Research, 12, 387 (1984), BLASTP, BLASTN, and FASTA (Atschul et ai, J. Molec. Biol. (1990) 215, 403). Preferably, a sequence has at least 70% identity, using the default parameters of the BLAST computer program (Atschul et al., J. Mol. Biol. (1990) 215, 403-410) provided by HGMP (Human Genome Mapping Project), to a sequence disclosed herein.

[1466] In particular, it will be appreciated that to calculate the percentage identity of two sequences, the sequences must be aligned. Any suitable technique may be used to perform an alignment of two sequences. The skilled person would be aware of such techniques for example BLAST, NEEDLE or Clustal. It will further be appreciated that it is beneficial to minimize gaps in such an alignment. Any suitable technique may be used to minimize gaps such as prioritizing aligning conserved regions, adjusting scoring parameters to penalize gaps, using algorithms or software tools that optimize gap placement and / or refining the alignment by manually reviewing and adjusting gap positions

[1467] It will be appreciated that the following equation may be used to calculate percentage identity: Percentage Identity = ( Number of Matches / Total length of alignment) x 100

[1468] For example, the two sequences may be aligned using BLAST where to minimize gaps the scoring parameters may be adjusted to penalize gaps.

[1469] The term a “variant” in referring to protein and nucleic acid sequences (including the FOXJ1 , OTX2, NEUROD1 , CRX, MEF2C, MESP2, RAX2, NEUROG2, ASCL1, ATOH7, ATOH1, NRL, ONECUT1, RAX, MEF2D and RXRG sequences provided herein) are typically characterised by possession of at least 60%, 70%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99% sequence identity counted over the full-length alignment with the amino acid or nucleotide sequences. The present invention contemplates the use of variants of the nucleic acid sequences, promoters and transcription factors described herein. The variant could be a fragment of a full-length sequence, a codon-optimised sequence, or a naturally occurring splice variant. The variant could be a polypeptide or nucleic acid molecule at least 60%, 70%, 80%, 85%, 90%, 95%, 98%, or 99% identical to a full length sequence, wherein the fragment is at least 50%, 60%, 70%, 80%, 85%, 90%, 95%, 98%, or 99% as long as the full length wild type polypeptide or nucleic acid molecule, or a domain thereof has a functional activity of interest such as the ability to promote conversion of a source cell type to a target cell type. The domain may be at least 100, 200, 300, or 400 amino acids in length, beginning at any amino acid position in the sequence and extending toward the C-terminus. Variations known in the art to eliminate or substantially reduce the activity of the protein may be avoided. The variant may lack an N- and / or C-terminal portion of the full-length polypeptide, e.g. up to 10, 20, or 50 amino acids from either terminus is lacking. The polypeptide may have the sequence of a mature (full length) polypeptide, by which is meant a polypeptide that has had one or more portions such as a signal peptide removed during normal intracellular proteolytic processing (e.g. during co-translational or post-translational processing). When the protein is produced other than by purifying it from cells that naturally express it, the protein may be a chimeric polypeptide, by which is meant that it contains portions from two or more different species. When a protein is produced other than by purifying it from cells that naturally express it, the protein may be a derivative, by which is meant that the protein may comprise additional sequences not related to the protein so long as those sequences do not substantially reduce the biological activity of the protein. One of skill in the art will be aware of, or will readily be able to ascertain, whether a particular polypeptide variant, fragment, or derivative is functional using assays known in the art. Other convenient assays include measuring the ability to activate transcription of a reporter construct containing a transcription factor binding site operably linked to a nucleic acid sequence encoding a detectable marker. For example, the skilled person knows how to perform a luciferase assay to determine whether a variant of a transcription factor is a functional variant. For instance, if the variant activates the luciferase assay and / or has at least 50% of the activity of the full-length wild type polypeptide or nucleic acid molecule, it may be defined as a functional variant. Alternatively, the skilled person may compare transcriptomic changes following exposure to a transcription factor and a variant of the transcription factor, for instance using RNA sequencing, in order to determine whether the variant of the transcription factor is a functional variant. The transcriptomic changes may be upregulation and / or downregulation of gene expression. For instance, if the variant upregulates at least 50% of the genes upregulated by the full- length wild type polypeptide or nucleic acid molecule, it may be defined as a functional variant. Or, if the variant downregulates at least 50% of the genes downregulated by the full-length wild type polypeptide or nucleic acid molecule, it may be defined as a functional variant. Or, if the variant upregulates at least 50% of the genes upregulated by the full-length wild type polypeptide or nucleic acid molecule and downregulates at least 50% of the genes downregulated by the full-length wild type polypeptide or nucleic acid molecule, it may be defined as a functional variant. Alternatively, the skilled person may compare transcriptomic changes in known targets of a transcription factor following exposure to the transcription factor and a variant of the transcription factor, for instance using RT-qPCR, in order to determine whether the variant of the transcription factor is a functional variant. The transcriptomic changes may be upregulation and / or downregulation of the gene expression of the known target. For instance, a functional variant may exhibit significant overlap of either downstream targets or regulated pathways. By way of further example, if the variant upregulates a known target of the transcription factor by at least 30%, such as at least 40% or at least 50% of the level the known target is upregulated by the full-length wild type polypeptide or nucleic acid molecule, it may be defined as a functional variant. Or, if the variant downregulates a known target of the transcription factor by at least 30%, such as at least 40% or at least 50% of the level the known target is upregulated by the full-length wild type polypeptide or nucleic acid molecule, it may be defined as a functional variant. Alternatively, the skilled person may compare the effects of a transcription factor and a variant of the transcription factor on cell conversion, for instance by comparing the effects on a reduction in one or more characteristics of a source cell (such as retinal macroglia cells) and / or an increase in one or more characteristics of a target cell (such as photoreceptor cells), in order to determine whether the variant of the transcription factor is a functional variant. For instance, if at least 30%, such as at least 40% or at least 50% of the proportion of cells downregulating one or more source cell characteristic (such as the presence of at least one marker and / or at least one morphological trait of a retinal macroglia cell) following exposure to the full-length wild type polypeptide or nucleic acid molecule also downregulate the one or more source cell characteristic following exposure to the variant transcription factor, the variant may be defined as a functional variant. Or, if at least 30%, such as at least 40% or at least 50% of the proportion of cells upregulating one or more target cell characteristic (such as the presence of at least one marker and / or at least one morphological trait and / or at least one functional characteristic of a photoreceptor cell) following exposure to the full-length wild type polypeptide or nucleic acid molecule also upregulate the one or more target cell characteristic following exposure to the variant transcription factor, the variant may be defined as a functional variant. A functional variant or fragment may have at least 30%, such as at least 40%, at least 50%, 60%, 70%, 80%, 90%, 95% or more of the activity of the full-length wild type polypeptide or nucleic acid molecule. A functional variant or fragment may have at least 30%, such as at least 40%, at least 50%, 60%, 70%, 80%, 90%, 95% or more of the activity of a codon optimised molecule disclosed herein; references to the full-length wild type polypeptide or nucleic acid molecule in the above descriptions of how to ascertain whether a particular variant, fragment, or derivative is functional may be replaced by references to a codon optimised molecule disclosed herein. As used herein, the term “functional variant” preferably refers to a molecule, e.g. a polypeptide or nucleic acid molecule that retains at least about 70% or more (including at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or 100%) of the biological activity of a molecule disclosed herein, such as a nucleic acid sequence, a coding sequence, a codon optimised sequence or an amino acid sequence. Biological activity may for instance refer to one or more of activity in a luciferase assay, transcriptomic changes and / or effects on cell conversion. Preferably, a “functional variant” is defined by reference to both sequence identity percentage and biological activity. For instance, a “functional variant” may possess at least 70% (including at least 80%, at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity counted over the full length alignment with the amino acid or nucleotide sequences) and at least about 70% or more (including at least 75%, at least 80%, at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or 100%) of the biological activity of a molecule disclosed herein, such as a nucleic acid sequence, a coding sequence, a codon optimised sequence or an amino acid sequence. A “functional variant” may possess at least 80% (including at least 85%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity counted over the full length alignment with the amino acid or nucleotide sequences) and at least about 80% or more (including at least 85%, at least 90%, at least 95%, at least 97%, at least 99%, or 100%) of the biological activity of a molecule disclosed herein, such as a nucleic acid sequence, a coding sequence, a codon optimised sequence or an amino acid sequence. A “functional variant” may possess at least 90% (including at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% sequence identity counted over the full-length alignment with the amino acid or nucleotide sequences) and at least about 90% or more (including at least 95%, at least 97%, at least 99%, or 100%) of the biological activity of a molecule disclosed herein, such as a nucleic acid sequence, a coding sequence, a codon optimised sequence or an amino acid sequence. A “functional variant” may possess at least 95% (including at least 96%, at least 97%, at least 98%, or at least 99% sequence identity counted over the full-length alignment with the amino acid or nucleotide sequences) and at least about 95% or more (including at least 97%, at least 99%, or 100%) of the biological activity of a molecule disclosed herein, such as a nucleic acid sequence, a coding sequence, a codon optimised sequence or an amino acid sequence.

[1470] Variants may comprise one or more amino acid substitutions. Amino acid substitutions are typically conservative substitutions, i.e., replacement of one amino acid with another with generally similar properties, such that the overall function is probably not seriously affected. Thus, the amino acids glycine, alanine, valine, leucine, and isoleucine can often be substituted for one another (amino acids with aliphatic side chains). Among these potential substitutions, glycine and alanine are used to replace each other (as they have relatively short side chains), valine, leucine and isoleucine replace each other It is preferred that they be used because they have larger aliphatic side chains that are hydrophobic. Other amino acids that can often be substituted for one another are: phenylalanine, tyrosine, and tryptophan (amino acids with aromatic side chains); lysine, arginine, and histidine (amino acids with basic side chains); aspartic acid and glutamic acid (acidic side) asparagine and glutamine (amino acids with amide side chains); and cysteine and methionine (amino acids with sulphur containing side chains) are included.

[1471] The nucleic acid molecule may be isolated. The nucleic acid molecule may be recombinant. The nucleic acid molecule may be engineered or non-naturally occurring. The terms “isolated”, “recombinant”, “engineered” and “non-naturally occurring”, when referring to a nucleic acid molecule indicate that it is at least substantially free from at least one other component with which they are naturally associated in nature and as found in nature. In addition, the terms can indicate that the nucleic acid molecule has a sequence not found in nature.

[1472] The nucleic acid molecule may be forexpression of transcription factors in a source cell. The nucleic acid molecule may be for expression of transcription factors in a retinal source cell. The nucleic acid molecule may be for expression of transcription factors in macroglia. The nucleic acid molecule may be for expression of transcription factors in a cell type selected from the group consisting of a Muller glia or astrocyte. The nucleic acid molecule may be for expression of transcription factors in a Muller glia. The nucleic acid molecule may be for expression of transcription factors in an astrocyte.

[1473] The nucleic acid molecule may comprise a promoter. A "promoter" refers to a DNA sequence recognized by the synthetic machinery of the cell, or introduced synthetic machinery, required to initiate the specific transcription of a gene. One or more transcription factors may be operably linked to the promoter. The phrase “under transcriptional control” or “operably linked to” means that the promoter is in the correct location and orientation in relation to the nucleic acid to control RNA polymerase initiation of transcription and expression of the gene. A promoter also optionally includes distal enhancer or repressor elements. Accordingly, the nucleic acid sequence encoding FOXJ1 may be “under transcriptional control of or “operably linked to” the promoter.

[1474] Any promoter suitable fordriving expression of the transcription factors in source cells, particularly retinal cells, more particularly macroglia, may be used. For example, the promoter may be a constitutive promoter, an inducible promoter, a cell-specific promoter, a tissue-specific promoter, a cell-selective promoter, or a tissue-selective promoter. A “constitutive promoter” is a promoter that is continuously active. Constitutive promoters can therefore allow continuous expression of any operably linked genes. Constitutive promoters may not be subject to regulation by external signals or molecules. For example, constitutive promoters include CAG, CBA, CBh, sCAG, CMV, beta actin, ubiquitin C, PGK, EF1 a, SV40, SFFV, RSV and MMLV. In contrast, the activity of an “inducible promoter” is regulated by an external signal or molecule (for example a transcription factor). A “cellspecific promoter” or “tissue-specific promoter” is a promoter that directs expression of a nucleic acid molecule in particular cells or tissues of interest, but not other cell or tissue types. For example, cell-specific promoters that are known to lead to expression in Muller glia and astrocytes include, retinaldehyde-binding protein 1 (RLBP1) and Glial fibrillary acidic protein (GFAP). Where a promoter preferentially directs expression of a nucleic acid molecule in particular cells or tissues but also directs expression in other cells or tissues at a lower level, it may be referred to as a “cell-selective promoter” or a “tissue-selective promoter”. A number of promoters may be used to induce the expression of the nucleic acid which is operably linked to the promoter sequence. Promoters may be both constitutive and cell (or tissue)-specific. Promoters may be both constitutive and cell (or tissue)-selective.

[1475] A promoter may be naturally occurring, such as the RLBP1 and GFAP promoters. A promoter may be synthetic, such as the ProB2 promoter and others described in Juttner et al (Nature Neuroscience (2019) 22:1345-1356, which is herein incorporated by reference in its entirety). Functional fragments and minimal promoters (also referred to as mini promoters), such as those derived from any promoter described herein may also be used according to the invention. By way of example, the Pleiades Promoter Project has generated mini promoters for expression in Muller glia cells, such as Ple316 (NR2ET) as described in Korecki et al (Gene Therapy (2021) 28:351-372, which is herein incorporated by reference in its entirety).

[1476] Some other promoters that have been shown to lead to Muller glia specific expression are ProB2 and SLC1A3 (which was historically known as GLAST). Promoters suitable for directing expression in Muller glia include sequences from nine Muller glia-associated genes: CAR2, CD44, GFAP, GLUL, PDGFRA, RLBP1, SWOB, SLC1A3, and vimentin (VIM) and variants thereof shown to be able to drive reporter gene expression in Muller glia by Geller et al (2008) Molecular Vision 2008; 14:691-705, hereby incorporated herein by reference.

[1477] The promoter may be selected from the group consisting of GFAP, CAR2, CD44, GLUL, PDGFRA, RLBP1, SWOB, SLC1A3, VIM, ProB2 CAG and CMV. The promoter may be selected from the group consisting of GFAP, RLBP1, ProB2 and SLC1A3. The promoter may be a macroglia specific promoter. The macroglia may be retinal macroglia. The macroglia may be Muller glia and / or astrocytes. The macroglia may be Muller glia. The promoter may be a GFAP promoter. The GFAP promoter may be a shortened or truncated GFAP promoter. The promoter may be a gfaABCI D GFAP promoter. The GFAP promoter may consist of or may comprise SEQ ID NO: 79 (a 681 bp sequence). The GFAP promoter may consist of or may comprise SEQ ID NO: 80 (a 699 bp sequence comprising the sequence of SEQ ID NO: 97).

[1478] SEQ ID NO: 79

[1479] AACATATCCTGGTGTGGAGTAGGGGACGCTGCTCTGACAGAGGCTCGGGGGCCTGAGCTGGCTCTGTGAGCTGGGGAG GAGGCAGACAGCCAGGCCTTGTCTGCAAGCAGACCTGGCAGCATTGGGCTGGCCGCCCCCCAGGGCCTCCTCTTCATG CCCAGTGAATGACTCACCTTGGCACAGACACAATGTTCGGGGTGGGCACAGTGCCTGCTTCCCGCCGCACCCCAGCCC CCCTCAAATGCCTTCCGAGAAGCCCATTGAGCAGGGGGCTTGCATTGCACCCCAGCCTGACAGCCTGGCATCTTGGGAT AAAAGCAGCACAGCCCCCTAGGGGCTGCCCTTGCTGTGTGGCGCCACCGGCGGTGGAGAACAAGGCTCTATTCAGCCT GTGCCCAGGAAAGGGGATCAGGGGATGCCCAGGCATGGACAGTGGGTGGCAGGGGGGGAGAGGAGGGCTGTCTGCTT CCCAGAAGTCCAAGGACACAAATGGGTGAGGGGAGAGCTCTCCCCATAGCTGGGCTGCGGCCCAACCCCACCCCCTCA GGCTATGCCAGGGGGTGTTGCCAGGGGCACCCGGGCATCGCCAGTCTAGCCCACTCCTTCATAAAGCCCTCGCATCCCA GGAGCGAGCAGAGCCAGAGCAGGTTGGAGAGGAGACGCATCACCTCCGCTGCTCGC

[1480] SEQ ID NO: 80

[1481] CTAGTGATCTAACATATCCTGGTGTGGAGTAGGGGACGCTGCTCTGACAGAGGCTCGGGGGCCTGAGCTGGCTCTGTGA GCTGGGGAGGAGGCAGACAGCCAGGCCTTGTCTGCAAGCAGACCTGGCAGCATTGGGCTGGCCGCCCCCCAGGGCCT CCTCTTCATGCCCAGTGAATGACTCACCTTGGCACAGACACAATGTTCGGGGTGGGCACAGTGCCTGCTTCCCGCCGCA CCCCAGCCCCCCTCAAATGCCTTCCGAGAAGCCCATTGAGCAGGGGGCTTGCATTGCACCCCAGCCTGACAGCCTGGCA TCTTGGGATAAAAGCAGCACAGCCCCCTAGGGGCTGCCCTTGCTGTGTGGCGCCACCGGCGGTGGAGAACAAGGCTCT ATTCAGCCTGTGCCCAGGAAAGGGGATCAGGGGATGCCCAGGCATGGACAGTGGGTGGCAGGGGGGGAGAGGAGGGC TGTCTGCTTCCCAGAAGTCCAAGGACACAAATGGGTGAGGGGAGAGCTCTCCCCATAGCTGGGCTGCGGCCCAACCCCA CCCCCTCAGGCTATGCCAGGGGGTGTTGCCAGGGGCACCCGGGCATCGCCAGTCTAGCCCACTCCTTCATAAAGCCCTC GCATCCCAGGAGCGAGCAGAGCCAGAGCAGGTTGGAGAGGAGACGCATCACCTCCGCTGCTCGCGGGGATCC

[1482] Promoters described herein by reference to the associated gene include variants of the corresponding promoter as well as “full length” promoters. A “full-length” promoter may comprise around 2000 bases or around 1500 bases upstream relative to the transcriptional start site (TSS). A variant of a promoter may be a truncated promoter consisting of up to around 1000 bases, up to around 900 bases, up to around 800 bases, up to around 700 bases, up to around 600 bases or up to around 500 bases of the “full length” promoter. The bases of the truncated promoter may be consecutive bases proximal to the TSS. “Proximal to” may refer to the furthest base from the TSS being up to 100 bases, up to 90 bases, up to 80 bases, up to 70 bases, up to 60 bases, up to 50 bases, up to 40 bases, up to 30 bases, up to 20 bases, up to 10 bases, up to 5 bases or 0 bases upstream from the TSS. The TSS may be identified using RefSeq sequences (NCBI), for instance those compiled into single data files available at ECRbase. A variant of the promoter may be an evolutionarily conserved region (ECR), preferably the most proximal ECR relative to the TSS. ECR sequences may be identified in full length promoter regions mandating a minimum of 70% sequence homology between human and mouse genomes over a 100 base pair window. The promoter or variant thereof may further comprise the 5’ UTR, or a fragment thereof, associated with the gene. Preferably, the one or more nucleic acids encoding for at least one or more transcription factors is under the control of a GFAP promoter. The use of a GFAP promoter restricts the expression of the transcription factors to Muller glia and astrocytes only. Preferably a promoter of between 400 and 800 bp is used, for example, the truncated GFAP promoter gfaABCID having 681 bp (Lee, 2008 DOI: 10.1002 / glia.20622), identified below as SEQ ID NO: 79, which is reported to have essentially the same expression pattern as the 2210 bp gfa2 promoter, and about twofold greater activity.

[1483] The promoter may comprise an enhancer region and a promoter region. The promoter may further comprise an intron sequence. The enhancer region may be arranged 5’ relative to the promoter region. The intron sequence may be arranged 3’ relative to the promoter region.

[1484] The promoter may comprise a chicken |3 actin promoter region, or a functional variant thereof. Examples of promoters comprising a chicken |3 actin promoter region include CAG, CBA, CBh and sCAG. The chicken |3 actin promoter region may refer to the following nucleic acid sequence, identified as SEQ ID NO: 81

[1485] SEQ ID NO: 81

[1486] TCGAGGTGAGCCCCACGTTCTGCTTCACTCTCCCCATCTCCCCCCCCTCCCCACCCCCAATTTTGTATTTATTTATTTTTTA ATTATTTTGTGCAGCGATGGGGGCGGGGGGGGGGGGGGGGCGCGCGCCAGGCGGGGCGGGGCGGGGCGAGGGGCG GGGCGGGGCGAGGCGGAGAGGTGCGGCGGCAGCCAATCAGAGCGGCGCGCTCCGAAAGTTTCCTTTTATGGCGAGGC GGCGGCGGCGGCGGCCCTATAAAAAGCGAAGCGCGCGGCGGGCG

[1487] The promoter may comprise a cytomegalovirus (CMV) promoter region, or a functional variant thereof. Examples of promoters comprising a cytomegalovirus promoter region include CMV1 and CMV2. The CMV promoter region may refer to the following nucleic acid sequence, identified as SEQ ID NO: 82

[1488] SEQ ID NO: 82

[1489] GTGATGCGGTTTTGGCAGTACATCAATGGGCGTGGATAGCGGTTTGACTCACGGGGATTTCCAAGTCTCCACCCCATTGA CGTCAATGGGAGTTTGTTTTGGCACCAAAATCAACGGGACTTTCCAAAATGTCGTAACAACTCCGCCCCATTGACGCAAAT GGGCGGTAGGCGTGTACGGTGGGAGGTCTATATAAGCAGAGCT

[1490] The promoter may comprise a CMV enhancer region, or a functional variant thereof. Examples of promoters comprising a CMV enhancer region include CAG, CBA, CBh, sCAG, CMV1 and CMV2. The CMV enhancer region may refer to the following nucleic acid sequence, identified as SEQ ID NO: 83

[1491] SEQ ID NO: 83

[1492] CGTTACATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGT TCCCATAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACAT CAAGTGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATG ACCTTATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATG The promoter may comprise CAG, CBA, CBh, sCAG or CMV, or a functional variant thereof. The promoter may consist of or consist essentially of CAG, CBA, CBh, sCAG or CMV, or a functional variant thereof.

[1493] The promoter may comprise CAG, or a functional variant thereof. The promoter may consist of or consist essentially of CAG, or a functional variant thereof. CAG may refer to the following nucleic acid sequence, identified as SEQ ID NO: 84

[1494] SEQ ID NO: 84

[1495] CTCGACATTGATTATTGACTAGTTATTAATAGTAATCAATTACGGGGTCATTAGTTCATAGCCCATATATGGAGTTCCGCGTTA CATAACTTACGGTAAATGGCCCGCCTGGCTGACCGCCCAACGACCCCCGCCCATTGACGTCAATAATGACGTATGTTCCCA TAGTAACGCCAATAGGGACTTTCCATTGACGTCAATGGGTGGAGTATTTACGGTAAACTGCCCACTTGGCAGTACATCAAG TGTATCATATGCCAAGTACGCCCCCTATTGACGTCAATGACGGTAAATGGCCCGCCTGGCATTATGCCCAGTACATGACCTT ATGGGACTTTCCTACTTGGCAGTACATCTACGTATTAGTCATCGCTATTACCATGGTCGAGGTGAGCCCCACGTTCTGCTTC ACTCTCCCCATCTCCCCCCCCTCCCCACCCCCAATTTTGTATTTATTTATTTTTTAATTATTTTGTGCAGCGATGGGGGCGGG GGGGGGGGGGGGGCGCGCGCCAGGCGGGGCGGGGCGGGGCGAGGGGCGGGGCGGGGCGAGGCGGAGAGGTGCG GCGGCAGCCAATCAGAGCGGCGCGCTCCGAAAGTTTCCTTTTATGGCGAGGCGGCGGCGGCGGCGGCCCTATAAAAAG CGAAGCGCGCGGCGGGCGGGAGTCGCTGCGCGCTGCCTTCGCCCCGTGCCCCGCTCCGCCGCCGCCTCGCGCCGCC CGCCCCGGCTCTGACTGACCGCGTTACTCCCACAGGTGAGCGGGCGGGACGGCCCTTCTCCTCCGGGCTGTAATTAGC GCTTGGTTTAATGACGGCTTGTTTCTTTTCTGTGGCTGCGTGAAAGCCTTGAGGGGCTCCGGGAGGGCCCTTTGTGCGG GGGGAGCGGCTCGGGGGGTGCGTGCGTGTGTGTGTGCGTGGGGAGCGCCGCGTGCGGCTCCGCGCTGCCCGGCGG CTGTGAGCGCTGCGGGCGCGGCGCGGGGCTTTGTGCGCTCCGCAGTGTGCGCGAGGGGAGCGCGGCCGGGGGCGGT GCCCCGCGGTGCGGGGGGGGCTGCGAGGGGAACAAAGGCTGCGTGCGGGGTGTGTGCGTGGGGGGGTGAGCAGGG GGTGTGGGCGCGTCGGTCGGGCTGCAACCCCCCCTGCACCCCCCTCCCCGAGTTGCTGAGCACGGCCCGGCTTCGGG TGCGGGGCTCCGTACGGGGCGTGGCGCGGGGCTCGCCGTGCCGGGCGGGGGGTGGCGGCAGGTGGGGGTGCCGGG CGGGGCGGGGCCGCCTCGGGCCGGGGAGGGCTCGGGGGAGGGGCGCGGCGGCCCCCGGAGCGCCGGCGGCTGTC GAGGCGCGGCGAGCCGCAGCCATTGCCTTTTATGGTAATCGTGCGAGAGGGCGCAGGGACTTCCTTTGTCCCAAATCTG TGCGGAGCCGAAATCTGGGAGGCGCCGCCGCACCCCCTCTAGCGGGCGCGGGGCGAAGC...

Claims

Claims1. A nucleic acid molecule comprising a promoter operably linked to a nucleic acid sequence encoding the transcription factor Forkhead Box protein J1 (FOXJ1), or a functional variant thereof, wherein the promoter is for expression of FOXJ1 in macroglia.

2. The nucleic acid molecule according to claim 1 , which further encodes one or more transcription factor selected from the group consisting of OTX2, NEUROD1, CRX, MEF2C, MESP2, RAX2, NEUROG2, ASCL1, ATOH7, ATOH1, NRL, ONECUT1, RAX, MEF2D and RXRG.

3. A nucleic acid molecule encoding at least two transcription factors, wherein one transcription factor is FOXJ1 and wherein the at least two transcription factors further comprise at least one transcription factor selected from the group consisting of 0TX2, NEUROD1, CRX, MEF2C, MESP2, RAX2, NEUROG2, ASCL1, ATOH7, ATOH1, NRL, ONECUT1, RAX, MEF2D and RXRG.

4. The nucleic acid molecule according to claim 2 or 3, wherein the transcription factors comprise:(a) FOXJ1 and OTX2;(b) FOXJ1 and NEURODI;(c) FOXJ1 and CRX;(d) FOXJ1, OTX2 and CRX;(e) FOXJ1. OTX2 and NEURODI;(f) FOXJ1, NEUROD1 and CRX;(g) FOXJ1, OTX2, NEUROD1 and CRX;(h) FOXJ1, 0TX2 and RAX2;(i) FOXJ1, 0TX2 and MEF2C;0) FOXJ1, OTX2 and MESP2;(k) FOXJ1 , NEUROG2 and OTX2; or(l) FOXJ1, NEUROG2 and CRX; preferably wherein the transcription factors comprise: FOXJ1, OTX2 and NEURODI or FOXJI, OTX2, NEUROD1 and CRX.

5. The nucleic acid molecule according to any preceding claim wherein:(a) the nucleic acid molecule encodes:(i) FOXJ1 and OTX2, or functional variants thereof;(ii) FOXJ1 and NEUROD1, or functional variants thereof;(iii) FOXJ1, OTX2 and NEUROD1, or functional variants thereof; and / or(iv) FOXJ1 and one or more proneural bHLH transcription factor; and / or(b) the nucleic acid molecule further encodes CRX, or a functional variant thereof.

6. The nucleic acid molecule according to any preceding claim wherein the transcription factors comprise:(a) FOXJ1 and one or more further transcription factor selected from the group consisting of NEUROD1 , NEUROG2, ASCL1. ATOH7 and ATOHI ;(b) FOXJ1 , OTX2 and one or more further transcription factor selected from the group consisting of NEUROD1 , NEUROG2, ASCL1 , ATOH7 and ATOHI ; or(c) FOXJ1 , CRX and one or more further transcription factor selected from the group consisting of NEUROD1 , NEUROG2, ASCL1 , ATOH7 and ATOHI .

7. The nucleic acid molecule according to any preceding claim wherein the nucleic acid sequence encoding:(a) NEUROD1 is 5’ relative to the nucleic acid sequence encoding FOXJ1 ; and / or(b) OTX2 is 5’ relative to the nucleic acid sequence encoding CRX.

8. The nucleic acid molecule according to any preceding claim further comprising a linker sequence separating sequences encoding the transcription factors, optionally wherein the linker sequence encodes a 2A family peptide or comprises an IRES, optionally wherein the 2A family peptide is selected from the group consisting of P2A, T2A, E2A and F2A.

9. The nucleic acid molecule according to any preceding claim wherein:(a) the nucleic acid molecule is for expression of the transcription factors in a source cell, optionally wherein a source cell is a macroglia cell, optionally a retinal cell, optionally wherein the retinal macroglia cell is selected from the group consisting of a Muller glia and an astrocyte; and / or(b) the nucleic acid molecule comprises a promoter operably linked to the sequences encoding the at least two transcription factors, wherein the promoter is for expression of the at least two transcription factors in a source cell, optionally wherein a source cell is a macroglia cell, optionally a retinal cell, optionally wherein the retinal macroglia cell is selected from the group consisting of a Muller glia and an astrocyte, and optionally:(i) the promoter is selected from the group consisting of ProB2, CAR2, CD44, GFAP, GLUL, PDGFRA, RLBP1, S OB, SLC1A3, VIM, CAG, CBA, CBh, sCAG, Ef1a, CMV1 and CMV2;(ii) the promoter comprises a CMV enhancer region, or a functional variant thereof, preferably wherein the promoter is selected from the group consisting of CAG, CBA, CBh, sCAG, CMV1 and CMV2;(iii) the promoter comprises a chicken [3 actin promoter region, or a functional variant thereof, optionally wherein the promoter is selected from the group consisting of CAG, CBA, CBh and sCAG, preferably wherein the promoter comprises CAG; the promoter comprises a CMV enhancer region, or a functional variant thereof, preferably wherein the promoter is selected from the group consisting of CMV1 and CMV2;(iv) the promoter comprises a macroglia selective or specific promoter;(v) the promoter comprises a retinal macroglia selective or specific promoter;(vi) the promoter comprises a Muller glia selective or specific promoter;(vii) the promoter comprises an astrocyte selective or specific promoter;(viii) the promoter is a GFAP promoter; and / or(ix) the promoter is a gfaABCI D GFAP promoter.

10. A vector comprising the nucleic acid molecule according to any one of claims 1 to 9 .

11. A vector according to claim 10, wherein the vector is:(a) a viral vector, optionally wherein the viral vector is selected from the group consisting of an adeno-associated virus (AAV) vector, a lentiviral vector, a Sendai vector, a Herpes simplex virus (HSV) vector, an Adenoviral vector, an episomal vector and a retroviral vector; or(b) a non-viral vector, optionally wherein the non-viral vector is selected from the group consisting of a liposome, a nanoparticle, an exosome, a virus-like particle (VLP), a lipid nanoparticle (LNP), naked DNA, a plasmid, a transposon, a saRNA vector, mRNA, and stabilised RNA.

12. A vector according to any one of claims 10 or 11 , wherein the vector is a viral vector which comprises:(a) a capsid for transduction of macroglia cells, optionally retinal macroglia cells, optionally wherein the vector comprises a capsid for transduction of a cell type selected from the group consisting of Muller cells, and astrocytes; and / or(b) a capsid selected from the group consisting of AAV1 , AAV2, AAV4, AAV5, AAV6, AAV8, AAV9, AAV2.7m8, ShH10, ShHIOY and ShH13, preferably a capsid selected from the group consisting of AAV5, ShH10, AAV2.7m8, ShHIOY and ShH 13, more preferably an AAV2.7m8 capsid.

13. A composition comprising the nucleic acid molecule according any one of claims 1 to 9, or the vector according to any one of claims 10 to 12, and a pharmaceutically acceptable carrier.

14. A product comprising:(a) a first nucleic acid molecule, encoding FOXJ1 , or a functional variant thereof, and(b) a second nucleic acid molecule, encoding at least one transcription factor, or a functional variant thereof, selected from the group consisting of OTX2, NEUROD1 , CRX, MEF2C, MESP2, RAX2, NEUROG2, ASCL1 , ATOH7, ATOH1 , NRL, ONECUT1 , RAX, MEF2D and / or RXRG; wherein the first nucleic acid molecule and the second nucleic acid molecule each encode different transcription factors; as a combined preparation for simultaneous, separate, or sequential use in the treatment of retinal disease or degeneration.

15. The product according to claim 14, wherein the first and / or second nucleic acid molecule is a nucleic acid molecule according to any one of claims 1 to 9.

16. The product according to any one of claims 14 to 15, wherein:(a) the first and second nucleic acid molecules together encode transcription factors or functional variants thereof comprising:(i) FOXJ1 and 0TX2;(ii) FOXJ1 and NEURODI;(iii) FOXJ1 and CRX;(iv) FOXJ1, 0TX2 and CRX;(v) FOXJ1. OTX2 and NEURODI;(vi) FOXJ1, NEUROD1 and CRX;(vii) FOXJ1, 0TX2, NEUROD1 and CRX;(viii) FOXJ1, OTX2 and RAX2;(ix) FOXJ1, OTX2 and MEF2C;(x) FOXJ1, OTX2 and MESP2;(xi) FOXJ1, NEUROG2 and OTX2; or(xii) FOXJ1, NEUROG2 and CRX; preferably wherein the first and second nucleic acid molecules together encode transcription factors or functional variants thereof comprising: FOXJ1, 0TX2 and NEUROD1 or FOXJ1, 0TX2, NEUROD1 and CRX;(b) the first nucleic acid molecule encodes FOXJ1 or a functional variant thereof, and the second nucleic acid molecule encodes OTX2, or a functional variant thereof;(c) the first nucleic acid molecule encodes FOXJ1 and OTX2, or functional variants thereof;(d) the first nucleic acid molecule encodes FOXJ1 or a functional variant thereof, and the second nucleic acid molecule encodes NEU OD1, or a functional variant thereof;(e) the first nucleic acid molecule encodes FOXJ1 and NEUROD1, or functional variants thereof;(f) the first nucleic acid molecule encodes FOXJ1 and NEUROD1, or functional variants thereof, and the second nucleic acid molecule encodes one or more transcription factor selected from the group consisting of OTX2, CRX, MEF2C, MESP2, RAX2, NEUROG2, ASCL1, ATOH7, ATOH1, NRL, ONECUT1, RAX, MEF2D and RXRG, or functional variants thereof;(g) the first nucleic acid molecule encodes FOXJ1 and NEUROD1, or functional variants thereof, and the second nucleic acid molecule encodes one or more transcription factor selected from the group consisting of OTX2 and CRX, or functional variants thereof;(h) the first nucleic acid molecule encodes FOXJ1 and NEUROD1, or functional variants thereof, and the second nucleic acid molecule encodes OTX2, or a functional variant thereof;(i) the first nucleic acid molecule encodes FOXJ1 and NEUROD1, or functional variants thereof, and the second nucleic acid molecule encodes OTX2 and CRX, or functional variants thereof; and / or(j) the first nucleic acid molecule or the second nucleic acid molecule further encodes CRX, or a functional variant thereof.

17. A product comprising:(a) a first nucleic acid molecule, configured to target for upregulation of FOXJ1, or a functional variant thereof, and(b) a second nucleic acid molecule, configured to target for upregulation of at least one transcription factor, or a functional variant thereof, selected from the group consisting of 0TX2, NEUROD1 , CRX, MEF2C, MESP2, RAX2, NEUROG2, ASCL1, AT0H7, AT0H1, NRL, ONECUT1, RAX, MEF2D and / or RXRG; as a combined preparation for simultaneous, separate, or sequential use in the treatment of retinal disease or degeneration.

18. The product according to claim 17, wherein:(a) the first and / or second nucleic acid molecule is a nucleic acid molecule according to any one of claims 1 to 9; and / or(b) the first and second nucleic acid molecules together encode transcription factors or functional variants thereof comprising:(i) FOXJ1 and 0TX2;(ii) FOXJ1 and NEURODI;(iii) FOXJ1 and CRX;(iv) FOXJ1, OTX2 and CRX;(v) FOXJ1. OTX2 and NEURODI;(vi) FOXJ1, NEUROD1 and CRX;(vii) FOXJ1, 0TX2, NEUROD1 and CRX;(viii) FOXJ1, 0TX2 and RAX2;(ix) FOXJ1, 0TX2 and MEF2C;(x) FOXJ1, OTX2 and MESP2;(xi) FOXJ1, NEUROG2 and 0TX2; or(xii) FOXJ1, NEUROG2 and CRX; preferably wherein the first and second nucleic acid molecules together encode transcription factors or functional variants thereof comprising: FOXJ1, 0TX2 and NEUROD1 or FOXJ1, OTX2, NEUROD1 and CRX.

19. A kit for introducing and / or increasing the protein expression of FOXJ1, or a functional variant thereof, in macroglia; wherein optionally said kit is further for introducing and / or increasing the protein expression of one or more transcription factor selected from the group consisting of 0TX2, NEUROD1, CRX, MEF2C, MESP2, RAX2, NEUROG2, ASCL1, ATOH7, ATOH1, NRL, ONECUT1, RAX, MEF2D and RXRG.

20. A kit for introducing and / or increasing the protein expression of at least two transcription factors, or functional variants thereof, in a source cell, wherein one transcription factor is FOXJ1 and wherein the at least two transcription factors further comprise at least one transcription factor selected from the group consisting of OTX2, NEUROD1, CRX, MEF2C, MESP2, RAX2, NEUROG2, ASCL1, ATOH7, ATOH1, NRL, ONECUT1, RAX, MEF2D and RXRG.

21. A kit according to any one of claims 19 to 20,(a) the transcription factors for introducing and / or increasing comprise:(i) FOXJ1 and 0TX2;(ii) FOXJ1 and NEURODI;(iii) FOXJ1 and CRX;(iv) FOXJ1, 0TX2 and CRX;(v) FOXJ1. OTX2 and NEURODI;(vi) FOXJ1, NEUROD1 and CRX;(vii) FOXJ1, 0TX2, NEUROD1 and CRX;(viii) FOXJ1, 0TX2 and RAX2;(ix) FOXJ1, 0TX2 and MEF2C;(x) FOXJ1, 0TX2 and MESP2;(xi) FOXJ1, NEUROG2 and OTX2; or(xii) FOXJ1, NEUR0G2 and CRX; preferably wherein the transcription factors for introducing and / or increasing comprise: FOXJ1, 0TX2 and NEUROD1 or FOXJ1, 0TX2, NEUROD1 and CRX;(b) said kit is for the introduction of transcription factors comprising a nucleic acid molecule according to any one of claims 1 to 9, a vector according any one of claims 10 to 12, a composition according to claim 13 or a product according to any one of claims 14 to 16; or(c) said kit is for the increasing the protein expression of transcription factors a vector according to any one of claims 10 to 12, a composition according to claim 13 or a product according to any one of claims 17 to 18.

22. A product or kit according to any one of claims 14 to 21 , further comprising instructions for use.

23. A method of converting a source cell to a target cell by introducing and / or increasing the protein expression of FOXJ1, or a functional variant thereof, into the source cell, thereby converting the source cell into the target cell.

24. The method according to claim 23, wherein:(a) said method comprises introducing and / or increasing the protein expression at least two transcription factors, or functional variants thereof, in a source cell, wherein one transcription factor is FOXJ1 and wherein the at least two transcription factors further comprise at least one transcription factor selected from the group consisting of OTX2, NEUROD1, CRX, MEF2C, MESP2, RAX2, NEUROG2, ASCL1, ATOH7, ATOH1, NRL, ONECUT1, RAX, MEF2D and RXRG; and / or(b) the transcription factors introduced and / or increased comprise:(i) FOXJ1 and OTX2;(ii) FOXJ1 and NEURODI;(iii) FOXJ1 and CRX;(iv) FOXJ1, OTX2 and CRX;(v) F0XJ1, 0TX2 and NEUR0D1;(vi) F0XJ1, NEUR0D1 and CRX;(vii) F0XJ1, 0TX2, NEUR0D1 and CRX;(viii) F0XJ1, 0TX2 and RAX2;(ix) F0XJ1, 0TX2 and MEF2C;(x) F0XJ1, 0TX2 and MESP2;(xi) F0XJ1, NEUR0G2 and OTX2; or(xii) F0XJ1, NEUR0G2 and CRX; preferably wherein the transcription factors introduced and / or increased comprise: FOXJ1, OTX2 and CRXor FOXJ1, OTX2, NEUROD1 and CRX.

25. The method according to any one of claims 23 or 24 wherein:(a) the method is for introducing the transcription factors and the transcription factors may be introduced via a nucleic acid molecule according to any one of claims 1 to 9, a vector according to any one of claims 10 to 12, a composition according to claim 13, a product according to any one of claims 14 to 16 or a kit according to any one of claims 19 to 22;(b) the method is for introducing the transcription factors and the transcription factors may be introduced via a vector according to any one of claims 10 to 12, a composition according to claim 13, a product according to any one of claims 17 to 18 or a kit according to any one of claims 19 to 22; and / or(c) the method is an in vitro method comprising comprise culturing under suitable conditions for a time period suitable for conversion of the source cell to the target cell, optionally culturing under suitable conditions for at least 7 days.

26. The method according to any one of the claims 23 to 25, wherein:(a) the source cell is a retinal source cell, optionally a retinal macroglia cell, preferably a Muller glia or astrocyte; and / or(b) the target cell is a retinal target cell, optionally a photoreceptor cell or a photoreceptor-like cell, preferably a cone photoreceptor cell or a rod photoreceptor cell, or a cone photoreceptor-like cell or rod photoreceptor-like cell.

27. A cell produced by the method of claims 23 to 26.

28. A nucleic acid molecule according to any one of claims 1 to 9, a vector according any one of claims 10 to 12, a composition according to 13, a kit according to any one of claims 19 to 22, or a cell according to claim 27 for use in the treatment of retinal disease or degeneration.

29. A method of treating retinal disease or degeneration in a subject in need thereof comprising administering to the subject a therapeutically effective amount of a nucleic acid molecule according to any one of claims 1 to 9, a vector according any one of claims 10 to 12, a composition according to 13, a product according to any one of claims 14 to 18, a kit according to any one of claims 19 to 22, or a cell according to claim 27.

30. A nucleic acid molecule, vector, composition, product, kit, a method, cell, substance or composition for use or a method of treatment according to any preceding claim, wherein:(a) a source cell is a retinal macroglia cell, optionally a Muller glia or astrocyte; and / or(b) a target cell is a photoreceptor cell or a photoreceptor-like cell.

31. A nucleic acid molecule, vector, composition, product, kit, a method, cell, substance or composition for use or a method of treatment according to any preceding claim, wherein a cell or a cell population in which the transcription factors are introduced and / or increased:(a) upregulates one or more photoreceptor hair cell markers;(b) downregulates one or more cell markers of a retinal macroglia cell;(c) undergoes one or more morphological change indicative of conversion from a retinal macroglia cell to a photoreceptor cell; and / or(d) is annotated as a photoreceptor cell by inspecting the expression of marker genes, for example by annotation using SingleR, such as version 2.0.0.

32. A nucleic acid molecule, vector, composition, product, kit, a method, cell, substance or composition for use or a method of treatment according to claim 31 , wherein a cell or a cell population upregulates one or more of:(a) OPN1SW, OPN1 MW, OPN1LW, GNAT2, GNGT2, PDE6C, PDE6H, CNGA3, GRK7, ARR3, and GUCA1C; and / or(b) NRL, NR2E3, RHO, GNAT1, GNGT1, PDE6A, PDE6B, PDE6G, and CNGA1; and optionally one or more of: OTX2, CRX, RCVRN, GRK1, MYO7A, ROM1, PRPH2, RP1, IMPG2, TULP1, KCNV2, RIMS2, CDHR1, PROM1, EYS, ABCA4, and ELOVL4.

33. A nucleic acid molecule, vector, composition, product, kit, a method, cell, substance or composition for use or a method of treatment according to claim 31 or 32, wherein a cell or a cell population:(a) downregulates one or more of: SOX2, SOX9, PAX2, RLBP1, AQP4, KCNJ10, GLUL, SLC1A3, GFAP, VIM, and S100A16; and / or(b) does not upregulate the expression of one or more of: BEST1, RLBP1, MITF, TYR, PMEL, SERPINF1 , VSX1, VSX2, PCP2, LRTM1, CA10, and TRPM1.

34. A product according to any one of claims 14 to 18, a nucleic acid molecule, vector, composition, product, kit, a method or cell for use according to any one of claims 28 or 30 to 33, or a method of treatment according to any one of claims 29 to 33, wherein the retinal disease or disorder is an inherited retinal dystrophy (IRD), age-related macular degeneration (AMD), retinitis pigmentosa (RP), late-stage Best disease, Stargardt macular dystrophy, cone dystrophy (CD or COD) or cone-rod dystrophy (CRD or CORD).

35. A product according to any one of claims 14 to 28 or 34, a nucleic acid molecule, vector, composition, product, kit, a method or cell for use according to any one of claims 28 or 30 to 33, or a method of treatment according to any one of claims 29 to 33, wherein the administration is to one or more retina of the subject, optionally by intravitreal administration, topical administration, subconjunctival administration, subretinal administration or suprachoroidal administration, preferably by intravitreal, suprachoroidal or subretinal injection.

36. A nucleic acid molecule, vector, composition, product, kit, method, cell, substance or composition for use or method of treatment according to any preceding claim, wherein the nucleotide sequence encoding FOXJ1, or a functional variant thereof comprises a nucleic acid sequence encoding:(a) SEQ ID NO: 1,(b) SEQ ID NO: 2,(c) an amino acid sequence having at least 70% identity to SEQ ID NO: 1 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 1 , or(d) an amino acid sequence having at least 70% identity to SEQ ID NO: 2 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 2.

37. A nucleic acid molecule, vector, composition, product, kit, method, cell, substance or composition for use or method of treatment according to any preceding claim, wherein the nucleotide sequence encoding FOXJ1, or a functional variant thereof comprises:(a) SEQ ID NO: 3,(b) SEQ ID NO: 4,(c) SEQ ID NO: 5, or(d) a nucleotide sequence having at least 60% identity to SEQ ID NO: 3 or SEQ ID NO: 5, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 1, or(e) a nucleotide sequence having at least 60% identity to SEQ ID NO: 4, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 2.

38. A nucleic acid molecule, vector, composition, product, kit, method, cell, substance or composition for use or method of treatment according to any preceding claim, wherein:(a) the nucleotide sequence encoding NEUROD1, or a functional variant thereof comprises a nucleic acid sequence encoding:(i) SEQ ID NO: 6,(ii) SEQ ID NO: 7,(Hi) an amino acid sequence having at least 70% identity to SEQ ID NO: 6 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 6, or(iv) an amino acid sequence having at least 70% identity to SEQ ID NO: 7 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 7;(b) the nucleotide sequence encoding OTX2, or a functional variant thereof comprises a nucleic acid sequence encoding:(i) SEQ ID NO: 11,(ii) SEQ ID NO: 12,(Hi) an amino acid sequence having at least 70% identity to SEQ ID NO: 11 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 11 , or(iv) an amino acid sequence having at least 70% identity to SEQ ID NO: 12 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 12;(c) the nucleotide sequence encoding CRX, or a functional variant thereof comprises a nucleic acid sequence encoding:(i) SEQ ID NO: 16,(ii) SEQ ID NO: 17,(Hi) an amino acid sequence having at least 70% identity to SEQ ID NO: 16 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 16, or(iv) an amino acid sequence having at least 70% identity to SEQ ID NO: 17 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 17;(d) the nucleotide sequence encoding NRL, or a functional variant thereof comprises a nucleic acid sequence encoding:(i) SEQ ID NO: 21,(ii) SEQ ID NO: 22,(Hi) an amino acid sequence having at least 70% identity to SEQ I D NO: 21 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 21, or(iv) an amino acid sequence having at least 70% identity to SEQ I D NO: 22 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 22;(e) the nucleotide sequence encoding ONECUT1, or a functional variant thereof comprises a nucleic acid sequence encoding:(i) SEQ ID NO: 26,(ii) SEQ ID NO: 27,(Hi) an amino acid sequence having at least 70% identify to SEQ I D NO: 26 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 26, or(iv) an amino acid sequence having at least 70% identify to SEQ I D NO: 27 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 27;(f) the nucleotide sequence encoding MEF2C, or a functional variant thereof comprises a nucleic acid sequence encoding:(i) SEQ ID NO: 31,(ii) SEQ ID NO: 32,(Hi) an amino acid sequence having at least 70% identity to SEQ I D NO: 31 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 31 , or(iv) an amino acid sequence having at least 70% identity to SEQ I D NO: 32 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 32;(g) the nucleotide sequence encoding RAX, or a functional variant thereof comprises a nucleic acid sequence encoding:(i) SEQ ID NO: 36,(ii) SEQ ID NO: 37,(Hi) an amino acid sequence having at least 70% identity to SEQ I D NO: 36 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 36, or(iv) an amino acid sequence having at least 70% identity to SEQ I D NO: 37 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 37;(h) the nucleotide sequence encoding NEUROG2, or a functional variant thereof comprises a nucleic acid sequence encoding:(i) SEQ ID NO: 41,(ii) SEQ ID NO: 42,(Hi) an amino acid sequence having at least 70% identity to SEQ I D NO: 41 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 41, or(iv) an amino acid sequence having at least 70% identity to SEQ I D NO: 42 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 42;(i) the nucleotide sequence encoding ASCL1, or a functional variant thereof comprises a nucleic acid sequence encoding:(i) SEQ ID NO: 46,(ii) SEQ ID NO: 47,(Hi) an amino acid sequence having at least 70% identity to SEQ I D NO: 46 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 46, or(iv) an amino acid sequence having at least 70% identity to SEQ I D NO: 47 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 47;(j) the nucleotide sequence encoding MESP2, or a functional variant thereof comprises a nucleic acid sequence encoding:(i) SEQ ID NO: 51,(ii) SEQ ID NO: 52,(Hi) an amino acid sequence having at least 70% identity to SEQ I D NO: 51 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 51, or(iv) an amino acid sequence having at least 70% identity to SEQ I D NO: 52 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 52;(k) the nucleotide sequence encoding RAX2, or a functional variant thereof comprises a nucleic acid sequence encoding:(i) SEQ ID NO: 56, or(ii) an amino acid sequence having at least 70% identity to SEQ ID NO: 56 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 56;(l) the nucleotide sequence encoding ATOH7, or a functional variant thereof comprises a nucleic acid sequence encoding:(i) SEQ ID NO: 59,(ii) SEQ ID NO: 60,(Hi) an amino acid sequence having at least 70% identity to SEQ I D NO: 59 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 59, or(iv) an amino acid sequence having at least 70% identity to SEQ I D NO: 60 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 60;(m) the nucleotide sequence encoding ATOH1, or a functional variant thereof comprises a nucleic acid sequence encoding:(i) SEQ ID NO: 64,(ii) SEQ ID NO: 65,(Hi) an amino acid sequence having at least 70% identity to SEQ I D NO: 64 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 64, or(iv) an amino acid sequence having at least 70% identity to SEQ I D NO: 65 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 65;(n) the nucleotide sequence encoding MEF2D, or a functional variant thereof comprises a nucleic acid sequence encoding:(i) SEQ ID NO: 69,(ii) SEQ ID NO: 70,(Hi) an amino acid sequence having at least 70% identity to SEQ I D NO: 69 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 69, or(iv) an amino acid sequence having at least 70% identity to SEQ I D NO: 70 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 70; and / or(o) the nucleotide sequence encoding RXRG, or a functional variant thereof comprises a nucleic acid sequence encoding:(i) SEQ ID NO: 74,(ii) SEQ ID NO: 75,(Hi) an amino acid sequence having at least 70% identity to SEQ ID NO: 74 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 74, or(iv) an amino acid sequence having at least 70% identity to SEQ I D NO: 75 wherein the amino acid sequence defines a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 75.

39. A nucleic acid molecule, vector, composition, product, kit, method, cell, substance or composition for use or method of treatment according to any preceding claim, wherein:(a) the nucleotide sequence encoding NEUROD1 , or a functional variant thereof comprises:(i) SEQ ID NO: 8,(ii) SEQ ID NO: 9,(Hi) SEQ ID NO: 10, or(iv) a nucleotide sequence having at least 60% identity to SEQ ID NO: 8 or SEQ ID NO: 10, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 6, or(v) a nucleotide sequence having at least 60% identity to SEQ ID NO: 9, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 7;(b) the nucleotide sequence encoding OTX2, or a functional variant thereof comprises:(i) SEQ ID NO: 13,(ii) SEQ ID NO: 14,(Hi) SEQ ID NO: 15, or(iv) a nucleotide sequence having at least 60% identity to SEQ ID NO: 13 or SEQ ID NO: 15, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 11, or(v) a nucleotide sequence having at least 60% identity to SEQ ID NO: 14, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 12;(c) the nucleotide sequence encoding CRX, or a functional variant thereof comprises:(i) SEQ ID NO: 18,(ii) SEQ ID NO: 19,(Hi) SEQ ID NO: 20, or(iv) a nucleotide sequence having at least 60% identity to SEQ ID NO: 18 or SEQ ID NO: 20, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 16, or(v) a nucleotide sequence having at least 60% identity to SEQ ID NO: 19, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 17;(d) the nucleotide sequence encoding NRL, or a functional variant thereof comprises:(i) SEQ ID NO: 23,(ii) SEQ ID NO: 24,(Hi) SEQ ID NO: 25, or(iv) a nucleotide sequence having at least 60% identity to SEQ ID NO: 23 or SEQ ID NO: 25, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 21, or(v) a nucleotide sequence having at least 60% identity to SEQ ID NO: 24, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 22;(e) the nucleotide sequence encoding ONECUT 1 , or a functional variant thereof comprises:(i) SEQ ID NO: 28,(ii) SEQ ID NO: 29,(Hi) SEQ ID NO: 30, or(iv) a nucleotide sequence having at least 60% identity to SEQ ID NO: 28 or SEQ ID NO: 30, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 26, or(v) a nucleotide sequence having at least 60% identity to SEQ ID NO: 29, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 27;(f) the nucleotide sequence encoding MEF2C, or a functional variant thereof comprises:(i) SEQ ID NO: 33,(ii) SEQ ID NO: 34,(Hi) SEQ ID NO: 35, or(iv) a nucleotide sequence having at least 60% identity to SEQ ID NO: 33 or SEQ ID NO: 35, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 31, or(v) a nucleotide sequence having at least 60% identity to SEQ ID NO: 34, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 32;(g) the nucleotide sequence encoding RAX, or a functional variant thereof comprises:(i) SEQ ID NO: 38,(ii) SEQ ID NO: 39,(Hi) SEQ ID NO: 40, or(iv) a nucleotide sequence having at least 60% identity to SEQ ID NO: 38 or SEQ ID NO: 40, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 36, or(v) a nucleotide sequence having at least 60% identity to SEQ ID NO: 39, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 37;(h) the nucleotide sequence encoding NEUROG2, or a functional variant thereof comprises:(i) SEQ ID NO: 43,(ii) SEQ ID NO: 44,(Hi) SEQ ID NO: 45, or(iv) a nucleotide sequence having at least 60% identity to SEQ ID NO: 43 or SEQ ID NO: 45, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 41, or(v) a nucleotide sequence having at least 60% identity to SEQ ID NO: 44, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 42;(i) the nucleotide sequence encoding ASCL1 , or a functional variant thereof comprises:(i) SEQ ID NO: 48,(ii) SEQ ID NO: 49,(Hi) SEQ ID NO: 50, or(iv) a nucleotide sequence having at least 60% identity to SEQ ID NO: 48 or SEQ ID NO: 50, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 46, or(v) a nucleotide sequence having at least 60% identity to SEQ ID NO: 49, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 47;(j) the nucleotide sequence encoding MESP2, or a functional variant thereof comprises:(i) SEQ ID NO: 53,(ii) SEQ ID NO: 54,(iii) SEQ ID NO: 55, or(iv) a nucleotide sequence having at least 60% identity to SEQ ID NO: 53 or SEQ ID NO: 55, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 51, or(v) a nucleotide sequence having at least 60% identity to SEQ ID NO: 54, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 52;(k) the nucleotide sequence encoding RAX2, or a functional variant thereof comprises:(i) SEQ ID NO: 57,(ii) SEQ ID NO: 58, or(iii) a nucleotide sequence having at least 60% identity to SEQ ID NO: 57 or SEQ ID NO: 58, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 56;(l) the nucleotide sequence encoding ATOH7, or a functional variant thereof comprises:(i) SEQ ID NO: 61,(ii) SEQ ID NO: 62,(iii) SEQ ID NO: 63, or(iv) a nucleotide sequence having at least 60% identity to SEQ ID NO: 61 or SEQ ID NO: 63, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 59, or(v) a nucleotide sequence having at least 60% identity to SEQ ID NO: 62, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 60;(m) the nucleotide sequence encoding ATOH 1 , or a functional variant thereof comprises:(i) SEQ ID NO: 66,(ii) SEQ ID NO: 67,(iii) SEQ ID NO: 68, or(iv) a nucleotide sequence having at least 60% identity to SEQ ID NO: 66 or SEQ ID NO: 68, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 64, or(v) a nucleotide sequence having at least 60% identity to SEQ ID NO: 67, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 65;(n) the nucleotide sequence encoding MEF2D, or a functional variant thereof comprises:(i) SEQ ID NO: 71,(ii) SEQ ID NO: 72,(iii) SEQ ID NO: 73, or(iv) a nucleotide sequence having at least 60% identity to SEQ ID NO: 71 or SEQ ID NO: 73, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 69, or(v) a nucleotide sequence having at least 60% identity to SEQ ID NO: 72, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 70; and / or(o) the nucleotide sequence encoding RXRG, or a functional variant thereof comprises:(i) SEQ ID NO: 76,(ii) SEQ ID NO: 77,(Hi) SEQ ID NO: 78, or(iv) a nucleotide sequence having at least 60% identity to SEQ ID NO: 76 or SEQ ID NO: 78, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 74, or(v) a nucleotide sequence having at least 60% identity to SEQ ID NO: 77, wherein the nucleotide sequence encodes a polypeptide which is a functional variant of a polypeptide defined by SEQ ID NO: 75.

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