Agent delivery to the retina

Abstract

The invention provides means and methods for administering agents, including therapeutic agents, to the retina of a subject The methods comprise injecting the agent directly into the optic nerve.

Description

The invention relates to means and methods for delivering agents, including therapeutic agents and imaging agents, to the retina. Background Inherited retinal diseases, including retinitis pigmentosa and inherited optic neuropathies such as Leber congenital optic neuropathy (LHON) are estimated to affect 1 in 3,000 people worldwide and are the leading cause of untreatable blindness in the younger population in developed countries. They comprise a heterogeneous group of neurodegenerative disorders associated with mutations in over 300 genes (https: / / sph.uth.edu / retnet), which ultimately lead to irreversible blindness with substantial impact on affected individuals and families, healthcare systems and the society. Despite these pressures, clinical management of the majority of retinal diseases remains largely conservative and is at best limited to nutritional supplements which may have marginal effects in slowing down the rate of disease progression. The focus for treatment development has been on genetic therapies, many of which have reached a clinical trial stage. Despite the encouraging results these trials are providing, including the only approved retinal gene therapy treatment, Luxtuma (voretigene neparvovec), only a small proportion of diseases are currently amenable to such therapies. Thus, for patients with unknown mutations, for those who present late where the photoreceptors are compromised or lost, or for conditions where the primary pathology affects the inner and not the outer retinal cells such as retinal ganglion cells in optic neuropathies, gene supplementation to outer retinal cells may not be suitable. These conditions include glaucoma (the most frequent cause of irreversible blindness, affecting 3.5% of the world’s population over the age of 40 years) and inherited optic neuropathies. Both conditions result in the primary degeneration of retinal ganglion cells and can therefore lead to irreversible loss of vision. Most adult-onset glaucoma has a complex aetiology, involving multiple genetic and environmental factors. Hence, gene-based therapies for it have focused on neuroprotection to slow down the loss of retinal ganglion cells. By contrast, Leber hereditary optic neuropathy is caused by single-gene defects in mitochondrial DNA, and gene therapies for the treatment of this genetic defect have made notable progress over the past few decades. Moreover, the inner retinal cells become the primary target cells for vision restoration strategies such as optogenetics in any late-stage outer retinal degenerative disease, including age related macular degeneration the most common cause of sight loss among the elderly (AMD affects 5% of the human population older than 75 years). Although genetic therapies can be targeted to retinal ganglion cells (RGCs) in a mouse model using enzymatic treatment to enhance transduction (Cehajic-Kapetanovic et al. Curr Biol. 25(16):2111-2122 (2015)) or via modified adeno-associated viral (AAV) vectors (rationally designed or evolved from complex AAV capsid libraries)(Fig la-b; McClements et al. JBiomed Res Int. Feb 9;2021:1-8(2021)), efficient targeting of these cells in non-human primates (NHPs) has not been achieved to date (Fig Ic-d; Yin et al. Invest Ophth Vis Sci. 52:2775-2783 (2011); Dalkaraeta / . Sci TranslMed. 5:189ral76 (2013)). The method of surgical delivery of AAV vectors is a critical determinant of effective dose and target cell transduction, yet remains an unexplored aspect of gene therapy. The subretinal approach is used to target the outer retinal components including the retinal pigment epithelium in Luxturna therapy (Russell et al. Lancet. 390:849-860 (2017)) or the photoreceptors as reported for retinitis pigmentosa (Cehajic-Kapetanovic et al. Nat Med. 26(3):354-359 (2020)). The intravitreal delivery method aims to target AAV to inner retinal cells as in optogenetic applications, including clinical trials (NCT02556736, NCT03326336), and in LHON gene therapy trials (NCT02652767, NCT02652780). However, emerging data highlight limitations of the intravitreal approach in primates (Fig Ic-d), including humans. Adjunctive enzymatic treatment in NHPs to digest a barrier membrane at the vitreo-retinal interface, previously shown to be effective in mice (Cehajic-Kapetanovic et al. Mol Ther Meth Clin Dev. 9:192-202 (2017)) did not improve transduction beyond the central foveal ring (Dalkara et al. Sci Transl Med. 5:189ral76 (2013)). Vector delivery under the membrane was possible with very small volumes (up to lOpl), but only transduced cells under this small bleb (Boye at al. Hum Gene Ther. 27(8):580-597 (2016)). Intravitreal vectors led to formation of neutralising antibodies in NHPs which further limited the retinal transduction (Kotterman et al. Gene Ther. 22(2):116-26 (2015)). Human data from LHON trials show no clear efficacy to date (Guy et al. Ophth. 124:1621-1634 (2017); Vignal et al. Ophth. 125:945-947 (2018)) and a report recently released from a phase III trial shows that it has not met its primary endpoint GenS1sht-bioiogics.com [n addition, strong inflammatory responses are reported with modified AAV capsids, engineered to improve retinal transduction (Cukras et al. Mol Ther. 26:2282-2294 (2018)). Hence, there remains a need to develop improved therapeutic targeting of primate retinas. Summary In a first aspect the invention provides a method for delivering an agent to the retina of a subject, the method comprising administering the agent directly into the optic nerve. In a further aspect, the invention provides a method of treating a disease or condition of the retina, or loss of vision caused by a disease or condition of the retina, the method comprising administering a therapeutic agent for treating the disease or condition directly into the optic nerve. In a further aspect, the invention provides a therapeutic agent for use in a method of treatment in a subject in need thereof, wherein the method comprises administering the therapeutic agent directly into the optic nerve. The invention also provides: - a therapeutic agent for use in a method of treatment of a disease or condition of the retina, or loss of vision caused by a disease or condition of the retina, wherein the method comprises administration of the therapeutic agent by direct injection into the optic nerve; and - the use a therapeutic agent in the manufacture of a medicament, wherein the medicament is for administration by direct injection into the optic nerve, and for treating a disease or disorder of the retina, or loss of vision caused by a disease or condition of the retina. In a further aspect, the invention provides a method of diagnosing a disease or condition of the retina, the method comprising administering an imaging agent directly into the optic nerve and imaging the retina. In a further aspect, the invention provides an imaging agent for use in a method of diagnosing a disease or condition of the retina, wherein the method comprises administering the imaging agent directly into the optic nerve. In a further aspect, the invention provides, a device for delivering an agent to the retina of the eye of a subject, wherein the agent is a therapeutic agent for treatment of a disease or condition of the retina, a vector encoding a light-sensitive protein, or an imaging agent for imaging the retina, the device comprising: a hollow needle having a proximal end and a distal tip end connected by a channel through which the agent may flow; and a reservoir containing a volume of the agent; wherein the reservoir is in fluid communication with the channel; wherein the distal tip end has an axial length of at least 5 mm at about 30 WO 2025 / 149645                                   PCT / EP2025 / 050589 to 52 gauge; and the needle is sufficiently rigid that the distal tip end of the needle can be inserted into the optic nerve and can penetrate through the lamina cribrosa. In a further aspect, the invention provides system for delivering an agent to the retina of the eye of a subject, wherein the agent is a therapeutic agent for treatment of a disease or condition of the retina, a vector encoding a light-sensitive protein, or an imaging agent for imaging the retina, the system comprising: a robotic arm a hollow needle having a proximal end and a distal tip end connected by a channel through which the agent may flow; and a reservoir containing a volume of the agent; wherein the reservoir is in fluid communication with the channel; wherein the distal tip end has an axial length of at least 5 mm at about 30 to 52 gauge; the needle is sufficiently rigid that the distal tip end of the needle can be inserted into the optic nerve and can penetrate through the lamina cribrosa; and wherein the robotic arm is operatively connected to the needle and configured to guide the distal tip end of the needle into the optic nerve. The invention will now be described in more detail, by way of example and not limitation, and by reference to the accompanying drawings. Many equivalent modifications and variations will be apparent, to those skilled in the art when given this disclosure. Accordingly, the exemplary embodiments of the disclosure set forth are considered to be illustrative and not limiting. Various changes to the described embodiments may be made without departing from the scope of the invention which is defined by the claims. All documents cited herein, whether supra or infra, are expressly incorporated by reference in their entirety. The present disclosure includes the combination of the aspects and features described except where such a combination is clearly impermissible or is stated to be expressly avoided. Section headings are used herein for convenience only and are not to be construed as limiting in any way. Description of the Figures Fig 1. Rhodopsin expression (green) in bipolar cells (arrows) of rd1 mouse eyes using a modified AAV vector, AAV2 / 8(BP2), with bipolar promoter (grm6) in flat-mounts (a) and cross-sections (b) (McClements et al 2021)9 GFP expression (white) using AAV2 / 2(7m8) and a pan-neuronal promoter is restricted to a central foveal ring (red arrow) in NHP retinas (c). A cross-section shows expression limited to Muller glia (yellow arrow) and occasional RGC (blue arrow) (d) (c-d from Dalkara etal 2013). Fig 2. Biocytin uptake by retinal ganglion cells following trans-vitreal injection into the NHP optic nerve ex vivo. Fig 3. Biocytin uptake by retinal ganglion cells following trans-vitreal injection into the optic nerve in mice in vivo. Biocytin dye is seen as white fluorescence on SLO images and green fluorescence on light and confocal microscopy. OCT imaging shows intact optic nerve head indicating that the procedure does not damage the optic nerve tissue. Fig 4. Retinal GFP expression following trans-vitreal injection of AAV2-GFP into the optic nerve in mouse in vivo. GFP expression is seen as white fluorescence in SLO imaging as early as 3 days post injections. The fluorescence increased with time up to the last followup at 18 days. Histology shows widespread AAV transduction and GFP expression of the treated retina at 18 days after treatment. OCT imaging shows undamaged optic nerve head 18 days after the injection. Fig 5. Robot-assisted optic nerve gene therapy. A) Intraoperative view of NHP retina and optic nerve during robot-assisted optic nerve injection. Unexpectedly, we observed no reflux of the drug into the vitreous cavity and no bleeding from the optic nerve despite direct injection of the optic nerve. B) Schematic showing trans-vitreal injection into the optic nerve. C) Anatomy of optic nerve. Cross-section of intraocular part of optic nerve - the optic nerve head. Fig 6. In vivo fundus autofluorescence images of fluorescent protein (FP) expression following AAV-mediated gene therapy. A) Current intravitreal delivery method for targeting retinal ganglion cells in non-human primates showing transduction limited to a very small area of the retina at the foveal ring (AAV2, AAV2 / 4YF and AAV2 / 7m8 capsids) and mid-peripheral patches (AAV2 / 7m8 capsid evolved for targeting photoreceptors via intravitreal delivery). B-E) Autofluorescence images following optic nerve delivery of AAV vectors showing targeted and widespread expression of fluorescent proteins (GFP and RFP) in the distribution of retinal nerve fibre layer and ganglion cell layer. The expression pattern was dependent on the site of injection. For example, superotemporal injection at the optic nerve resulted in protein expression in supero-temporal retina following retrograde axonal transport into retinal ganglion cells (B, LE). Multiple vector infusions of at different depths and at multiple sites resulted in more widespread expression. Higher volumes resulted in stronger expression (B, RE v D, RE). Expression increased with time reaching about 70-80% by 2 weeks, maximum at 1 months and sustained at latest timepoint of examination at 4 months. Fig 7. Optical coherence tomography (OCT) images of optic nerve and fovea. Images demonstrate normal retinal anatomy including optic nerve thickness (no swelling) and foveal thickness (no fluid or cystoid macular oedema) with no signs of inflammation consistent with our observation of no vector reflux into the vitreous during the injection procedure. Fig 8. Microscopy at 2 weeks following optic nerve injections. Light microscope image showing GFP expression in retinal nerve fibre layer and ganglion cell layer (left). High magnification confocal microscope image demonstrating GFP expression in retinal ganglion cell axons and cell bodies (right). Fig 9. Electrophysiology testing at baseline and 2 months post procedure. The retinal electroretinogram (ERG) confirms normal retinal electrophysiology function (light and dark-adapted ERGs indicating normal cone and rod photoreceptor responses). The photopic negative responses (PhNR) which originate in the retinal ganglion cells confirm normal ganglion cell function. The brain visual evoked potentials (flash VEP) confirm intact visual pathways (optic nerve to visual cortex) and normal visual function post procedures. Fig 10. Cross-sectional schematic of the tip end of a device of the invention having an extendible needle in (A) retracted position and (B) protracted position. Description of the Sequences SEQ ID NO: 1 set forth the sequence of a 2AAV 5TTR. SEQ ID NO: 2 sets forth a human rhodopsin kinase promoter (GRK1) sequence. SEQ ID NO: 3 sets forth a human rhodopsin promoter (RHOp) sequence. SEQ ID NO: 4 sets forth a chicken beta-actin promoter exon-intron-exon sequence. SEQ ID NO: 5 sets forth the Kozak consensus sequence (GCCACC) SEQ ID NO: 6 set forth the 2AAV 3TTR sequence. SEQ ID NO: 7 sets forth the woodchuck hepatitis post-transcriptional regulatory element (WPRE) sequence. SEQ ID NO: 8 sets forth the bovine growth hormone polyadenylation tail sequence. Detailed Description The inventors have developed a new method of delivering agents to the retina. The method involves injection into the optic nerve. The procedure has been demonstrated ex vivo and in vivo in mouse and NHP models using dyes and adeno-associated virus (AAV) vectors, with transduction of retinal ganglion cells which is far superior compared to existing delivery routes. In addition, the procedure is safe with a surprising absence of tissue damage, bleeding, reflux into the vitrous, edema and inflammation. There is also no detectable damage to the outer retina (rods and cones), inner retina (retina ganglion cells) or visual pathways using this method. Inflammation has been a limiting factor in prior art delivery routes, especially the intravitreal route needed for ganglion cell targeting, where even low vector doses lead to inflammation and have a sub-therapeutic effect. In contrast, injection into the optic nerve permits administration of larger volumes and higher vector doses (as per subretinal delivery doses with demonstrated efficacy3,8) which are likely to be therapeutic when translated to human studies. Drug delivery can be achieved across the retina (e.g. inner and outer retina delivery) using this method and can be targeted for specific areas of the retina depending on the site of injection. Hence, delivery is both more concentrated and the location of delivery can be more precisely controlled than that achieved using previous methods. In an NHP model, a widespread retinal transduction can be achieved, which will facilitate rescue and restoration of visual function. Methods of therapy and medical uses The invention provides methods of treating or prevening loss of vision in a subject, or of treating or preventing a disease or condition of the retina, or retinal degradation, and therapeutic agents for use in such methods. The loss of vision may be partial or complete and may be caused by an acute or chronic disease or condition or by an event such as a trauma or injury to the eye or the retina. The loss of vision may be progressive. In some cases, the treatment achieves or is intended to achieve any one or more of the following effects: - Improvement from baseline in microperimetry o Proportion of patients with improved microperimetry - Improvements in best corrected visual acuity (BCVA) o ETDRS visual acuity chart - Improvements on retinal function on microperimetry o Change in sensitivity (dB) - Spectral domain optical coherence tomography (SD-OCT) o Changes in reflectivity of the ellipsoid zone o Changes in outer segment length (i.e. regeneration of photoreceptor outer segments) o Changes in outer nuclear layer thickness at pre-defined retinal loci (i.e. prevention of photoreceptor cell death) o Changes in the external limiting membrane - Fundus autofluorescence (AF) o To assess changes in the retina from baseline in autofluorescence imaging (i.e. reduction in the rate of central macular degeneration) - Visual Fields o Octopus 900 pro will be used to assess changes in central peripheral vison from baseline - Electroretinography: Changes in rod or cone responses Changes in macular responses (i.e. pattern ERG) Also, where applicable for patients: regeneration of the photoreceptor outer segment; prevention of photoreceptor (rod and / or cone) cell death; reduced rate of photoreceptor (rod and / or cone) cell death; increased photoreceptor layer thickness; increased retina thickness; increased superior retina thickness; increased inferior retina thickness; increased outer retinal thickness, increased inner retina thickness; increased distance between the outer plexiform layer and the retinal pigment layer; lengthening of the photoreceptor outer segment band; thickening of the ellipsoid band; increased distance between the inner and outer boundaries of the photoreceptors; thickening or regeneration of the external limiting membrane; restoration of the photoreceptor outer segment band; improved cone and / or rod photoreceptor function; improved / increased electroretinography (A-wave amplitudes and / or B-wave amplitudes) responses; improved eyesight or vision, improved eyesight or vision at low light intensity; improved night vision; a prevention of decline in any one or more of these measurements or the prevention of blindness. Any suitable method(s) may be used to measure these outcomes. The methods comprise administering a therapeutic agent directly into the optic nerve. The administration results in delivery of the agent to the optic nerve itself and to the retina. Hence, the invention provides methods for treating loss of vision that is caused by or significantly involves a disease or condition or pathology of the retina or the optic nerve. The loss of vision may be caused by the loss of, or damaged or defective, light detecting cells or photoreceptors. Hence, the method may be for treating or preventing loss or damage to photoreceptors. The loss of vision, or the disease or condition of the retina, may be caused by inflammation in the eye, or a vascular condition. The disease or condition may be a retinal degenerative / neurodegenerative disease or condition. The disease or condition may be an inherited / genetic retinal disease or condition (IRD), for example one caused by a mutation described by the Retinal Information Network (https: / / sph.uth.edu / retnet), e.g. retinitis pigmentosa or Leber congenital optic neuropathy (LHON). The disease or condition may be an aquired retinal disease or condition. The disease or condition may be an inherited or acquired optic neuropathy, such Leber Hereditary Optic Neuropathy, Dominant Optic Atrophy, or an inflammatory, degenerative or traumatic optic neuropathy. Other exemplary conditions that may be treated according to the invention are glaucoma (for which a neuroprotective agent or a gene therapy or gene editing vector may be particularly suitable); or an inherited or acquired macular degeneration (for which is a gene therapy vector, a gene editing vector, a VEGF antagonist, a molecule targeting the complement cascade, or a neuroprotective agent may be particularly suitable), including monogenic and polygenic inherited macular degeneration (e.g. Geographic Atrophy, or Stargardt’s Disease), age-related macular degeneration, or a cone or cone-rod dystrophy affecting the macular. The most common forms of retinal disease / degeneration for which treatments are sought for the largest population impact are retinal pigmentosa and age-related macular degeneration. The methods of the invention are particularly and surprisingly effective at delivering an agent to the inner retina, which has been difficult to achieve using prior methods. Hence, in some embodiments the disease or condition is one that affects or primarily affects the inner retina, or is for treatment of loss of vision that can be treated by delivery of a therapeutic agent to the inner retina. Some degenerative diseases, such as age-related macular degeneration, initially (primarily) affect the outer retina, but affect the inner retina at later stages. Hence, in some embodiments, the disease is a late stage degenerative disease of the outer retina. The therapeutic agent can be delivered to different sites in the eye / retina depending on which part of the optic nerve is targeted. Hence, the method can be used to treat or prevent a pathology that affects particular parts of the retina, such as the superior retina, the temporal retina, the nasal retina, the inferior retina, the supero-temporal retina, the infero-temporal retina, the supero-nasal retina, the infero-nasal retina, the macula, or any combination thereof. For example, sectoral retinitis pigmentosa, glaucoma, or optic nerve pathology may predominantly affect one part of the retina e.g. supero-temporal retina or macula dystrophies which affect macula only, and hence targeted drug delivery into this area may be preferential to pan-retinal delivery, potentially reducing off-target effects, WO 2025 / 149645                                   PCT / EP2025 / 050589 lowering the effective dose and increasing safety. The method can also be used to deliver a therapeutic agent to particular cell types found at these specific sites, such as retinal ganglion cells or bipolar cells, e.g. using appropriate tags or vectors, as described elsewhere herein. The subject may be a human or a non-human animal. Non-human animals include, but are not limited to, rodents (including mice and rats), and other common laboratory, domestic and agricultural animals, including rabbits, guinea pigs, dogs, cats, horses, pigs and non-human primates (NHP). The most common experimental animals in the field are pigs, dogs, rabbits, rats, mice and NPH. Imaging and Diagnostic Uses In some embodiments, the invention provides methods and means, as described herin, for delivering an imaging agent, or other detectable agent, to the retina by administering the agent directly into the optic nerve. Such methods may be used experimentally, for example to study retinal ganglion cells, the anatomy and physiology in the retina, visual pathways to the brain and / or associated pathology. For example, characterising different types of retinal ganglion cells (>12 distinct types) e.g. M cells, P cells, K cells and where retinal axons are distributed in the brain, which types of ganglion cells contribute to these pathways, and associated pathology with these pathways (neurodegenerative / vascular / neuropsychiatric, circadian rhythms, sleep disorders etc.). Also provided are methods of diagnosing a disease or condition of the retina or optic nerve. The method may comprise administering a dye or other imaging or otherwise detectable agent (such as those described elsewhere herein) directly into the optic nerve. The agent may then be detected to provide information about the health or disease state of the retina or the optic nerve. The method may comprise obtaining (a) signal(s) from the agent or visualising or obtaining an image of the retina or optic nerve, or a part or particular cells therof, for example as described elsewhere herein. The method may comprise tracing the uptake of the agent into the retina or the optic nerve, or a part or particular cells therof, for example as described elsewhere herein. For example, the retinal nerve fibre layer or the ganglion cell layer. The signal(s), visualisation or image may be analysed, measured and / or compared to equivalent standards or reference images, signal(s) or measurement values. This may be used, optionally in combination with other parameters, to provide / determine a diagnosis of a disease or condition, or a prognosis for a subject having a disease or condition, or to monitor a disease or condition in a subject, for example, over time, or before and after administration of a treatment. As a specific example, uptake of a detectable marker into the retinal nerve fibre layer and / or ganglion cell layer could be monitored, detected, visualised or imaged and used for diagnosis, prognosis or monitoring of glaucoma in a subject. A similar approach could be used for other retinal disease including vascular and neurodegenerative disorders such as diabetic retinopathy. Also, since the transport of molecules from the site of injection is also anterograde, it is also contemplated to image / visualise / diagnose / prognose pathologies in ganglion cell projections via optic nerve and visual pathways into the brain: optic nerve, optic chiasm, optic tracts, lateral geniculate nucleus, optic radiations and visual cortex and its cortical projections. Agents and Therapeutic Agents Most typically, the therapeutic agent comprises a gene therapy vector, including gene or RNA editing vectors. In other embodiments, the therapeutic agent may be a neuroprotective agent. In some embodiments, the therapeutic agent comprises a VEGF antagonist. In some embodiments, the therapeutic agent comprises a molecule that targets the complement cascade. For example, Complement factor I (CFI) and / or Complement Factor H may be supplemented (by administration of CFI itself or an agonist thereof and / or Complement Factor H itself or an agonist thereof) or inhibited (by administration of an antagonist therof), depending on the disease or condition concerned. In specific embodiments, the therapeutic agent comprises an inhibitor / antagonist of C3 or an inhibitor / antagonist of C5, for example for the treatment of geographic atrophy. An antagonist may be, for example, an anti-target (i.e. VEGF, CFI, Complement Factor H, C5, C3) antisense molecule, anti-target iRNA, an anti-target antibody (or an antigen-binding fragment thereof, such as a nanobody (a single domain antibody (sdAbs)), a Fab’ fragment, or a Fcab) or an anti-target aptamer. In other embodiments, the therapeutic agent comprises therapeutic cells, as described elsewhere herein. Alternatively, any other suitable therapeutic agent or drug may be used, as long as it is suitable for delivery via injection into the optic nerve. In general, any therapeutic agent that is currently deliverd into the vitreous, e.g. to treat retinal infection and inflammation or other conditions, could be injected into the optic nerve, including antibiotics (e.g. cefuroxime, ceftazidime, vancomycin), anti-virals (e.g. acyclovir, valaciclovir), anti-fungals (e.g. fluconizole, Voriconazole), anti-inflammatory therapeutic agents such as corticosteroids (e.g. dexamethasone, fluocinolone acetonide), anti-TNFa (e.g. adalimumab, infliximab) or any other immunomodulating agents / biological DMARDs (e.g. methotrexate, mycophenolate mofetil (MMF), azathioprine, cyclosporine A (CsA), leflunomide). Neuroprotective Agents In some embodiments, the agent is a neuroprotective agent. A neuroprotective agent is an agent that reduces or prevents neuron injury (for example neuron injury that results from mechanisms such as low oxygen or glucose supply, oxidative stress, mitochondrial failure, excitotoxicity, inflammation, iron accumulation and protein aggregation) or that prolongs or improves neuron function following stress or injury. Many neuroprotective agents reduce damage and injury caused by oxidative stress or excitotoxicity. For example, glutamate antagonists act as inhibitors of excitotoxicity by inhibiting the binding of glutamate to NMDA receptors, leading to reduced Ca2+ accumulation. Examples of glutamate antagonists that have been proposed for use as therapeutic neuroprotective agents include estrogen or 17P-estradiol, ginsenoside rd, progesterone, simvastatin, amaladine, memantine and riluzole. Examples of antioxidants that have been proposed for use as therapeutic neuroprotective agents include acetylcysteine, crocin, estrogen (such as 17a-estradiol and 17P-estradiol), fish oil, minocycline, pyrroloquinoline quinone (PQQ), resveratrol, vinpocetine, THC (Delta 9-tetrahydrocannabinol) and vitamin E. Other neuroprotective agents include selective inhibitors of MAO-B, such as selegiline, caspase inhibitors, trophic factors such as CNTF, IGF-1, VEGF, and BDNF, and erythropoietin, lithium neuroprotectins, such as neuroprotectin D1 and resolvins, such as RvDl, RvD2, RvD3, RvD4, RvD5, and RvD6. Neuroprotectin DI, a metabolically resistant analog of RvEl, has been proposed for the treatment of retinal disease such as age-related macular degeneration (Brazen et al, 2018). Neuroprotective agents have been proposed for the treatment of retinitis pigmentosa (Falsini et al., 2013). A nonspecific Ca2+ channel blocker has been shown to protect photoreceptors from light damage. L-type calcium channel blocker, d-cis diltiazem, has been shown to slow the course of photoreceptor cell death and loss of ERG function in the Pde6brdI mouse, a model for retinitis pigmentosa. Another Ca2+ channel blocker, nilvadipine, has been shown to slow photoreceptor loss in RCS rats, Pde6brdI mice, and rds mice, all models for RP. Diphenylhydantoin has been shown to be neuroprotective in a rat model with elevated IOP from cautery of episcleral veins. Neuroprotective agents have also been proposed for the treatment of glaucoma, specifically neuroprotective agents that prevent neurotrophic factor deprivation, excitotoxicity, P-amyloid plaque formation, mitochondria dysfunction, and / or the formation of reactive oxygen species, and thereby reduce retinal ganglion cell apoptosis (Coxon et al, 2010). Any of these agents may be used according to the present invention. In some embodiments the neuroprotective agent is one selected from Ciliary Neurotrophic Factor, Recombinant Human Nerve Growth Factor, Brain-derived Neurotrophic Factor, Glial Cell-derived Neurotrophic Factor (GDNF), an antioxidant, and alpha2 agonist, optionally brimonidine, or a glutamate N-methyl-D-aspartate (NMDA) receptor antagonist, optionally memantine, metalloproteinase-3 or MMP3. Optogenetic Therapy In some embodiments, the invention relates to the delivery of optogenetic therapy. Optogentic therapy involves administration of one or more light-sensitive (i.e. lightsensing, light-detecting, light-responsive) molecules, ligands or components of the phototransduction cascade, a gene therapy vector that encodes a light-sensitive molecule or component of the phototransduction cascade, or a gene editing vector for editing a nucleic acid that encodes a light-sensitive molecule or component of the phototransduction cascade. This replaces or repairs lost, damaged or defective light- sensitive molecules or cascade components in the retina of the patient. This can improve or restore the function of surviving photoreceptor cells and / or effectively convert secondary / tertiary retinal neurons into primary neurons, leading to improved / restored light sensitivity. Typically, the light-sensitive molecule is an opsin, or a variant, mutant or chimera thereof. The opsin may be a microbial (type I) or vertebrate opsins (type II) or an invertebrate opsin. Examples include rhodopsin, cone opsins, melanopsins, chanelrhodopsins and the variants / mutants / chimeras thereof. Other or more specific examples include melanopsin (OPN4), channel rhodopsin (ChR2), chloromonas oogama channel rhodopsin (CoChR), red-shifted channel rhodopsin (ReaChR), modified version of channel rhodopsin (mVChRl), medium wavelength cone opsin (MW opsin), metabotropic glutamate receptor (mGluR6), channelopsin (Chop-2), natronomonas halo rhodopsin (eNpHR), MC01 (multicharateriStic opsin), ChrimsonR, CatCh, ex3mVl, ChR2 (H134R) and mGluR6 / OPN4 chimera. Table 1 shows exemplary clinical trials for optogenetic therapy. In some embodiments, the agent may be, or comprise the opsin and / or the vector 13 of, any of the agents listed in Table 1. In some embodiments, the light-sensitive molecule is encoded by a vector that is targeted to a particular cell type, e.g. retinal ganglion cells, bipolar cells, rods or cones. In other embodiments, all of the cells of the retina are targeted. Table 1 Product Company Indication Opsin Vector Route of Administration RST-001 Abb Vie / Retrosense Therapeutics Retinitis pigmentosa Channelrhodopsin-2 (ChR2) rAAV2.7m8 Intravitreal injection GS030 GenSight Biologies Retinitis pigmentosa ChrimsonR rAAV2.7m8 Intravitreal injection MCO-010 Nanoscope therapeutics Retinitis pigmentosa, Stargardt’s disease MC01 opsin rAAV2 Intravitreal injection BS01 Bionic Sight Retinitis pigmentosa ChronosFP rAAV2 Intravitreal injection KIO-301 Kiora Pharmaceuticals Retinitis pigmentosa, choroideremia azobenzene photoswitch compound Intravitreal injection Another type of light-sensitive molecule or ligand is a light-switch (photo-switch), such as LiGluR or a chemical such as DNAQ. Therapeutic Cells Retinal cell therapy is envisioned as a treatment for degenerative retinal diseases. Hence, intraocular delivery of cell-based therapeutics is being developed as a means to preserve or restore vision in people with a wide range of degenerative retinal diseases, including those with monogenic or multifactorial aetiology, including non-neovascular and vascular age-related macular degeneration, retinal vascular occlusions, inherited retinal degenerations, glaucoma, and optic nerve pathologies. There are two main strategies: paracrine therapy and cell-replacement therapy. Clinical-stage paracrine therapeutics encompass a range of cell types. Umbilical tissue cells and bone marrow stem cells or stromal cells are cell types of mesenchymal origin and intermediate lineage potency. When placed into the eye therapeutically, these cells may act as vehicles to deliver diffusible trophic factors to viable retinal cells (including neural retina and the RPE). These factors appear to reduce glial reactivity, preserve synaptic connectivity and promote neurite outgrowth in dystrophic rodent retinae. Mesenchymal stem or stromal cells are known to release trophic factors that are carried in extracellular vesicles. The role of extracellular WO 2025 / 149645                                   PCT / EP2025 / 050589 vesicles in the context of retinal cell therapy is yet to be clarified, but may include effects such as immune modulation, growth-factor delivery and transcription-factor delivery. The cell-replacement approach may replace any retinal cell type, including photoreceptors and retinal ganglion cells. Source of such cells may include human induced pluripotent stem cells (hiPSCs) or spermatogonial stem cells. Hence, cell therapy for the regeneration of retinal ganglion cells may leverage pluripotent-stem-cell technology and might achieve sustained ganglion-cell neuroprotection. For example, human iPSCs have been reported to promote transplanted ganglion-cell survival and neurite extension in a murine model. The effect was thought to be mediated at least partially through the secretion of diffusible neuroprotective factors. Hence, in some embodiments, the therapeutic agent comprises therapeutic cells, such as any of those described herein. Gene Therapy Vectors and Gene Editing Vectors In some embodiments of the invention, the therapeutic agent comprises or consists of a gene therapy vector. Other, non-therapeutic aspects of the invention involve delivery, via the optic nerve, of a non-therapeutic gene delivery vector. Such other vectors for non-therapeutic uses are discussed further elsewhere herein, but relevant sections described here also apply to non-therapeutic embodiments of the invention. A gene therapy vector is any vector suitable for use in gene therapy, i.e. any vector suitable for the therapeutic delivery of nucleic acid polymers into target cells. The vector may be of any suitable type, such as a plasmid vector or a minicircle DNA. Most typically, however, the vector is a viral vector. The viral vector may, for example, be an adeno-associated virus (AAV), a retrovirus, a lentivirus, a herpes simplex virus, or an adenovirus. Most typically, the vector is an AAV viral vector. Relevant sections of the description relating the AAV derived vectors also apply in the case of vectors derived from other sources, such as those discussed further herein. The therapeutic nucleic acid delivered by the vector may encode a gene for expression from the vector or from a patient cell after transfer into the patient genome. This gene may be referred to herein as a “transgene”. The transgene may be any gene the expression of which in a subject would provide therapeutic benefit to the subject, either alone or in combination with other therapeutic measures, such as co-expression of a second transgene, knocked down expression of another gene or administration of a drug. In some embodiments, the therapeutic nucleic acid is a gene (transgene) that encodes a therapeutic protein, for example an optogenetic or neuroprotective agent, as described elsewhere herein. In some embodiments, the therapeutic protein is one that replaces or augments a defective protein or a protein that is not expressed or is defectively expressed in the subject. The therapy may be gene augmentation or gene replacement therapy. Such approaches are particularly suitable for treating monogenetic recessive disorders. For example, several conditions are caused by or associated with a mutation in the CDHR1 gene, including CDHR1 -associated retinal degeneration or retinal dystrophy, cone-rod dystrophy, cone-dystrophy, rod-dystrophy, rod-cone dystrophy (retinitis pigmentosa), macular dystrophy, or late-onset macular dystrophy, macular degeneration, central areolar choroidal degeneration or geographic atrophy. In another example, Leber Hereditary Optical Neuropathy (LHON) is an inherited mitochondrial disease generally caused by a mutation in the ND4 gene. Hence, in a specific exemplary embodiment, the transgene is ND4 (e.g. wild type ND4), or a vector encoding ND4 (e.g. recombinant adeno-associated viral vector serotype 2 (rAAV2 / 2) containing the wild-type ND4 gene (rAAV2 / 2-ND4); NCT02652767, NCT02652780 & NCT02652780). In another example, Leber congenital amaurosis (LCA) is an inherited disease that may be caused by mutations in a variety of genes. In a specific exemplary embodiment, the transgene is RPE-65, or the agent is voretigene neparvovec (AAV2 vector containing human RPE65 cDNA with a modified Kozak sequence). In other embodiments, the gene encodes a light-sensitive molecule, as described elsewhere herein. In other embodiments, the therapeutic nucleic acid may alter the expression of a target gene or correct a genetic mutation. In some embodiments the therapeutic nucleic acid knocks down expression of a target gene. For example, the nucleic acid may encode an antisense molecule, an interfering RNA, such as a small interfering RNA (siRNA) or a small hairpin RNA (shRNA), or a mirtron. Both antisense and RNAi technology interfere with mRNA. A mirtron is a hairpin intron that is spliced out and functions as a microRNA. The term “mirtron” as referred to herein includes classical mirtrons, in which the 5’ and 3’ splice sites are located near the base of the hairpin, and 5’ or 3’ tailed mirtrons, which may be further processed by exonuclease digestion after splicing. Considerations that may be taken into account when designing artificial mirtrons have been described previously in, for example, Seow et al. (RNA (2012) 18: 1328-1337), Kock et al. (Nucleic Acids Research (2015) and in WO 2020 / 084318 and WO 2020 / 084319. Such approaches are particularly suitable for treating monogenetic dominant disorders. Examples include retinitis pigmentosa, Autosomal dominant Stargardt-like macular dystrophy, autosomal dominant and autosomal recessive Best disease, Pattern dystrophy, Doyne honeycomb dystrophy, autosomal dominant drusen, progressive bifocal chorioretinal atrophy, Sorsby fundus dystrophy or age-related macular degeneration. In some embodiments, one or more vectors may be used to achieve complementary gene knock down and gene augmentation / replacement as a single therapy, i.e. to knock down the expression of a gene and replace it with a variant of the same gene. This may be referred to as “block and replace” treatment or use of a “block and replace” vector. In some embodiments, the gene therapy vector is a gene editing vector or an RNA editing vectors. An example is described in PCT / GB2023 / 052472. Such vectors may provide DNA or RNA editing machinery and a suitable guide nucleic acid or RNA to target a specific edit in a particular gene or in a particular RNA that is expressed at the target sight (e.g., the retina). In some embodiments, the treatment may involve the administration of two or more vectors. For example, one vector may encode nucleic acid for knocking down expression of a gene and a second vector may encode a replacement gene, or one vector might provide DNA or RNA editing machinery and a second vector provide a guide nucleic acid for gene or RNA editing. In other embodiments, multiple therapeutic nucleic acids, or multiple nucleic acids used for a particular therapy, may be encoded on the same or on separate vectors used for a treatment. Selection of one or more different vectors for use in a treatment may be determined by the size of the inserts (i.e. transgenes and the like, as described herein) and the carrying capacity of the selected vector(s). AA V vectors The vector may comprise a genome from a naturally derived serotype, isolate or clade of AAV or a derivative or one or more functional units thereof. An AAV genome is a polynucleotide sequence which encodes one or more functions needed for production of an AAV viral particle. Naturally occurring AAV viruses are replication-deficient and rely on the provision of helper functions in trans for completion of a replication and packaging cycle. Accordingly, the AAV genome of the vector of the invention is typically replicationdeficient. The AAV genome may be in single-stranded form, either positive or negativesense, or in double-stranded form. The use of a double-stranded form allows bypass of the DNA replication step in the target cell and so can accelerate transgene expression. In general, for therapeutic purposes, the only sequences required in cis, in addition to the therapeutic element, is at least one inverted terminal repeat sequence (ITR). In naturally derived AAV, the ITR sequence(s) act in cis to provide a functional origin of replication, and allows for integration and excision of the vector from the genome of a cell. The natural AAV genome also comprises packaging genes, such as rep and / or cap genes which encode packaging functions for an AAV viral particle. The rep gene encodes one or more of the proteins Rep78, Rep68, Rep52 and Rep40 or variants thereof. The cap gene encodes one or more capsid proteins such as VP1, VP2 and VP3 or variants thereof. These proteins make up the capsid of an AAV viral particle. Capsid variants are discussed below. A promoter may be operably linked to each of the packaging genes. Specific examples of such promoters include the p5, pl9 and p40 promoters (Laughlin et al., 1979, PNAS, 76:5567-5571). For example, the p5 and pl9 promoters may be used to express the rep gene, while the p40 promoter may be used to express the cap gene. In therapeutic AAVs, the cap and / or rep genes may be removed. The removal of the viral genes renders rAAV incapable of actively inserting its genome into the host cell DNA. Instead, the rAAV genomes fuse via the ITRs, forming circular, episomal structures, or insert into pre-existing chromosomal breaks. For viral production, the structural and packaging genes, now removed from the rAAV, are supplied in trans, in the form of a helper plasmid. This is discussed further below. Removal of the cap and / or rep genes provides additional capacity for the insertion of one or more transgenes or the like. Hence, the gene therapy vectors are recombinant viral vectors. AAV viruses occurring in nature may be classified according to various biological systems. Commonly, AAV viruses are referred to in terms of their serotype. A serotype corresponds to a variant subspecies of AAV which, owing to its profile of expression of capsid surface antigens, has a distinctive reactivity that can be used to distinguish it from other variant subspecies. Typically, a virus having a particular AAV serotype does not efficiently cross-react with neutralising antibodies specific for any other AAV serotype. AAV serotypes include AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV 10 and AAV11, also recombinant serotypes, such as Rec2 and Rec3, identified from primate brain. In vectors of the invention, the genome may be derived from any suitable AAV serotype, such as AAV2, AAV2 / 2, AAV7m8 or AAV5. The capsid may also be derived from any suitable AAV serotype, such as AAV8 or AAV2 (or derivatives therof). Reviews of AAV serotypes may be found in Choi etal. (Curr Gene Ther. 2005; 5(3); 299-310) and Wu et al (Molecular Therapy. 2006; 14(3), 316-327). Exemplary AAV genome sequences, or functional sequence units (including ITR sequences, rep or cap genes and regulatory elements) thereof, may be derived from the following accession numbers: Adeno-associated virus 1 NC_002077.1, AF063497; Adeno-associated virus 2 NC_001401.2; Adeno-associated virus 3 NC_001729.1; Adeno-associated virus 3B NC_001863; Adeno-associated virus 4 NC_001829; Adeno-associated virus 5 Y18065, AF085716; Adeno-associated virus 6 NC_001862; Avian AAV ATCC VR-865 AY186198, AY629583, NC_004828; Avian AAV strain DA-1 NC_006263, AY629583; Bovine AAV NC_005889, AY388617. AAV viruses may also be referred to in terms of clades or clones. This refers to the phylogenetic relationship of naturally derived AAV viruses, and typically to a phylogenetic group of AAV viruses which can be traced back to a common ancestor, and includes all descendants thereof. Additionally, AAV viruses may be referred to in terms of a specific isolate, i.e. a genetic isolate of a specific AAV virus found in nature. The term genetic isolate describes a population of AAV viruses which has undergone limited genetic mixing with other naturally occurring AAV viruses, thereby defining a recognisably distinct population at a genetic level. Exemplary clades and isolates of AAV that may be suitable include: Clade A: AAV1 NC_002077, AF063497, AAV6 NC_001862, Hu. 48 AY530611, Hu 43 AY530606, Hu 44 AY530607, Hu 46 AY530609; Clade B: Hu. 19 AY530584, Hu. 20 AY530586, Hu 23 AY530589, Hu22 AY530588, Hu24 AY530590, Hu21 AY530587, Hu27 AY530592, Hu28 AY530593, Hu 29 AY530594, Hu63 AY530624, Hu64 AY530625, Hul3 AY530578, Hu56 AY530618, Hu57 AY530619, Hu49 AY530612, Hu58 AY530620, Hu34 AY530598, Hu35 AY530599, AAV2 NC_001401, Hu45 AY530608, Hu47 AY530610, Hu51 AY530613, Hu52 AY530614, Hu T41 AY695378, Hu S17 AY695376, Hu T88 AY695375, Hu T71 AY695374, Hu T70 AY695373, Hu T40 AY695372, Hu T32 AY695371, Hu T17 AY695370, Hu LG15 AY695377; Clade C: Hu9 AY530629, HulO AY530576, Hull AY530577, Hu53 AY530615, Hu55 AY530617, Hu54 AY530616, Hu7 AY530628, Hul8 AY530583, Hul5 AY530580, Hul6 AY530581, Hu25 AY530591, Hu60 AY530622, Ch5 AY243021, Hu3 AY530595, Hui AY530575, Hu4 AY530602 Hu2, AY530585, Hu61 AY530623; WO 2025 / 149645                                   PCT / EP2025 / 050589 Clade D: Rh62 AY530573, Rh48 AY530561, Rh54 AY530567, Rh55 AY530568, Cy2 AY243020, AAV7 AF513851, Rh35 AY243000, Rh37 AY242998, Rh36 AY242999, Cy6 AY243016, Cy4 AY243018, Cy3 AY243019, Cy5 AY243017, Rhl3 AY243013; Clade E: Rh38 AY530558, Hu66 AY530626, Hu42 AY530605, Hu67 AY530627, Hu40 AY530603, Hu41 AY530604, Hu37 AY530600, Rh40 AY530559, Rh2 AY243007, Bbl AY243023, Bb2 AY243022, RhlO AY243015, Hul7 AY530582, Hu6 AY530621, Rh25 AY530557, Pi2 AY530554, Pil AY530553, Pi3 AY530555, Rh57 AY530569, Rh50 AY530563, Rh49 AY530562, Hu39 AY530601, Rh58 AY530570, Rh61 AY530572, Rh52 AY530565, Rh53 AY530566, Rh51 AY530564, Rh64 AY530574, Rh43 AY530560, AAV8 AF513852, Rh8 AY242997, Rhl AY530556; Clade F: Hul4 (AAV9) AY530579, Hu31 AY530596, Hu32 AY530597, Clonal Isolate AAV5 Y18065, AF085716, AAV 3 NC_001729, AAV 3B NC_001863, AAV4 NC_001829, Rh34 AY243001, Rh33 AY243002, Rh32 AY243003 / . The skilled person can select an appropriate serotype, clade, clone or isolate of AAV for use in the present invention on the basis of their common general knowledge. The AAV genome used in the invention may be the full genome of a naturally occurring AAV virus. However, while such a vector may in principle be administered to patients, this will be done rarely in practice. The AAV genome may instead be derivatised for the purpose of administration to patients. Such derivatisation is standard in the art and the present invention encompasses the use of any suitable known derivative of an AAV genome, and derivatives which could be generated by applying techniques known in the art. Derivatisation of the AAV genome and of the AAV capsid (discussed below) are reviewed in Coura and Nardi (Virology Journal, 2007, 4:99), and in Choi etal. and Wu et al., referenced above. Derivatives of an AAV genome include any truncated or modified forms of an AAV genome which allow for expression of the therapeutic nucleic acid from the vector in vivo. Typically, it is possible to truncate the AAV genome significantly to include minimal viral sequence yet retain the above function. It may also reduce the possibility of integration of the vector into the host cell genome, reduce the risk of recombination of the vector with wild-type virus, and avoid the triggering of a cellular immune response to viral gene proteins in the target cell. Typically, a derivative will include at least one inverted terminal repeat sequence (ITR), or two ITRs or more. Typically, the vector will have two ITRs, that flank the transgene / therapeutic element. In some embodiments, the ITRs may be derived from AAV 20 genomes having different serotypes, or may be a chimeric or mutant ITR. An example mutant ITR is one having a deletion of a trs (terminal resolution site). This deletion allows for continued replication of the genome to generate a single-stranded genome which contains both coding and complementary sequences i.e. a self-complementary AAV genome. This allows for bypass of DNA replication in the target cell, and so enables accelerated transgene expression. The inclusion of one or more ITRs may aid concatemer formation of the vector in the nucleus of a host cell, for example following the conversion of single-stranded vector DNA into double-stranded DNA by the action of host cell DNA polymerases. The formation of such episomal concatemers protects the vector construct during the life of the host cell, thereby allowing for prolonged expression of the transgene in vivo. The ITR sequences may, for example, be those of AAV2 having, for example, the sequence of SEQ ID NOs: 1 (5TTR) and / or 6 (3’UTR) or variants having at least 80% or 85%, or 90%, or 95% or 98% or 99% sequence identity to SEQ ID NOs: 1 or 6, or up to 1, 2, 3, 4 or 5 insertions, deletions, or substitutions in the amino acid sequences of SEQ ID NO: 1 or 6. In some embodiments, ITR elements may be the only AVV sequences retained in the vector. In some embodiments, one or more rep and / or cap genes or other viral sequences may be retained. Naturally occurring AAV virus integrates with a high frequency at a specific site on human chromosome 19, and shows a negligible frequency of random integration, such that retention of an integrative capacity in the vector may be tolerated in a therapeutic setting. The invention additionally encompasses the provision of sequences of an AAV genome in a different order and configuration to that of a native AAV genome. The invention also encompasses the replacement of one or more AAV sequences or genes with sequences from another virus or with chimeric genes composed of sequences from more than one virus. Such chimeric genes may be composed of sequences from two or more related viral proteins of different viral species. Capsid coats, Viral particles, Vesicles, Nanoparticles and Exosomes A viral vector of the invention may have a capsid coat. Such an encapsidated vector may be referred to as a viral particle. The vectors or particles of the invention include transcapsidated forms wherein a genome or derivative having the ITR(s) or other genome components of one serotype or virus type, for example AAV2, is packaged in the capsid of a different serotype, for example AAV8. This may be referred to as pseudotyping. The vectors or particles may be mosaic forms wherein a mixture of modified or unmodified capsid proteins from two or more different serotypes makes up the viral coat. The capsid protein sequences from different serotypes, clades, clones, or isolates within the same vector or viral particle. The vector may be a chimeric, shuffled or capsid modified derivative. The capsid coat is typically selected to provide one or more desired functionalities for the viral vector, such as increased efficiency of gene delivery, decreased immunogenicity (humoral or cellular), an altered tropism range and / or improved targeting of a particular cell type compared to a viral vector comprising a naturally occurring genome. Increased efficiency of gene delivery may be affected by improved receptor or coreceptor binding at the cell surface, improved internalisation, improved trafficking within the cell and into the nucleus, improved uncoating of the viral particle and improved conversion of a single-stranded genome to double-stranded form. Increased efficiency may also relate to an altered tropism range or targeting of a specific cell population, such that the vector dose is not diluted by administration to tissues where it is not needed. The capsid may determine the tissue specificity or tropism of a viral vector. Accordingly, the capsid serotypes for use in the invention will typically be one that has natural tropism for or a high efficiency of infection of the target cells. For example, AAV8 capsid serotypes have a natural tropism for cells of the retina, whilst AAV2 and AAV9 have a natural tropism for neurons. Chimeric capsid proteins include those generated by recombination between two or more capsid coding sequences of naturally occurring serotypes. This may be performed for example by a marker rescue approach in which non-infectious capsid sequences of one serotype are cotransfected with capsid sequences of a different serotype, and directed selection is used to select for capsid sequences having desired properties. The capsid sequences of the different serotypes can be altered by homologous recombination within the cell to produce novel chimeric capsid proteins. Chimeric capsid proteins also include those generated by engineering of capsid protein sequences to transfer specific capsid protein domains, surface loops or specific amino acid residues between two or more capsid proteins, for example between two or more capsid proteins of different serotypes. Shuffled or chimeric capsid proteins may also be generated by DNA shuffling or by error-prone PCR. For example, hybrid AAV capsid genes can be created by randomly fragmenting the sequences of related AAV genes e.g. those encoding capsid proteins of multiple different serotypes and then subsequently reassembling the fragments in a selfpriming polymerase reaction, which may also cause crossovers in regions of sequence homology. A library of hybrid genes created in this way by shuffling the capsid genes of several serotypes can be screened to identify viral clones having a desired functionality. Similarly, error prone PCR may be used to randomly mutate capsid genes to create a diverse library of variants which may then be selected for a desired property. The sequences of the capsid genes may also be genetically modified to introduce specific deletions, substitutions or insertions with respect to the native wild-type sequence. In particular, capsid genes may be modified by the insertion of a sequence of an unrelated protein or peptide within an open reading frame of a capsid coding sequence, or at the N-and / or C-terminus of a capsid coding sequence. The unrelated protein or peptide may advantageously be one which acts as a ligand for a particular cell type. It may thereby confer improved binding to a target cell or improve targeting or the specificity of targeting of the vector to a particular target cell population, for example, photoreceptor cells of the retina, or other target cells di cussed herein. In other embodiments, the unrelated protein may be one which assists purification of the viral particle as part of the production process i.e. an epitope or affinity tag. The site of insertion will typically be selected so as not to interfere with other functions of the viral particle e.g. internalisation, trafficking of the viral particle. The skilled person can identify suitable sites for insertion based on their common general knowledge. Particular sites are disclosed in Choi et al., referenced above. The vectors or particles also includes chemically modified forms bearing ligands adsorbed to the capsid surface. For example, such ligands may include antibodies for targeting a particular cell surface receptor. In some embodiments, the viral or non-viral vectors described herein may be packaged in a vesicle, liposome, exosome or nanoparticle or other suitable means of packaging as are known to those skilled in the art. Retrovirus derived vectors The vector may comprise a retrovirus genome or a derivative thereof. Derivatives of a retrovirus genome include any truncated or modified forms of a retrovirus genome which allow for expression of a transgene / therapeutic element from the vector in vivo in accordance with the present invention. As with AAV derived vectors, a retrovirus derived vector will typically comprise a derivative of a retroviral genome comprising the minimal viral sequences required for packaging and subsequent integration into a host. For retrovirus derived vectors, one or more long terminal repeats (LTRs) are the minimum element required for replication and packaging of the vectors and subsequent integration into the target cell to provide permanent transgene expression. However, other elements may also be present. For example, a human immuno deficiency virus (HIV) derived vector will typically comprises the HIV 5’ LTR, which is necessary for integration into the host cell genome, the Psi signal, which is necessary for packaging of viral RNA into virions, a promoter for the transgene, and the 3’ LTR. Other suitable retroviral vectors may for example be derived from murine leukemia virus (MuLV), gibbon ape leukemia virus (GaLV), Simian Immuno deficiency virus (SIV), and combinations thereof. The tropism of a retrovirus derived vector is determined by the viral envelope proteins. Targeting of the appropriate cells, for example photoreceptor cells or RPE cells of the retina, may be enhanced by incorporating ligands for the target cells into the viral envelope. Adenovirus derived vector The vector may comprise an adenovirus genome or a derivative thereof. Derivatives of an adenovirus genome include any truncated or modified forms of an adenovirus genome which allow for expression of a transgene / therapeutic element from the vector in vivo in accordance with the present invention. A large number of human adenoviral serotypes have been identified and they are categorized into six subgenera (A through F) based on nucleic acid comparisons, fibre protein characteristics, and biological properties. For example, group A includes serotypes 12 and 31, group B includes serotypes 3 and 7, group C includes serotypes 2 and 5, group D includes serotypes 8 and 30, group E includes serotype 4, and group F includes serotypes 40 and 41. The core of an adenovirus virion contains the linear double-stranded DNA genome and associated proteins V, VII, X (mu), IVa2, and terminal protein (TP). The genome organization of different adenoviruses is conserved and has been proposed to have a timing function, wherein the ends of the genome are transcribed first (the immediate early genes El and E4 are located at opposite ends of the linear genome). Early transcription of El and E4 leads to the opening of the central region of the genome, allowing transcription of the central region. Adenoviral genomes typically comprise eight RNA polymerase II transcriptional units: five early units, El A, E1B, E2A-E2B, E3, and E4; two delayed early units, IX and IVa2; and the Major Late transcriptional unit. The Major Late transcriptional unit is further subdivided into L1-L5 regions based upon the use of alternative splicing sites. The transcriptional units often express proteins of similar function. For example, the El A unit codes for two proteins responsible for activation of transcription and induction of S-phase upon cellular infection; the E1B transcription unit encodes two proteins that inhibit cellular apoptosis; the E3 transcriptional unit is involved in evasion of the immune response; and the Major Late transcriptional unit encodes structural proteins necessary for assembly of the capsid. Heterologous transgene sequences may be inserted into adenoviral genomes, for example in the early transcriptional units and in the coding regions of various structural proteins, such as hexon, penton, and fiber. Deletions may have been made in the adenoviral genome (e.g., in the El regions) to create replication-defective adenoviral vectors, which have generally been considered safer for administration to human subjects. In the present invention, the adenovirus may be any adenovirus or derivative suitable for delivery of the transgene to target cells. The adenovirus may be any serotype but is typically Ad5 or Ad2. An adenovirus derived vector of the invention may comprise all or part of the genome of any adenoviral serotype, as well as combinations thereof (i.e., hybrid genomes). The adenoviral vector used in the invention may be either replication incompetent or replication competent. Such vectors are well known. For example, in a replication incompetent vector the El region may be deleted and replaced with an expression cassette with an exogenous promoter driving expression of the heterologous transgene. Usually, the E3 region is also deleted. Deletion of E3 allows for larger inserts into the El region. Such vectors may be propagated in appropriate cell lines such as HEK 293 cells which retain and express the El A and E1B proteins. Other vectors also lack the E4 region, and some vectors further lack the E2 region. E2 and E4 vectors must be grown on cell lines that complement the El, E4 and E2 deletions. Vectors may also be helper dependent vectors, which lack most or all of the adenoviral genes but retain cis-acting sequences such as the inverted terminal repeats as well as packaging sequences that are required for the genome to be packaged and replicated. These vectors are propagated in the presence of a helper adenovirus, which must be eliminated from the vector stocks. Once again, such systems are well known in the art. The capsid is composed of seven structural proteins: II (hexon), III (penton), Illa, IV (fiber), VI, VII, and IX. The capsid comprises 252 capsomeres, of which 240 are hexon capsomeres and 12 are penton capsomeres. Hexon capsomeres, which are trimers of the hexon protein, make up about 75% of the protein of the capsid. Penton capsomeres, which are pentamers of the penton protein, are situated at each of the 12 vertices of the virion. Each penton capsomer is bound to six adjacent hexon capsomeres and a fiber. The fiber, which is usually a trimer of the fiber protein, projects from the penton capsomer. The hexon protein and, to a lesser extent, the fiber protein comprise the main antigenic determinants of an adenovirus and also determine serotype specificity. An adenovirus derived vector is particularly suitable for use when a transient expression of a transgene is preferred. Herpes simplex virus derived vectors The vector may comprise a herpes simplex virus (HSV) genome or a derivative thereof. Derivatives of an HSV genome include any truncated or modified forms of a HSV genome which allow for expression of a transgene / therapeutic element from the vector in vivo in accordance with the present invention. Herpes simplex virus (HSV) naturally establishes a life-long latent infection of human peripheral sensory neurons. Recombinant HSV vectors are genetically modified to be incapable of replication, but establish a latent-like state in neurons in vitro and in vivo. Promoters and other regulatory elements In the vector, the nucleic acid encoding the therapeutic nucleic acid, is typically operably linked to a promoter. In some embodiments, the promoter may be constitutive i.e. operational in any host cell background, for example, the ubiquitous CAG promoter. More typically, the promoter is a cell-specific promoter, which drives expression in a particular target cell type, for example photoreceptor cells of the retina. Example promoters include the human rhodopsin kinase promoter (GRK1), which may have the sequence of SEQ ID NO: 2, or the human rhodopsin promoter, which may have the sequence of SEQ ID NO: 3, or functional variants thereof. One or more other regulatory elements, such as enhancers, postregulatory elements and polyadenylation sites may also be present in addition to the promoter. A regulatory sequence that is operably linked to the transgene is any sequences that facilitates or controls expression of the transgene, for example by promoting or otherwise regulating transcription, processing, nuclear export of mRNA or stability. The term “operably linked” means that the regulatory element is present at an appropriate position relative to another nucleic acid sequence (such as a transgene) so as to effect expression of that nucleic acid sequence., i.e. in their intended manner. A control sequence (e.g. a promoter) “operably linked” to a transgene is ligated in such a way that expression of the transgene is achieved under conditions compatible with the control sequences. Other exemplary promoters / enhancers include chicken beta-actin promoter (CAG,); cytomegalovirus (CMV); glutamate metabotropic receptor (GRM6, 4xGRM6, mGRM6), (hRHO) human rhodopsin (hRHO), human red opsin (hRO); mouse cone arrestin-3 (mCAR), woodchuck hepatitis post-transcriptional regulatory element (WPRE), Simian vacuolating virus 40 (SV40), synapsin (Syn), human synapsin (hSyn, hSynl), hybrid CMV enhancer / chicken beta-actin (CBA), thymocyte differentiation antigen 1 (Thy-1) and SNCG (Gamma synuclein). An exemplary vector may comprise the following elements in a 5’ to 3’ direction: (a) an inverted terminal repeat sequence (5TTR), such as any ITR sequence or 5TTR sequence described herein, or the sequence of SEQ ID NO: 1, or a variant having at least 70%, or 80% or 85% or 90% or 95 % or 98% or 99% sequence identity to SEQ ID NO:1; (b) a promoter sequence, for example any promoter described herein, wherein the promoter is operably linked to a sequence encoding the therapeutic nucleic acid, for example the GRK1 promoter comprising the sequence of SEQ ID NO: 2; (c) a translation initiation sequence, such as the Kozak consensus sequence GCCACC (SEQ ID NO: 5); (d) optionally a chicken beta-actin promoter exon-intron-exon sequence (Ex / InZEx), such as the sequence of SEQ ID NO: 4, or a variant having at least 70%, or 80% or 85% or 90% or 95 % or 98% or 99% sequence identity to SEQ ID NO: 4; (e) a sequence encoding the therapeutic nucleic acid or transgene; (f) optionally a woodchuck hepatitis post-transcriptional regulatory element (WPRE) having the sequence of SEQ ID NO: 7, or a variant having at least 70%, or 80% or 85% or 90% or 95 % or 98% or 99% sequence identity to SEQ ID NO: 7; (g) a polyadenylation tail sequence, such as the bovine growth hormone polyadenylation tail sequence of SEQ ID NO: 8; and (h) a 3’ inverted terminal repeat sequence (3TTR), such as any ITR sequence or 5TTR sequence described herein, or the sequence of SEQ ID NO: 6, or a variant having at least 70%, or 80% or 85% or 90% or 95 % or 98% or 99% sequence identity to SEQ ID NO: 6. These components (a) to (h) ((d) WO 2025 / 149645                                   PCT / EP2025 / 050589 and (f) being optional, i.e. each independently either present or absent) may be referred to as an expression cassette. There may be intervening sequences between the some or all of the different components (a) to (h). An intervening sequence between any two adjacent elements in the sequence may in some cases be up to 200 nucleotides, or up to 150, 100, 75, 50, 40, 30, 20, 15, 10, or 5 nucleotides in length. The vector may also include additional nucleotide sequences encoding additional or alternative regulatory elements such as one or more (further) promoters or enhancers or locus control regions (LCRs). The vector may also comprise other sequence elements or remnants of sequence elements used for the construction, cloning, selection and so on of the vector, as are well known to those skilled in the art. Preparation of vector A vector of the invention may be prepared by standard means known in the art for provision of vectors for gene therapy. Thus, well established public domain transfection, packaging and purification methods can be used to prepare a suitable vector. This includes known methods for packaging vectors into vesicles, liposomes, exosomes or nanoparticles or the like. Viral vectors used in gene therapy are typically generated by producing a cell line that packages a nucleic acid vector into a viral particle. The vectors typically contain the minimal viral sequences required for packaging and subsequent integration into a host, as described above, other viral sequences being deleted, leaving capacity for an expression cassette for one or more transgenes. The missing viral functions are typically supplied in trans by the packaging cell line. Packaging cells are typically used to form virus particles that are capable of infecting a host cell. The packaging cells may be any suitable cell type known in the art. The packaging cells are typically human or human derived cells. Suitable cells include Human Embryonic Kidney (HEK) 293 or 293T cells, or HEK 293 derived cell clones (for example to package adenovirus derived vectors), HeLa cells (for example to package HIV or other lentivirus derived vectors) and \| / 2 cells or PA317 cells (for example to package retrovirus derived vectors). Other examples are BHK or CHO cells. AAV derived vectors may comprise the full genome of a naturally occurring AAV virus in addition to the elements for gene therapy. However, commonly a derivatised genome will be used, for instance a derivative which has at least one inverted terminal repeat sequence (ITR), but which may lack any AAV genes such as rep or cap. In order to provide for assembly of a derivatised or recombinant genome into the viral particle, additional genetic constructs providing AAV and / or helper virus functions will be provided in a host cell in combination with the derivatised / recombinant genome. For AVV vectors, these additional constructs will typically contain genes encoding structural AAV capsid proteins i.e. cap, VP1, VP2, VP3, and genes encoding other functions required for the AAV life cycle, such as rep. The selection of structural capsid proteins provided on the additional construct will determine the serotype of the packaged viral vector. For replication incompetent viral vectors, helper virus functions, for example adenovirus helper functions, will typically also be provided on one or more additional constructs to allow for replication. The additional constructs may be provided as plasmids or other episomal elements in the host cell, or alternatively one or more constructs may be integrated into the genome of the host cell. Suitable genes and constructs may in some embodiments be any of those described herein. The properties of the vectors and other products of the invention as described herein can be tested using techniques known by the person skilled in the art. In particular, a vector or other construct of the invention can be delivered to a test animal, such as a mouse, and the effects observed and compared to a control. Such use is also an aspect of the invention. Agent and Pharmaceutical Compositions The therapeutic agents, vectors or other therapeutic products of the invention as described herein may be formulated into pharmaceutical compositions. Such pharmaceutical compositions and their use in methods of treatment as described herein form part of the invention. Pharmaceutical compositions or other agents as described herein may comprise, in addition to the vector or other active component, a pharmaceutically acceptable excipient, carrier, buffer, stabiliser or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active component. Examples of suitable compositions and methods of administration are provided in Esseku and Adeyeye (2011) and Van den Mooter G. (2006). The precise nature of the carrier or other material may be determined by the skilled person. Examples of techniques and protocols can be found in Remington's Pharmaceutical Sciences, 20th Edition, 2000, pub. Lippincott, Williams & Wilkins. The agent is typically in the form of an aqueous solution. The solution is typically pyrogen-free and has suitable pH, isotonicity and stability. Those of skill in the art are well able to prepare suitable solutions using, for example, isotonic vehicles such as phosphate-buffered saline, Sodium Chloride Injection, Ringer's Injection, Lactated Ringer's Injection, Hartmann's solution. Preservatives, stabilisers, buffers, antioxidants and / or other additives may be included, as required. Dosages and dosage regimes can be determined within the normal skill of the (medical) practitioner responsible for administration of the agent. A suitable dose may be determined according to various parameters, especially according to the age, weight and condition of the patient to be treated and the required treatment regimen. The dosing range of vectors or other therapeutics used for retinal (gene) therapy in patients is typically determined through phases 1-3 of clinical trial. Administration is typically in a "prophylactically effective amount" or a "therapeutically effective amount" (as the case may be, although prophylaxis may be considered therapy), this being sufficient to show benefit to the patient / subject. In other words, the treatment is sufficient to result in a clinical response or to show clinical benefit to the individual, for example to cure the disease or condition, prevent or delay onset or progression of the disease or condition or one or more symptoms thereof, to ameliorate or alleviate one or more symptoms, to induce or prolong remission, or to delay relapse or recurrence. Typically, the treatment is sufficient to prevent or reduce loss of vision (and hence improve the subject’s eyesight). Typically, the treatment is sufficient to slow down, reduce or prevent (further) degeneration of the subject’s sight / vision over time. In specific embodiments, the treatment may improve or reduce loss of vision in low light conditions. The vision of the subject may be improved compared to their state of vision before treatment. In other embodiments, the subject’s vision may be improved over time compared to their vision had they not received treatment. Other exemplary outcome measures for therapeutic treatment are described elsewhere herein. A typical single dose of the one or more vectors as described herein may between 105, or 106, or 107, or 108, or 109 or 2.5xl09 or 5xl09; and 1015, or 1014, or 1013, or 1012, or 1011 or 5xl010 or 2.5xlO10 or 1010 viral genomes (vg), or any range thereof, such as a typical range of 2.5xl09 to 5xl010 vg. A single AAV capsid that contains a single stranded DNA molecule is a single viral genome (vg). Vg can be quantified by any suitable method as well known in the art, for example real-time PCR. One of the advantages of the present invention is that it is possible to deliver larger volumes of agent to the retina than has been possible using prior methods, at least without causing significant inflammation and / or damage. This allows the delivery of higher does of some useful medicaments which is expected to result in improved outcomes, for example for conditions such as Leber congenital optic neuropathy (LHON) and many others. Typically, the volume of agent that is injected into the optic nerve is between about 20 pl and 1 ml. More typically, the volume may be between about 100 pl and 500 pl, or between about 100 pl and about 600 pl, 700 pl, 800 pl, 900 pl or 1 ml. In general, higher volumes injected into the optic nerve result in delivery of a higher quantity of the agent, or the active component, as described herein, to the retina. Agent delivery may be targeted to different parts of the retina depending on the site of injection in the optic nerve. For example, supero-temporal injection at the optic nerve can be used to deliver agent to the supero-temporal retina. Similarly temporal injection can be used to deliver to the the temporal retina, infero-temporal injection can be used to deliver to the infero-temporal retina, and nasal injection can be used to deliver to the the nasal retina. Alternatively, widespread distribution of agent can be achieved by multiple infusions of at different depths and at multiple sites in the optic nerve. Higher volumes generally result in stronger expression at the target site. Depending on the treatment, administration of therapy may occur once, resulting in a permanent treatment, or may involve repeat administrations, with the same agent or a variant thereof, for example in the case of viral vectors, using a different serotype. A composition of the invention may be administered or for administration alone or in combination with other suitable therapeutic compositions or treatments. Published data exist regarding the safety of adjunctive substances, such as blue dye to aid subretinal delivery (PMID: 28706756), or hydroxychloroquine to augment the efficacy of gene therapy (PMID: 31309129) Other Agents Imaging Agents In some embodiments the agent is an imaging agent. The imaging agent may be delivered to the retina by injection into the optical nerve (as described herein) and used to image or visualise the retina of the eye, or particular parts of the retina, e.g. to which the dye is delivered via different parts of the optic nerve (as described elsewhere herein). Such methods find use in a variety of experimental, therapeutic and diagnostic methods. For example, imaging agents or dyes may be used for chromovitrectomy, the use of imaging agents / dyes during vitroretinal surgery to aid visualisation of the tissues being manipulated by the surgeon. Examplary dyes include (preservative free and non-preservative free) triamcinolone acetonide, tryptan blue, brilliant blue and indocyanine green and neuro-tracers / dyes including fluorescein, neurobiotin, biotin, Biotin Ethylenediamine, Hydrobromide (Neurobiotin™), biocytin etc. These can be conjugated with various fluorophores for visualisation under different excitation / emission spectra. Gene Delivery Vectors and Gene or RNA Editing Vectors Non-therapeutic gene delivery vectors or gene or RNA editing vectors could be delivered to the retina via the optic nerve using the methods and means described herein. Such vectors might generally have any of the features described elsewhere herein in relation to therapeutic gene. Such vectors find use in experimental methods carried out, for example, to better understand the basic biology, signalling pathways and so on of the healthy eye / retina or the pathology of any disease or condition of the retina, such as those described herein, or in the testing or development of new treatments. For example, such vectors, means and methods may be used in non-therapeutic gene therapy (used in pre-clinical models) and optogenetics experiments. Reporter genes such as GFP, RFP, YFP, tdTomato, mScarlet, etc can be used alone or fused to the gene of interest to study expression, function, toxicity, safety, immune reactions etc. Such experiments are typically carried out on experimental animals, such as non-human primates, pigs, dogs, rabbits, rats and mice. Modes of Administration Injection into the optic nerve may be achieved using either a trans-vitreal or transorbital approach. Trans-vitreal targeting of the optic nerve is minimally invasive and could be performed under local anaesthesia in human subjects. Accessing the optic nerve trans-orbitally would require a more invasive procedure under general anaesthesia. A vitrectomy may be used as a surgical set-up, or a pars plana vitrectomy (PPV), as is commonly used for procedures such as retinal detachment repair, though this is not essential. As shown in the Examples herein, injection of the agent may be into the pre-laminar or retrolaminar region of the optic nerve. Hence, the injection involves penetration 32 of a delivery device, such as a needle / cannula, into the optic nerve and through the dense lamina cribosa. Typically, the device penetrates the optic nerve head at the back of the eye, passes through the retinal nerve fibre layer, the pre-laminar region and the lamina cribosa region and into the retrolaminar region. The needle typically penetrates the optic nerve to a depth of between about 0.5mm and 20 mm or, more typically, between about 0.6 mm, 0.7 mm, 0.8 mm, 0.9mm or 1 mm and about 5 mm, or 6 mm, or 7 mm, or 8 mm, or 9 mm, or 10 mm or 12 mm or 15 mm. Most typically, the needle penetrates the optic nerve to a depth of between about 1 mm and 5 mm. The infusion pressure used is typically about 15 to 35 psi, or 15 to 35 psi, or about 18-32 psi, or 18-32 psi, or about 20-30 psi, or 20-30 psi. One of the advantages of the present invention is that it is possible to deliver larger volumes of agent to the retina than has been possible using prior methods, at least without causing significant inflammation and / or damage. Hence, the volume of agent that is delivered is typically between about 20 pl and 1 ml. More typically, the volume may be between about 100 pl and 500 pl, or between about 100 pl and about 600 pl, 700 pl, 800 pl, or 900 pl. The methods of the invention may be carried out using a device or system of the invention as decribed herein. Devices The inventors have determined that the injection system which is currently used for subretinal drug delivery is not effective for injection into the optical nerve. Hence, the invention provides a device for delivering an agent, such as any of the agents discussed herein, to the retina of the eye of a subject by injecting the agent into the optic nerve. The device is adapted for optic nerve penetration and agent infusion into the optic nerve (for delivery of the agent to the retina). The device comprises a hollow needle (or cannula). The needle is for penetrating / insertion into the optic nerve and delivering the agent. The device further comprises a reservoir (or chamber) containing a volume of the agent. The hollow interior of the needle forms a channel through which the agent can flow. The needle has a proximal end and a distal tip end connected by the channel. The distal tip end is for insertion into the optic nerve and comprises a tip opening through which the agent can flow out from the channel and into the optic nerve. The (proximal end of the) channel is in fluid communication with the reservoir such that, in use, the agent can flow from the reservoir and through the channel to the distal tip end and through the opening, into the optic nerve. The optic nerve may be accessed trans-orbitally or, more typically, trans-vitreally. Hence, the length of the needle (cannula) is typically sufficient to enter the eye, cross the vitreous, penetrate through the lamina cribosa, and enter the optic nerve (Figure 5B). A needle (cannula) length of typically about 30 mm is suitable for injection into the optic nerve of a human subject or other subject of a similar size. Hence, the needle is typically about 20 to 40 mm, 25 to 35 mm or 28 to 32 mm in length. However, longer needles, e.g. up to 50 mm, 60 mm or 75 mm or 100 mm could also be used, or shorter needles may be used, e.g. for smaller subjects such as dogs and cats. In use, the distal tip end of the needle penetrates into the optic nerve and through the lamina cribosa (Figure 5B and 5C). The distal tip end typically has about a 30 to 52g gauge (0.2 to 0.06 mm (i.e. 0.06 to 0.2 mm) external diameter of the needle), or about 35 to 45g (0.165 to 0.075mm), about 36 to 44g (0.15 to 0.08 mm), about 37 to 43g (0.155 to 0.085 mm), about 38 to 42g (0.12 to 0.087 mm), about 39 to 41g (0.11 to 0.09 mm) or abour 40g (0.1mm), along a distal tip end length of at least about 5 mm in an axial direction of the needle, or more typically about 5 mm to about 15 mm, or about 5 to about 10 mm, 9 mm, 8 mm, 7 mm or 6 mm. This allows for precision insertion into the optic nerve and reduced damage to the dense vasculature. The remaining length of the needle (cannula) may have a larger external diameter, typically about 23g to 27g gauge (0.4 mm to 0.6 mm), or about 24g to 26g (0.45 to 0.55 mm), or about 25g (0.5 mm), for example as used in a standard Pars Plana Vitrectomy. The needle is typically cyclindrical in shape, but may include (a) step change(s) in the cross-sectional diameter along its length, i.e. narrower distal tip end and wider prominal end, as discussed above. Typically, both the distal tip end and the proximal end are cylindrical and are axially arranged. The distal tip end typically has a smaller crosssectional diameter for insertion into the optic nerve and the proximal end has a larger diameter and crosses the vitreous (in use), as discussed herein. The inventors have determined that a typical polytetrafluoroethylene (Teflon; (Young’s modulus (E) = 0.564 GPa) needle is not rigid enough to use in the methods of the invention. The needle must be sufficiently rigid to enter the optic nerve and penetrate through the dense lamina cribosa. In some embodiments, the needle is metal, typically titanium (Young’s modulus (£)=116 GPa). Other metals having a similar rigidity and suitability for use as a medical needle (e.g. biocompatible) could also be used, for example 34 a titanium alloy (e.g. with aluminium, vanadium, nickel and / or iron, such as nickel titanium (nitinol; austenite £ = 41 GPa; martensite E = 75 GPa) or Grade 5 titanium alloy (6% aluminum, 4% vanadium, up to 0.25% iron, up to 0.2% oxygen, and the remainder titanium; £=114 GPa)). Other examples are stainless steel (£ = 78 GPa), aluminium (£ = 68 GPa), nickel (£ = 200 GPa) or Cobalt-Chromium alloys (E = 78 GPa). Alternatively, a non-metal material having sufficient rigidity and biocompatibility could be used, for example glass (E = 70 GPa) or ceramics. Typically, the needle is made of a material having a rigidity of at least about 30 GPa, or at least about 40, at least about 50, at least about 60, at least about 70, at least about 80, at least about 90, at least about 100 GPa, or at least about 110 GPa. Most typically, the needle is made of a material having a rigidity of about £ = 40 to 200 GPa. The distal tip end of the needle is typically straight in an axial direction of the needle, for penetration into the optic nerve. The remainder of the needle is also typically straight in an axial direction of the needle. Also envisaged is a device compring an extendable needle (Figure 10). The distal tip end of the extendable needle may have a straight distal section and a proximal section comprising or consisting of a curved portion. The straight distal section has features for insertion into the optic nerve and penetration of the lamina cribosa, e.g. shape and dimensions, similar to that of the distal tip end of a typical straight, non-extendable needle, as described above. The device or needle may further comprise a housing for a part of the distal end of the needle including at least the curved portion. The housing may have a similar shape and dimention as the proximal end of the needle as discussed above for a typical straight and non-extensible needle (for transorbital or trans-vitreal positioning in use), but is large enough to contain a portion of the distal tip end of the needle, as described herein. The position of the distal tip end of the needle relative to the housing is fixed in one of a pluraily of positions that are selectable by the user. In a first configuration (retracted position), the straight distal section, having features as described above for insertion into the optic nerve and pentration through the lamina cribosa, extends outside of the housing. The proximal section, having a curved portion, remains fixed inside the housing. In this first configuration, the part of the needle that extends from the device, outside of the housing, is straight and suitable for penetration into the optic nerve. In a second configuration (protracted position), for use after the insertion into the optic nerve, the the distal tip end of the needle is fixed in a second position relative to the housing, in which the curved portion of the needle is extended outside of the housing. In this second configuration the part of the needle that extends outside of the housing comprises the curved portion. The curve in the extended needle allows the distal tip end of the needle to be rotated in different directions, without altering the axial position of the housing, which passes through the eye, so that the agent may be more easily expelled from the channel at the distal tip end into different regions of the optic nerve. In these embodimement, the rigidity for insertion into the optic nerve and through the lamina cribosa is provided by the distal tip end of the needle and the housing, wherein the distal tip end of the needle and the housing are fixed in one of the plurality of selectable positions / configurations. Hence, the housing has the same rigidity / material features as described above, in relation to the needle in general. However, the needle may further comprise a flexible portion providing the channel inside the housing, wherein the flexible portion is made of a different, more flexible material, which allows the housing to accommodate the needle in both the retracted and protracted positions. The tip of the needle may be straight-cut or bevelled. One of the advantages of the present invention is that it is possible to deliver larger volumes of agent to the retina than has been achieved using prior methods, at least without causing significant inflammation and / or damage. This allows, for example, for the delivery of higher doses of medicaments which is expected to result in improved outcomes for conditions such as Leber congenital optic neuropathy (LHON) and many others. Hence, in some embodiments the volume of agent contained in the reservoir, and / or for delivery to the optic nerve from the device, is typically up to 1 ml, or between 20 pl and 1 ml. Larger volumes may also be contained in the reservoir, but much larger volumes are likely not to be injected into the subject and would therefore be wasted. More typically, the volume may be between about 100 pl and 500 pl, or between about 100 pl or 200 pl or 300 pl or 400 pl and about 600 pl, 700 pl, 800 pl, or 900 pl. More generally, the device may be used in any of the methods of the invention described herein. The device may accordingly be configured for providing any suitable feature described herein, e.g. delivery of the agent into the optic nerve at an infusion pressure of about 15 to 35 psi, or 15 to 35 psi, or about 20-30 psi. The device may further comprise means, such as a syringe, for propelling / expelling the agent from the reservoir, through the channel and out of the needle through the distal tip end. The device, or the system as described further below, may further comprise means for controlling the speed, pressure and / or volume of agent that is ejected from the needle tip / injected into the optic nerve. The device may further comprise a digitalised measure of the volume ejected / injected, for example a display of the volume ejected / injected or means for producing a sound when a pre-determined volume has been ejected / injected. The device may further comprise means for controlling the rate at which the agent is ejected / injected, e.g. a timer, which may be programmable to eject / inject a predetermined volume over a pre-determined time period. The device or system may comprise a viscous fluid control system. The device may be configured to provide an infusion pressure as described elsewhere herein, e.g. 20-30 psi. The device may further comprise means for mounting / connecting the device to a robotic arm configured to guide the distal tip end of the needle into the optic nerve of a subject when the device is connected / mounted on the robotic arm. Robotic Delivery Systems and Robot-Assisted Methods The invention benefits from the use of robotic means for positioning the needle for injection into the optic nerve, increasing the precision and accuracy of the insertion. Accordingly, any of the methods of the invention described herein may be robot-assisted methods. The invention also provides a robot-assisted system for delivering an agent to the retina of a subject. The system comprises a device, as described elsewhere herein, and a robotic arm. The robotic arm is operatively connected to the device and configured to guide the distal tip end of the needle into the optic nerve. Typically, the device is held by or mounted on the robotic arm. The system may further comprise any one or more or the following, which may typically be used when performing a pars plana virectomy, or other similar procedure: - a vitrectomy machine; -   a surgical microscope; -  a wide-angled viewing system; - an endoillumination light source or chandelier lighting systems; - vitrector (vitrectomy cutter); - a trocar-cannula system; -  one or more extrusion cannulas; -  a diathermy machine; - an endolaser; and / or - a fragmatome. In further embodiments, the invention provides a computer or processor configured to control the system described herin, i.e. to guide the needle into the optic nerve of a subject. In further embodiments, the invention provides a computer programme that, when executed, causes a computer or processor to control the system as described herein, i.e. to guide the needle into the optic nerve of a subject. The computer / processor / programme may be configured to provide any other suitable features of the invention as described herein, for example the volume of agent injected, the depth of penetration into the optic nerve (similar to the length of the the distal tip end of the device needle, as described herein), and / or the infusion pressure. Kits The therapeutic agents or device of the invention as described herein can be comprised in or packaged into a kit. The kit may additionally comprise suitable means for administering or using the product and / or instructions for use, e.g. in a method described herein. Such kits are an aspect of the present invention. Also provided are kits comprising a device as described herein, but without the agent contained within the reservoir, instead having a chamber / reservoir as described herein for containing an agent (as described herein) and a separate container comprising an (equivalent) volume of the agent. The kit may further comprise suitable further means for administering or using the product, instructions for use, and / or means for transferring the agent from the container into the reservoir / chamber of the device. Additional Definitions As used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the content clearly dictates otherwise. Thus, for example, reference to “a vector” includes two or more such entities (vectors). The term "and / or" as used in this application includes any and all combinations of one or more related listed items. The term “comprising” (means including but not limited to) specifically discloses / includes equivalent embodiments “consisting of’ (means limited to). The term “consisting essentially of’ should be understood to mean that the sequence comprises no additional sequence units or elements that materially affect the function of the sequence element. Numeric ranges are inclusive of the numbers defining the range. Thus, every numerical range disclosed herein is intended to encompass every narrower numerical range that falls within such broader numerical range, as if such narrower numerical ranges were all expressly written herein. It is also intended that every maximum (or minimum) numerical limitation disclosed herein includes every lower (or higher) numerical limitation, as if such lower (or higher) numerical limitations were expressly written herein. The term "about" as used herein means in quantitative terms plus or minus 5%, or in another embodiment plus or minus 10%, or in another embodiment plus or minus 15%, or in another embodiment plus or minus 20%. For the purpose of this invention, in order to determine the percent identity or similarity of two sequences (such as two nucleic acid sequences), the sequences are aligned for optimal comparison purposes (e.g., gaps can be introduced in a first sequence for optimal alignment with a second sequence). The amino acids at each position are then compared. When a position in the first sequence is occupied by the same amino acid as the corresponding position in the second sequence, then the amino acids are identical at that position. The percent identity or similarity between the two sequences is a function of the number of identical positions shared by the sequences (i.e., % identity = number of identical positions / total number of positions in the reference sequence (e.g. SEQ ID NO:1) x 100, or % identity = number of identical positions / total number of positions in either sequence x 100). Typically, the sequence comparison is carried out over the length of the reference sequence, for example, SEQ ID NO: 1 herein. If the sequence is shorter than the reference sequence, the gaps or missing positions should be considered to be non-identical positions. In some cases, however, the sequence comparison may alternatively be carried out over the length of the sequence being compared to the reference sequence. If the reference sequence is shorter than the comparator sequence, the gaps or missing positions should be considered to be non-identical positions. The skilled person is aware of different computer programs that are available to determine the homology or identity between two sequences using a mathematical algorithm. In an embodiment, the percent identity between two amino acid or nucleic acid sequences is determined using the Needleman and Wunsch (1970) algorithm which has been incorporated into the GAP program in the Accelrys GCG software package (available at http: / / www.accelrys.com / products / gcg / ), using either a Blosum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6. Other examples of suitable programs are the BESTFIT program provided by the UWGCG Package (for example used on its default settings) (Devereux et al (1984) Nucleic Acids Research 12, 387-395) and the PILEUP and BLAST algorithms c (for example used on its default settings), for example as described in Altschul S. F. (1993) J Mol Evol 36:290-300; Altschul, S, F et al (1990) J Mol Biol 215:403-10. Software for performing BLAST analyses is publicly available through the National Center for Biotechnology Information (http: / / www.ncbi.nlm.nih.gov / ). Unless otherwise defined, all technical and scientific terms used in this application have the same meaning as commonly understood by those skilled in the technical field of this application. The terminology used in the description of this application is only for the purpose of describing specific embodiments, and is not used to limit this application. The experimental methods without specific conditions in the following examples generally follow conventional conditions or the conditions recommended by the manufacturer. The various commonly used chemical reagents used in the examples are all commercially available products. Examples Example 1 In an ex vivo non-human primate eye, which closely resembles a human eye (approx. 1 / 3 of a human eye in size), the optic nerve was injected trans-vitreally with a neuronal biomarker (biocytin dye560). The dye uptake by retinal ganglion cell axons and its retrograde transport into the retinal ganglion cell bodies was traced (Figure 2). It was found that the injection system which is currently used for subretinal drug delivery (such as gene or cell therapy) had to be adapted for injection into the optic nerve. It was not possible to penetrate the optic nerve with a 41G polytetrafluoroethylene (Teflon) blunt-tipped subretinal cannula (DORC) as is currently used. The tip was too soft and had a tendency to bend. Several other options were tested: extendible 41G subretinal injection cannula (1270.ext, DORC), 27G disposable cubretinal injection cannula (38G) (1270.04, DORC), Poly tip cannulas from MedONE (3233 (5mm tip), 3254 (2mm green tip), (3247 extendible polytip cannula 25g / 38g), 3305 (polyvent cannula 25 / 3 8G, 5mm green tip) an all-metal nano-cannula (3263, 25 / 48g 0.06mm) 1.5mm tip MedOne, but none were successful, either because the needle / tip was too flexible or the tip was too short. The all metal MicroTip Beveled 25 / 40g (3261, MedOne) was custom modified from curved tip into a straight-tip cannula. This was the most successful needle for penetrating the optic nerve. Using this tip, widespread uptake of a neuronal dye in retinal ganglion cells was achieved following injection into the optic nerve in ex vivo NHP eye. Example 2 In vivo, in mice, intraneural injections were performed to deliver a neuronal dye (Biocytin) into the retina using a NanoFil™ syringe / cannula - a 10 pL syringe with the 35g bevelled nano cannula specially designed for subretinal injections in small animal models. Widespread neuronal dye uptake into retinal ganglion cells following optic nerve injection was achieved (Figure 3). Example 3 In vivo, in mice, intraneural injections of adeno-associated viral (AAV) vector carrying a fluorescent protein (GFP) gene were performed to deliver the GFP to the retina using the same system as in Example 2. Widespread AAV transduction of retinal ganglion cells following optic nerve injection was achieved (Figure 4). Example 4 In vivo, in an NHP model, optic intraneural injections of several different AAVs carrying fluorescent proteins (GFP or RFP) were performed. Attempts to inject the optic nerve using the current subretinal injection system and blunt or bevelled-tip Teflon cannula were unsuccessful. In all cases, AAV vectors were successfully delivered into the optic nerve using the customised injection system / straightened-tip cannula (MicroTip Beveled 25 / 40g MedOne) described in Example 1. The surgery consisted of a standard three-port 25-gauge core pars plana vitrectomy. The injection device was customised to fit the robotic system and connected to the viscous fluid control (VFC) port of the Alcon Constellation Vision System (Alcon, Fort Worth, TX, USA). The optic nerve was targeted transvitreally and vector solution was delivered using a robot-assisted approach for precise delivery and minimal disruption to the tissue, carefully avoiding major retinal vessels (Figure 5). The infusion pressure was controlled via a foot-pedal with the maximum limit set to the minimum that would produce a flow of fluid—generally this was 20-30 psi (compared with 12-14psi needed for subretinal injections). Injections were varied by vector (AAV2-CAG-GFP, AAV2-CAG-RFP, AAV2.7m8-CAG-GFP, AAV5-CAG-GFP), site within the optic nerve (temporal, superotemporal, infero-temporal, nasal), depth (1.3 mm to 5.0 mm) and volume (100 pl to a total of 455 pl) and combinations thereof for targeted delivery to retinal areas of interest (Figure 6). An overall aim was to achieve widespread retinal transduction including macular fibres for central, high acuity vision (Figure 6. C, D and E). The expression pattern was dependent on the site of injection. For example, supero-temporal injection at the optic WO 2025 / 149645                                   PCT / EP2025 / 050589 nerve resulted in protein expression in supero-temporal retina following retrograde axonal transport into retinal ganglion cells. Multiple vector infusions of at different depths and at multiple sites resulted in more widespread expression. Higher volumes resulted in stronger expression. Example 5 During the experiments described in Example 4, blanching of retinal vessels at the optic nerve was carefully monitored to avoid damage, haemorrhage or occlusion. Membrane Blue Dual (DORC, Zuidland, The Netherlands) was mixed with the vector solution to monitor for any reflux into the vitreous which would lead to inflammation. Surprisingly, no vector reflux into the vitreous was observed during the injection procedure. Optical coherence tomography (OCT) images of the optic nerve and fovea demonstrated normal retinal anatomy including optic nerve thickness (no swelling) and foveal thickness (no fluid or cystoid macular oedema) with no signs of inflammation (Figure 7). Also surprisingly, no bleeding was observed. Example 6 Two weeks after treatment, strong and widespread expression of fluorescent protein in retinal ganglion cells in histological retinal samples was confirmed under light and confocal microscopy (Figure 8). Example 7 Two months after treatment, retinal and brain electrophysiology testing confirmed that the procedure described in Example 4 does not damage the optic nerve and retinal tissue and that the electrical signals from the retina continue to be transferred to the brain via the optic nerve and visual pathways in a normal way (Figure 9). Further Embodiments Of The Invention 1.      A method for delivering an agent to the retina of a subject, the method comprising administering the agent directly into the optic nerve. 2.      A method of treating or preventing a disease or condition of the retina, the method comprising administering a therapeutic agent for treating the disease or condition directly into the optic nerve. WO 2025 / 149645                                   PCT / EP2025 / 050589 3. A therapeutic agent for use in a method of treating or preventing a disease or condition of the retina, wherein the method comprises administering the therapeutic agent directly into the optic nerve. 4.     The method of 2 or the therapeutic agent for use of 3, wherein the (a)     the therapeutic agent is a gene therapy vector or a gene editing vector, and the method is for treating or preventing inherited retinal disease in the subject; (b) the therapeutic agent comprises a light-sensitive molecule, a gene therapy vector that encodes a light-sensitive molecule, or a gene editing vector for editing a nucleic acid that encodes a light-sensitive molecule, and the method is for replacing lost, damaged or defective light-sensitive molecules or components of the phototransduction cascade in the retina of the subject; (c) the therapeutic agent is a gene therapy vector, a gene editing vector or a neuroprotective agent, and the method is for the treating or preventing glaucoma in the subject; (d) the therapeutic agent is a gene therapy vector, a gene editing vector, a VEGF antagonist, a molecule targeting the complement cascade, or a neuroprotective agent and the method is for treating or preventing macular degeneration or a cone or cone-rod dystrophy affecting the macular in the subject; or (e) the therapeutic agent is a gene therapy vector, a gene editing vector, or a neuroprotective agent, and the method is for treating or preventing an inherited or acquired optic neuropathy in the subject. 5. The method or the therapeutic agent for use of 4, wherein the disease or condition is Leber congenital optic neuropathy (LHON). 6.     A method of diagnosing a disease or condition of the retina, the method comprising administering an imaging agent directly into the optic nerve and imaging the retina. 7. An imaging agent for use in a method of diagnosing a disease or condition of the retina, wherein the method comprises administering the imaging agent directly into the optic nerve. 8. A device for delivering an agent to the retina of the eye of a subject, wherein the agent comprises a therapeutic agent for treatment of a disease or condition of the retina, a vector encoding a light-sensitive protein, or an imaging agent for imaging the retina, the device comprising: a hollow needle having a proximal end and a distal tip end connected by a channel through which the agent may flow; and a reservoir containing a volume of the agent, wherein the reservoir is in fluid communication with the channel; wherein the distal tip end has an axial length of at least 5 mm at about 30 to 52 gauge, and wherein the needle is sufficiently rigid that the distal tip end of the needle can be inserted into the optic nerve and can penetrate through the lamina cribrosa. 9. A system for delivering an agent to the retina of the eye of a subject, wherein the agent comprises a therapeutic agent for treatment of a disease or condition of the retina, a vector encoding a light-sensitive protein, or an imaging agent for imaging the retina, the system WO 2025 / 149645                                   PCT / EP2025 / 050589 comprising: a robotic arm; a hollow needle having a proximal end and a distal tip end connected by a channel through which the agent may flow; and a reservoir containing a volume of the agent, wherein the reservoir is in fluid communication with the channel; wherein the distal tip end has an axial length of at least 5 mm at about 30 to 52 gauge; wherein the needle is sufficiently rigid that the distal tip end of the needle can be inserted into the optic nerve and can penetrate through the lamina cribrosa; and wherein the robotic arm is operatively connected to the needle and configured to guide the distal tip end of the needle into the optic nerve. 10. The device of 8 or the system of 9, wherein the distal tip end of the needle is essentially straight. 11.     The device or system of any one of 8 to 10, wherein the tip end of the needle is bevelled. 12.     The device or system of any one of 8 to 11, wherein the distal tip end, having a gauge of 30 to 52, is about 5 mm to about 15mm in length. 13.     The device or system of any one of 8 to 12, wherein the needle is a metal needle. 14.     The device or system of 13, wherein the metal is titanium. 15. The method of 1, or the device or system of any one of 8 to 14, wherein the agent comprises a drug, an imaging agent, a vector encoding a light-sensitive protein, a gene therapy vector, a gene editing vector or therapeutic cells. 16. The method or the therapeutic or imaging agent for use of any one of 1 to 7 and 16, wherein the agent is administered into the optic nerve temporally, supero-temporally, infero-temporally or nasally, or the device or system of any one of 8 to 15, wherein the device is for administration of the agent into the optic nerve temporally, supero-temporally, infero-temporally or nasally, or the robotic arm is configured to administer the agent into the optic nerve temporally, supero-temporally, infero-temporally or nasally. 17. The method of dim 1, or the device or system of any one of 8 to 16, for delivering the agent to the inner retina, or the method or the therapeutic agent for use of any one of 2 to 5 and 16, wherein the treatment is for a disease or condition of the inner retina, or the method or the imaging agent of any of 6, 7 and 16, wherein the method is for diagnosing a disease or condition of the inner retina. 18. The method or the therapeutic or imaging agent of any one of 1 to 7 and 15 to 17, wherein the agent is administered into the optic nerve at an infusion pressure of about 15 to 35 psi, or the device or system of any one of 8 to 17, wherein the device is for administration of the agent into the optic nerve at an infusion pressure of about 15 to 35 psi, or the robotic arm of the system is configured to administer the agent into the optic nerve at an infusion pressure of about 15 to 35 psi. 19. The method, therapeutic or imaging agent for use, device or system of any one of the preceding embodimenys, wherein the volume of agent is between 20 pl and 1 ml.

Claims

1. A method for delivering an agent to the retina of a subject, the method comprising administering the agent directly into the optic nerve trans-vitreally.

2. A method of treating or preventing a disease or condition of the retina, the method comprising administering a therapeutic agent for treating the disease or condition directly into the optic nerve trans-vitreally.

3. A therapeutic agent for use in a method of treating or preventing a disease or condition of the retina, wherein the method comprises administering the therapeutic agent directly into the optic nerve trans-vitreally.

4. The method of claim 2 or the therapeutic agent for use of claim 3, wherein the(a) the therapeutic agent is a gene therapy vector or a gene editing vector, and the method is for treating or preventing inherited retinal disease in the subject;(b) the therapeutic agent comprises a light-sensitive molecule, a gene therapy vector that encodes a light-sensitive molecule, or a gene editing vector for editing a nucleic acid that encodes a light-sensitive molecule, and the method is for replacing lost, damaged or defective light-sensitive molecules or components of the phototransduction cascade in the retina of the subject;(c) the therapeutic agent is a gene therapy vector, a gene editing vector or a neuroprotective agent, and the method is for the treating or preventing glaucoma in the subject;(d) the therapeutic agent is a gene therapy vector, a gene editing vector, a VEGF antagonist, a molecule targeting the complement cascade, or a neuroprotective agent and the method is for treating or preventing macular degeneration or a cone or cone-rod dystrophy affecting the macular in the subject; or(e) the therapeutic agent is a gene therapy vector, a gene editing vector, or a neuroprotective agent, and the method is for treating or preventing an inherited or acquired optic neuropathy in the subject.

5. The method or the therapeutic agent for use of claim 4, wherein the disease or condition is Leber congenital optic neuropathy (LHON).

6. A method of diagnosing a disease or condition of the retina, the method comprising administering an imaging agent directly into the optic nerve trans-vitreally and imaging the retina.

7. An imaging agent for use in a method of diagnosing a disease or condition of the retina, wherein the method comprises administering the imaging agent directly into the optic nerve trans-vitreally.

8. A device for delivering an agent to the retina of the eye of a subject, wherein the agent comprises a therapeutic agent for treatment of a disease or condition of the retina, a vector encoding a light-sensitive protein, or an imaging agent for imaging the retina, the device comprising:a hollow needle having a proximal end and a distal tip end connected by a channel through which the agent may flow; anda reservoir containing a volume of the agent, wherein the reservoir is in fluid communication with the channel;wherein the distal tip end has an axial length of at least 5 mm at about 30 to 52 gauge,and wherein the needle is sufficiently rigid that the distal tip end of the needle can be inserted into the optic nerve trans-vitreally and can penetrate through the lamina cribrosa.

9. A system for delivering an agent to the retina of the eye of a subject, wherein the agent comprises a therapeutic agent for treatment of a disease or condition of the retina, a vector encoding a light-sensitive protein, or an imaging agent for imaging the retina, the system comprising:a robotic arm;a hollow needle having a proximal end and a distal tip end connected by a channel through which the agent may flow; anda reservoir containing a volume of the agent, wherein the reservoir is in fluid communication with the channel;wherein the distal tip end has an axial length of at least 5 mm at about 30 to 52 gauge;wherein the needle is sufficiently rigid that the distal tip end of the needle can be inserted into the optic nerve trans-vitreally and can penetrate through the lamina cribrosa;and wherein the robotic arm is operatively connected to the needle and configured to guide the distal tip end of the needle into the optic nerve.

10. The device of claim 8 or the system of claim 9, wherein the distal tip end of the needle is essentially straight.

11. The device or system of any one of claims 8 to 10, wherein the tip end of the needle is bevelled.

12. The device or system of any one of claims 8 to 11, wherein the distal tip end, having a gauge of 30 to 52, is about 5 mm to about 15mm in length.

13. The device or system of any one of claims 8 to 12, wherein the needle is a metal needle.

14. The device or system of claim 13, wherein the metal is titanium.

15. The method of claim 1, or the device or system of any one of claims 8 to 14, wherein the agent comprises a drug, an imaging agent, a vector encoding a lightsensitive protein, a gene therapy vector, a gene editing vector or therapeutic cells.

16. The method or the therapeutic or imaging agent for use of any one of claims 1 to 7 and 16, wherein the agent is administered into the optic nerve temporally, supero-temporally, infero-temporally or nasally, or the device or system of any one of claims 8 to 15, wherein the device is for administration of the agent into the optic nerve temporally, supero-temporally, infero-temporally or nasally, or the robotic arm is configured to administer the agent into the optic nerve temporally, supero-temporally, infero-temporally or nasally.

17. The method of claim 1, or the device or system of any one of claims 8 to 16, for delivering the agent to the inner retina, or the method or the therapeutic agent for use of any one of claims 2 to 5 and 16, wherein the treatment is for a disease or condition of the inner retina, or the method or the imaging agent of any of claims 6, 5          7 and 16, wherein the method is for diagnosing a disease or condition of the innerretina.

18. The method or the therapeutic or imaging agent of any one of claims 1 to 7 and 15 to 17, wherein the agent is administered into the optic nerve at an infusion pressure 10          of about 15 to 35 psi, or the device or system of any one of claims 8 to 17, whereinthe device is for administration of the agent into the optic nerve at an infusion pressure of about 15 to 35 psi, or the robotic arm of the system is configured to administer the agent into the optic nerve at an infusion pressure of about 15 to 35 psi.1519. The method, therapeutic or imaging agent for use, device or system of any one of the preceding claims, wherein the volume of agent is between 20 pl and 1 ml.

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