Systems and methods for the treatment of retinal diseases

Abstract

A method for providing primary therapy to restore functional blood flow to a back of an eye may include advancing a guidewire through an access site in a subject to an ostium of an ophthalmic artery (OA) via an internal carotid artery (ICA), advancing a microcatheter to the ostium of the OA, retracting the guidewire into the microcatheter, such that a distal tip of the microcatheter assumes a pre-shaped configuration, advancing the microcatheter to cannulate a short limb of the OA, advancing the guidewire to a position approximately at or beyond a central carotid artery (CRA) branch of the OA, removing the microcatheter, advancing a treatment device over the guidewire to a lesion site in the OA of the subject, performing a treatment with the treatment device, and removing the treatment device and the guidewire from the subject.

Description

SYSTEMS AND METHODS FOR THE TREATMENT OF RETINAL DISEASESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority of U.S. Provisional Patent Application No. 63 / 569,434, filed on March 25, 2024, and of U.S. Provisional Patent Application No. 63 / 632,814, filed on April 11, 2024, both of which are incorporated herein in their entireties.FIELD OF THE INVENTION

[0002] The present disclosure relates to systems and methods for the treatment of retinal diseases. More specifically, the present disclosure relates to systems and methods for restoring functional blood flow to the back of the eye, and systems and methods for providing direct choroidal and / or retinal delivery of a therapeutic compound...BACKGROUND

[0003] Modem innovations in pharmacology and technology have the promise to fundamentally improve treatment of retinal diseases. Some of these new treatments, including longer-acting anti-vascular endothelial growth factor (anti VEGF) agents, port delivery systems, gene therapy, and complement system (CS) inhibitors, have been approved by the United States Food and Drug Administration (FDA), and are available today. While these treatments may be clinically available, consistent demonstration of efficacy is challenging. To improve treatments for retinal diseases, numerous technologies are in various stages of development. These new approaches include single-target therapy, dual-target / multi target therapeutics, technolog -based approaches for increasing drug durability and delivery', gene therapy, and stem cell therapy, among others.

[0004] A significant area of utility which has not been explored is the improvement or restoration of functional blood flow to the back of the eye. Another significant area of utility which has not yet been explored is direct choroidal and / or retinal delivery of therapies designed to treat retinal diseases.

[0005] Another significant area of utility' which has not been explored is direct choroidal and / or retinal delivery of therapies designed to treat retinal diseases.

[0006] The systems and methods of the present disclosure are directed to addressing one or more of the problems described herein.SUMMARY

[0007] In one aspect, a method for providing primary therapy to restore functional blood flow to a back of an eye, using a system comprising a guidewire, a microcatheter, and a treatment device, is described. The method may include advancing the guidewire through an access site in a subject to an ostium of an ophthalmic artery (OA) via an internal carotid artery (ICA), advancing the microcatheter to the ostium of the OA, retracting the guidewire into the microcatheter, such that a distal tip of the microcatheter assumes a pre-shaped configuration, advancing the microcatheter to cannulate a short limb of the OA, advancing the guidewire to a position approximately at or beyond a central carotid artery (CRA) branch of the OA, removing the microcatheter, advancing the treatment device over the guidewire to a lesion site in the OA of the subj ect, performing a treatment with the treatment device, and removing the treatment device and the guidewire from the subject.

[0008] In another aspect, a method for providing direct choroidal and / or retinal delivery of a therapeutic compound using a system comprising a guidewire, a microcatheter, and a treatment device, may include advancing a cannulating device through a frontal facial access site in a subject to an artery, delivering a pharmaceutical compound, via an injector and the cannulating device, to a location in the arteiy, thereby forming a column within the arteiy of the pharmaceutical compound and inducing retrograde blood flow' to branches of the arteiy ; and removing the injector, thereby' allowing antegrade blood flow' to resume and the pharmaceutical compound to be delivered via natural circulation of blood.BRIEF DESCRIPTION OF FIGURES

[0009] FIG. 1 show's an eye and vasculature near the back of the eye.

[0010] FIG. 2 shows a cross section of a retina of the eye.

[0011] FIG. 3 is a graph showing mean volumetric blood flow for different stages of age-related macular degeneration.

[0012] FIG. 4 shows the anatomy of the vasculature behind an eye of a human subject.

[0013] FIG. 5A depicts the general anatomy of the eye, and FIG. 5B is a detail view of a macula of the eye shown in FIG. 5A.

[0014] FIG. 6A is a digital image depicting the histopathology of a normal ophthalmic artery (OA), FIG. 6B is a digital image depicting the histopathology of a total occlusionOA, and FIG. 6C is a digital image depicting histopathology of a short limb of an OA with medial calcifications.

[0015] FIG. 7A is a digital image depicting the vasculature of a subject without age- related macular degeneration (AMD), and FIG. 7B is a digital image depicting the vasculature of a subject with AMD.

[0016] FIG. 8 depicts possible targets under consideration for WAMD anti-VEGF treatments.

[0017] FIG. 9 shows gene therapy areas of development.

[0018] FIGs. 10A to 10F are graphs illustrating data for visual acuity, showing mean letter gains of eyes subject to treatment and eyes not subject to treatment.

[0019] FIGs. 11 A to 1 IF are graphs illustrating data for choroidal thickness, showing mean choroidal thicknesses of eyes subject to treatment and eyes not subject to treatment.

[0020] FIG. 12 shows a continuum as AMD progresses from a healthy eye to hypoxia.

[0021] FIG. 13 shows a comparison of visual acuity over time with different treatments, including treatment according to the present disclosure.

[0022] FIG. 14A and FIG. 14B show comparisons of visual acuity improvement as a result of treatments according to the present disclosure, compared to stem-cell derived subretinal RPEE bleb inj ection.

[0023] FIG. 15 is a flowchart of a method of treatment according to the present disclosure.

[0024] FIG. 16 is an image of an eye receiving an intravitreal inj ection.

[0025] FIG. 17 shows methods of delivering drugs to the retina.

[0026] FIG. 18 A and FIG. 18B show' an example of delivery of superset ective drugs to a short posterior ciliary artery (SPCA).

[0027] FIG. 19 shows branches through w hi ch superselective delivery of drug therapies may occur.

[0028] FIG. 20 is a cone beam computed tomography (CBCT) image showing an overlay ed example of a GW and a microcatheter within the vasculature behind the eye.

[0029] FIG. 21 depicts an example of a GW for use in the systems and methods according to the present disclosure.

[0030] FIG. 22 depicts an example of a microcatheter for use in the systems and methods according to the present disclosure.

[0031] FIG. 23 depicts an example of a rapid exchange micro-balloon catheter with a dual balloon design, for use in the systems and methods according to the present disclosure.

[0032] FIG. 24 shows a drug delivery device including a micro-balloon, for use in the systems and methods according to the present disclosure.

[0033] FIG. 25 depicts a process of activating a drug using an external light source, which may be used with the systems and methods according to the present disclosure.

[0034] FIG. 26 demonstrates the approach of a microcatheter for drug or therapeutic delivery7, according to the present disclosure.

[0035] FIG. 27 is a flowchart showing a method of direct choroidal and / or retinal delivery of a therapeutic compound.

[0036] FIG. 28 shows retrograde induced flow upon delivery of a pharmaceutical compound according to the method show n in FIG. 27, and FIG. 29 shows antegrade flow upon removal of an injection, according to the method shown in FIG. 27.

[0037] FIG. 30 shows a dual chamber syringe design which may be used with the systems and methods of the present disclosure.DETAILED DESCRIPTION

[0038] Various embodiments of the present disclosure relate generally to systems and methods for restoring functional blood flow to the back of the eye, and systems and methods for providing direct choroidal and / or retinal delivery of a therapeutic compound.

[0039] As used herein, the singular forms '‘a,” “an,” and “the” include plural reference, unless the context dictates otherw ise. The terms “approximately” and “about” refer to being nearly the same as a referenced number or value. As used herein, the terms “approximately” and “about” generally should be understood to encompass ± 10% of a specified amount or value, unless otherwise specified. The use of the term “or” in the specification and in the claims is used to mean “and / or” unless explicitly7indicated to refer to alternatives only, or the alternatives are mutually exclusive, although the disclosure supports a definition that refers to only alternatives and “and / or.” As used herein, “another” may mean at least a second or more. As used herein, the terms “comprises,” “comprising,” “including,” “having,” or other variations thereof, are intended to cover a non-exclusive inclusion such that a process, method, sy stem, article, or apparatus that comprises a list of elements does not include only those elements, butmay include other elements not expressly listed or inherent to such a process, method, system, article, or apparatus. Additionally, the term “exemplary” is used herein in the sense of “example.” rather than “ideal.” In addition, the term “between” used in describing ranges of values is intended to include the minimum and maximum values described herein. The term “proximal” is used to describe the end of a device that is located closest to an operator of the device when using a device on a subject, and the term “distal” is used to describe the end of a device that is located closest to a subject on whom the device is being used and located farthest away from the operator.

[0040] The terms and expressions which are employed herein are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions excludes any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the disclosure claimed.

[0041] FIG. 1 shows an eye 100, as well as vasculature near the back of the eye, including the ophthalmic artery (OA) 105, the posterior ciliary arteries 110, and the central retinal artery (CRA) 115. FIG. 1 also shows a choroid 120 and a retina 125 of the eye 100. Blood flow requirements to the eye 100 are supplied by the OA 105, which is the sole functional blood supply to the eye 100. Of the blood supplied by the OA 105 to the eye 100, about 85% passes through the choroid 120. This choroidal blood flow rate is about 1400 mL / min per 100 g of tissue, which is more perfusion than seen in the kidney. The choroid 120, in turn, supplies blood to the chori ocapil laris 130, shown in FIG. 2. It is understood that the choriocapillaris 130 is important to the health and survival of the retina 125, in particular, the retinal pigment epithelium (RPE) 135 and photoreceptors (PRs) 140, both shown in FIG. 2. As humans age, impairment in blood flow to the choriocapillaris 130 not only reduces blood flow to the retina 125. but also allows for the accumulation of metabolic waste products. This impairment of the choriocapillaris 130 sets the stage for exacerbation, and possibly initiation, of various retinal diseases, particularly Age-Related Macular Degeneration (AMD). In the example of AMD, impairment of blood flow to the choriocapillaris 130 is most pronounced in the central macula (at a center of the retina 125), where AMD predominates and the metabolic rate is the greatest. The cellular composition of the macula has the highest metabolic rate anywhere in the human body.

[0042] FIG. 2 depicts a cross section of the retina 125 and demonstrates how blood from the choriocapillaris 130 supplies nutrients, via diffusion, to the RPE 135, which in turnsupplies nutrients to the PRs 140. Also depicted is the movement of waste in the direction of arrow A, from the PRs 140 to the RPE 135 and out through the choriocapillaris 130. It is worth noting that the high metabolic demand of the macula requires nutrients and waste removal be constant, and in equilibrium. This movement of nutrients into and waste out of the RPE 135 is driven by oxygen partial pressure, which is directly impacted by adequate functional blood supply.

[0043] In addition to compromised blood flow to the eye via the OA 105. occlusive carotid artery disease (OCAD) directly impacts functional blood flow by affecting orbital hemodynamics. As a result, severity of OCAD, collateral vascular pathways (such as the external carotid, superficial temporal, and supraorbital arteries), and concomitant systemic vascular diseases (such as aortic arch and aortic valve disease) are likely contributing factors to gross ocular blood flow efficiency, which directly influences the progression rate and severity of AMD and many other retinal diseases.

[0044] Continuing with the example of AMD, it is a multi-factorial, progressive, neurodegenerative disease of the macula that has been projected to affect an estimated 288 million humans globally by 2040. AMD accounts for approximately 8.7% of all blindness in humans worldwide and is the most common cause of permanent central vision blindness in humans in developed countries, particularly in humans older than 60 years. Contributing factors include aging, genetics, and environmental influences, such as cigarette smoking and diet. The prevalence of AMD is estimated at 2.1% in humans of 40 to 49 years of age. increasing dramatically to greater than 30% in humans over 80 years of age. It is present in all regions of the world, however more prevalent in regions of Europe and the Americas, more frequently involving humans of European descent and slightly less prevalent in Asia.

[0045] The loss of visual function experienced by patients with AMD can have a profound effect on their quality of life (QoL), and for numerous years, researchers have recognized the need to assess the QoL in these patients. Patients with AMD have reported QoL scores, emotional distress, and functional levels similar to those with severe chronic systemic disease, such as arthritis, acquired immunodeficiency syndrome (AIDS), congestive obstructive pulmonary disease (COPD), and bone marrow transplants. Interestingly, those with profound loss or blindness in one eye are reportedly significantly more distressed than those who are blind in both eyes. Patients with AMD are also more likely to need assistance in their daily lives. This loss of independence is an important factor in the association between AMD and clinical depression in thispopulation. Further, visual impairment in the elderly brings with it a statistically significant increase in the risk of falls that result in injury’.

[0046] AMD is characterized by the progressive loss of central vision with symptoms that include the distortion of images and straight lines, blurred vision characterized by difficulty reading and recognizing faces, difficulty seeing in dim light, especially when driving at night, and the eventual loss of the central visual field. The underlying pathophysiological drivers for AMD are complex and the symptoms are manifested in multiple related, but distinct, forms. AMD is typically bilateral and staged as early, intermediate, or late. In the early and intermediate stages, the disease is characterized by the deposition of drusen, protein, and lipid rich extracellular deposits between the RPE cells and Bruch’s membrane (BM). This version of the disease is typically referred to as non-exudative, or Dry AMD (DAMD) and generally starts in both eyes.

[0047] As part of normal disease progression of DAMD, areas of geographic atrophy (GA) develop and represent the late form of the disease. These areas of GA enlarge to eventually encompass the entire macula and correspond with retinal regions having significantly impaired visual function due to the loss of photoreceptors, RPE, and the underlying choriocapillaris. DAMD may take ten years or longer to progress from the early to the late form of the disease.

[0048] WAMD is a devastating version of macular degeneration and, if left untreated, may cause blindness days after initiation. While there are approved intravitreal (IVT) anti-vascular endothelial growth factor (anti-VEGF) treatments for WAMD that slow the abnormal vascular growth and thus vision loss, these treatments are temporary and serv e to convert the wet form of the disease back to the dry form. Unfortunately, vision loss due to symptoms from DAMD will continue. Current FDA approved DAMD treatment modalities are limited and currently include one complement 3 (C3) and one complement 5 (C5) inhibitor. These complement system (CS) inhibitors have been shown to slow progression as compared to baseline (no treatment) by 22% to 35% with no improvement in visual function. Confoundingly, the C3 inhibitor has also produced clinical results demonstrating no benefit over a sham (or placebo) injection. Prior to approval of these drugs, nutritional supplements were the only recommended therapy upon initiation of symptoms.

[0049] Studies investigating choroidal circulatory changes in patients with AMD have been performed, such as the relationship between choroidal blood flow (ChBFlow) and AMD, choroidal vascular changes and AMD, and fundus characteristics and theincreased risk of macular neovascularization (MNV). The lowest circulatory parameters were observed in the eyes with the highest risk for MNV development and trends for choroidal blood velocity (ChBVel) and ChBFlow were still significant after adjustment for multiple factors. Further, a study evaluating ocular microcirculation following carotid artery stenting (CAS) found a significant increase in blood flow in the ophthalmic artery (OA). In cases demonstrating retrograde flow of the OA prior to stenting, flow changed to antegrade following the CAS procedure. While patients displaying retrograde flow of the OA have a poor prognosis, CAS corrected the flow to antegrade, suggesting visual loss could be prevented by ocular microcirculation improvements. Another study examined the influence of carotid endarterectomy on choroidal perfusion. This study found a rapid and significant increase in ipsilateral mean choroidal thickness suggesting an improvement in choroidal perfusion within one week of the procedure.

[0050] To add to the current body of knowledge, research including extensive cadaver studies involving the dissection of OA specimens with known history of AMD was performed. Evaluation was specifically concentrated on the OA and internal carotid artery (ICA) complex. Narrowing and / or blockage at, in, and around the ostium of these specimens was consistently noted.

[0051] Additional histology assessments of lesion material from the OA / ICA ostium and ophthalmic artery complexes from cadavers (with reported history of both cardiac disease and AMD) were performed by an independent lab (CBSSET, Inc.. Lexington, MA, USA). Cross-sectional samples were evaluated under magnification and demonstrated notable multifocal and segmental changes in the OA and the ICA arteries in the form of both medial and intimal calcification, as well as neointimal proliferation. These changes are thought to directly impact the functional blood supply through the OA.

[0052] Based on these the cadaveric research data, a study involving patients diagnosed with advanced AMD, as well as age matched healthy controls (no AMD), utilizing High- Field Strength Noncontrast Magnetic Resonance Angiography (7T - Martinos Center, Boston, MA, USA), was performed. The results of this study demonstrated detectable differences between the two patient groups, with the AMD patients having less volumetric blood flow through the OA to the choroid than the healthy, age matched persons. While quantifying flow through the OA was the primary goal of this study, flow through the ICA was also investigated to assess whether any systemic vascularchanges may be associated with or contributing to AMD, or whether AMD-related vascular changes are restricted to the OA. The increase in the resistance index (RI) in both the ICA and OA, combined with the decreased OA volumetric flow as a percentage of ICA volumetric flow, suggests that there are both systemic and local vascular changes contributing to AMD.

[0053] FIG. 3 is a graph showing a mean volumetric flow, in mL / min, for a control group, and for groups of vary ing stages of AMD, namely , early AMD, intermediate AMD, and late AMD. This graph demonstrates that, as volumetric blood flow through the OA decreases, AMD disease severity increases. This observation is consistent with a previous study that found a significant increase in blood flow following CAS. This data identified the possibility of treatment strategies targeting the OA to restore blood flow to the retina in AMD patients.

[0054] As a result, it was hypothesized that stenosis or atherosclerotic changes in the short limb of the OA, at the ICA ostium, non-normal OA / ICA ostial anatomy , and / or lesions in the OA prevent a functional blood supply from reaching the choroid and could be a contributing factor of AMD advancement. This compromised blood flow decreases the amount of oxygen, glucose, and other nutrients reaching the choroid and is thought to cause the acceleration of vision loss in eyes with AMD. In addition, reduction of blood flow out of the choroid impacts the removal of metabolic waste products from the eye, which may directly contribute to disease progression as well as directly contribute to disease initiation. Blood flow impediment will also impact the ability of any AMD treatment strategy that relies on treatment of any portion of the retina without first addressing the underlying blood supply. To date, there are no approved strategies that focus on addressing functional blood flow to the eye as a method of disease treatment.

[0055] With reference to FIG. 4, anatomy of the vasculature behind an eye of a human subject will be described. FIG. 4 is a digital image showing the internal carotid artery (ICA) 400 and the ophthalmic artery (OA) 405, including the short limb (SL) 410 of the OA, an angle ’a’ 415 of the OA, a long limb (LL) 420 of the OA, an angle b’ 425 of the OA, and a distal part 430 of the OA. The OA 405 is an autoregulating, terminal branch of the ICA 400, and provides the functional supply of blood to the eye. FIG. 4 shows the OA 405 as a branch of the ICA 400, and depicts the arrangement of the OA 405, including the arrangement of the SL 410, the angle ‘a’ 416, the LL 420, the angle ‘b’ 425, and the distal part 430 of the OA 405, as it branches from the ICA 400 in a non-diseased vessel. The retina (not show n) is supplied with oxygenated blood by the OA 405, rests in the back of the eye, and contains approximately 126 million photoreceptors.

[0056] FIG. 5A depicts the general anatomy of the eye, particularly the anatomy associated with AMD, and FIG. 5B is a detail view of a macula of the eye shown in FIG. 5A. More specifically, FIG. 5A shows an eye 500 with a macula 505 located towards a back of the eye 500. FIG. 5B shows a detail view of the macula 505, a fovea 510, a retina 515. photoreceptor cells 520, a rod 525, and a cone 530 of the eye 500.

[0057] FIG. 6A is a digital image depicting histopathology of a normal OA 605A as it branches from an ICA 600 A, FIG. 6B is a digital image depicting histopathology of an OA 605B that is blocked at the ostium of the OA 605B and an ICA 600B by a lesion 610 (also referred to as a total occlusion OA), and FIG. 6C is a digital image depicting histopathology of an SL 615C of an OA 605C, with medial calcifications 620C. The images of vasculature of FIGs. 6B and 6C are from a subject diagnosed with AMD and would be targets for interventional treatments, such as treatments using the systems and methods of the present disclosure, to restore functional blood flow' to the eye.

[0058] FIG. 7A is a digital image depicting the vasculature of a subject without age- related macular degeneration (AMD), including an ICA 700A and an OA 705B, and FIG. 7B is a digital image depicting the vasculature of a subj ect with AMD, with an ICA 700B and an OA 705B. Note the OA 705B of the subject with AMD, shown in FIG. 7B, is blocked by stenosis 710.

[0059] Assessing blood flow of diseased arteries is ty pically accomplished via digital subtraction angiography' (DSA), in w hich the level of blockage, or stenosis is measured. Once measured, an endoluminal interventional procedure may be performed to open the vessel and restore blood flow. In the example of the OA in a patient with AMD, treatment may be indicated in cases where luminal stenosis is 50% or less. It has not been previously contemplated that treatment of lesions with less than 50% stenosis would be meaningful. As noted above, PRs are the most mctabolically active tissue in the human body and even a luminal stenosis of less than 50% can have a devastating effect on delivery of nutrients and removal of w aste and. therefore, survival of PRs.

[0060] Table 1 lists examples of OAs, including specific diameters, cross-sectional areas, percentage decrease in cross-sectional areas, and percentage stenosis based on the percentage decrease in cross-sectional areas. In particular, in example OA number 2. a 16.67% stenosis has an impact equivalent to a 30% reduction in cross-sectional blood flow area. Further, in example OA number 4, a 50% stenosis has a 75% reduction incross-sectional blood flow area. At least these two example OAs show that luminal stenosis of 50% or less can have an impact equivalent to a percentage to a percentage decrease in cross-sectional area of, for example. 40.56%, 55.56%, or 75%, and. therefore, a luminal stenosis of 50% or less can significantly affect blood supply to the PRs and likewise affect the removal of metabolic wastes, both of which contribute directly to disease progression and severity.TABLE 11. Current & Future Treatment Strategies

[0061] In the example of AMD, strategies to treat this devastating disease are grouped into two categories: 1) Neovascular or exudative AMD, generally referred to as wet AMD (WAMD) and 2) non exudative AMD, generally referred to as dry AMD (DAMD). WAMD is a late stage of the disease as is DAMD with geographic atrophy. The late stage of both variants is where conventional treatment strategies are focused. a. WAMD

[0062] Currently, the most effective strategies for treating WAMD are indicated for anti- vascular endothelial growth factor (VEGF) agents, such as ranibizumab, bevacizumab, aflibercept. brolucizumab. and faricimab. These anti-VEGF therapies were developed for and have transformed the treatment of WAMD. However, there remains an unmet clinical need for new and improved therapies for WAMD, since many patients do not respond optimally, may lose response over time, or may exhibit sub-optimal durability. Evidence is emerging that targeting VEGF- A alone, as these therapies do, may beinsufficient and using an approach that targets multiple pathways (e.g., aflibercept, faricimab and others in development) may provide a more efficacious result.

[0063] FIG. 8 depicts a few of the possible targets under consideration and the relational complexity seen in WAMD anti-VEGF treatments (i.e., what treatment do you choose?). Other agents using the VEGF system and alternate pathways may include heparin- binding variants of VEGF receptor 1, conbercept and various derived stem cells. Ultimately, a combination of approaches targeting the VEGF system with other processes may be needed to address the unmet need of WAMD. Clinical response to current VEGF based therapies in WAMD suggest that different pathways exist between individual patients (as noted in FIG. 8). Targeting more than a single pathway could improve response, prevent resistance, and enable personalized treatments for WAMD. It is noted, however, that none of these single, or possible combination anti-VEGF or VEGF variant approaches does anything to address the underlying issue of functional blood flow to the retina via the ophthalmic artery.

[0064] Additional efforts to address WAMD are focused on the development of gene therapies. These include proposing alternative targets for designing new WAMD treatment options and investigating genetic distribution of WAMD associated risk variants. However, comprehensive understanding of the particular genes and their pathways involved in early AMD is still exploratory.

[0065] FIG. 9 shows gene therapy areas of development currently underway, that is, gene therapy options, which again illustrates another layer of complexity in addressing AMD. Options include viral vectors, including gene replacement and gene augmentation, non-viral gene therapies, including chemical methods (i.e.. nanostructured lipid carrier (NLC)) and physical methods (i.e., electroporation), and alternative therapies, including transformation of the eye into a biofactory. It is noted, however, that none of these gene therapy approaches does anything to address the underlying issue of functional blood flow to the retina via the ophthalmic artery. b. DAMP

[0066] Currently approved treatment modalities available for DAMD include one C3 inhibitor and one C5 inhibitor (collectively, CS inhibitors). These CS inhibitors have been shown clinically to slow progression as compared to baseline (sham or placebo injection) by 22% to 35%. Confoundingly, another C3 study demonstrated no benefitover a sham or placebo inj ection. Prior to these drugs, nutritional supplements were the only recommended therapy once early signs of the disease were identified.

[0067] DAMD work is underway evaluating the use of differentiated cell lines to avoid some of the issues seen in past non differentiated stem cell use such as teratomas. The use of differentiated stem cells into RPE or photoreceptor cells has seen some limited success. In one example, a study saw five patients with an average of 4.4 letters Best Corrected Visual Acuity (BCVA) gain in 3 months as compared to baseline after retinal bleb inj ections of differentiated RPE cells in and around the macula.

[0068] There is also work in optimizing drug delivery, including the use of nanoparticles to deliver drugs in a topical manner to reduce the invasiveness of current injections. Additionally, targeting mitochondrial dysfunction in the RPE is also under consideration as a therapy.

[0069] While these potential therapies may address a portion of the AMD disease pathway, none of them do anything to address the issue of reduced blood flow to the eye via the ophthalmic artery. Without an improved baseline of functional blood flow, none of these strategies can provide the maximum benefit patients seek.2. Systems Methods of Treatment

[0070] A basic issue of AMD disease progression, and possibly disease initiation, is directly related to lack of functional blood flow to the retina via the OA. Research relating to the systems and methods of the present disclosure shows other retinal diseases may also benefit from restoration of functional OA blood flow to the retina. In clinical studies with AMD. stenosed segments of the OA were imaged, identified, and targeted with an interventional endovascular treatment, according to the systems and methods of the present disclosure. This treatment restored functional blood flow to the lumen of the OA.

[0071] In the case of treatment of an eye of a subject with DAMD, as a result of the systems and methods of treatment according to the present disclosure, the treated eye experienced improvements in visual acuity and choroidal thickness, while a fellow eye (i.e., an untreated eye) did not.

[0072] FIGs. 10A to 10F illustrate this data for visual acuity, showing the mean letter gains of eyes subject to treatment (study eyes) for different cohorts and the mean letter gains of eyes not subject to treatment (fellow eyes). Specifically, FIG. 10A is a graph showing mean letter gain from preop (before treatment) to week four after treatment forstudy eyes for a cohort of nine, FIG. 1 OB is a graph showing mean letter gain for the same time frame as in FIG. 10A for fellow eyes for a cohort of eleven, FIG. IOC is a graph showing mean letter gain from preop to three months after treatment, for study eyes for a cohort of four, FIG. 10D is a graph showing mean letter gain for the same time frame as in FIG. 10D for fellow eyes for a cohort of nine, FIG. 10E is a graph showing mean letter gain from preop to six months after treatment for study eyes for a cohort of three, and FIG. 10E is a graph showing mean letter gain for the same time frame as in FIG. 10E for fellow eyes for a cohort of four. In terms of results, FIG. 10A shows a 7.2 letter gain (about 1.4 lines) by four weeks after treatment, FIG. 10B shows stability of fellow eyes for the same time frame as in FIG. 10A, FIG. IOC shows an 8.4 letter gain (about 1.7 lines) by three months after treatment, FIG. 10D shows varying mean letter gain / loss for the same time frame as in FIG. IOC, FIG. 10E shows a 9.3 letter gain (about 2 lines) by six months after treatment, and FIG. 1 OF shows varying mean letter gain / loss in the same time frame as in FIG. 10E.

[0073] FIGs. 11 A to 1 IF illustrate this data for choroidal thickness, showing the mean choroidal thicknesses of study eyes for different cohorts and the mean choroidal thicknesses of fellow eyes. Specifically, FIG. 11 A is a graph showing mean choroidal thickness from preop to three weeks after treatment for study eyes for a cohort of eleven, FIG. 1 IB is a graph showing mean choroidal thickness for the same time frame as in FIG. 11 A for fellow' eyes for a cohort of eleven, FIG. 11C is a graph showing mean choroidal thickness from preop to three months after treatment for study eyes for a cohort of nine, FIG. 1 ID, is a graph showing mean choroidal thickness for the same time frame as in FIG. 11C for study eyes for a cohort of nine, FIG. 1 IE is a graph showing mean choroidal thickness from preop to six months after treatment for fellow eyes for a cohort of nine, and FIG. 1 IF is a graph showing mean choroidal thickness for the same time frame as in FIG. 1 IE for fellow eyes for a cohort of four. In terms of results, FIG. 11A shows a statistically significant increase in choroidal thickness of study eyes from preop to three weeks after treatment. FIG. 1 IB shows stability of fellow' eyes for the same time frame as in FIG. 11A, FIG. 11C shows a statistically significant increase in choroidal thickness of study eyes from preop to three months after treatment, FIG. 1 ID shows stability of choroidal thickness of fellow eyes for the same time frame as in FIG. 11C, FIG. 1 IE show s a statistically significant increase in choroidal thickness of study eyes from preop to six months after treatment, and FIG. 1 IF shows stability of choroidal thickness of fellow eyes for the same time frame as in FIG. 1 IE.

[0074] As demonstrated by the graphs shown in FIGS. 10A to 10F and 11 A to 1 IF, interventional treatment of the upstream OA blood supply to the eye according to the systems and methods of the present disclosure was performed, and resulted in statistically significant improvements in visual acuity, measured as mean letter gain, and choroidal thickness in the treated eye (or study eye) as compared the fellow or untreated, eye.

[0075] FIG. 12 shows the disease continuum as AMD progresses from a healthy eye, to a reduction in choroidal perfusion, to ischemia, and on to hypoxia. It is worth noting that the previously mentioned approved C3 and C5 inhibitors target CS expression late in the disease state. Treatments according to the systems and methods of the present disclosure can be administered anywhere in the disease process (that is. anywhere along the disease continuum), and will provide increased perfusion of the eye, which will treat many of the retina’s responses to ischemia and hypoxia before progressing to the point of needing pharmaceutical intervention. In the case of AMD, these conditions may range from mitochondrial dysfunction (a proposed future pharmaceutical target) to VEGF to complement inhibition (current FDA approved therapy for DAMD).

[0076] FIG. 13 shows a comparison of visual acuity over time with treatments, including treatment using Syfovre®, treatment using Izervay™, also referred to as the C3 and C5 inhibition drugs (or complement inhibitors) currently approved by the U.S. Food and Drug Administration (FDA) and treatment according to the systems and methods of the present disclosure (denoted as Ocudyne), over the course of at least six months, up to twelve months. As show n, the treatments according to the sy stems and methods of the present disclosure provide almost immediate visual acuity improvement, where the C3 and C5 inhibition drugs do not. Both complement inhibitors do not improve visual acuity, but rather slightly slow disease progression.

[0077] FIGs. 14A and 14B show comparisons of visual acuity improvement as a result of treatments according to the systems and methods of the present disclosure, as compared to a stem cell derived subretinal RPE bleb injection, over the course of at least six months. In particular. FIG. 14A shows a comparison of mean Early Treatment of Diabetic Retinopathy Study (ETDRS) change in BCVA treated eyes (solid line) and fellow eyes (dashed line), from preop to six months after treatment, and as a result, shows an increase in the mean ETDRS for the BCVA treated eyes during that time frame and a decrease in the mean ETDRS for the fellow eyes during that time frame. And FIG. 14B shows a comparison of mean ETDRS change in treated eyes (solid line)and in fellow eyes (dashed line) from preop to fifteen months after treatment, and as a result, shows an increase in mean ETDRS for treated eyes as compared to a decrease in mean ETDRS for fellow eyes during that time frame.3. Description of Systems and Methods of Treatment

[0078] Systems and methods of treatment according to the present disclosure may be used as part of a single therapy, a primary combination therapy, or a secondary7combination therapy for the improved treatment of retinal diseases, including any retinal disease where the reduced flow of blood may contribute to the reduction in the delivery of nutrients to the retina and the subsequent impainnent of the removal of waste products from the retina, such that the retinal disease process initiates and / or is exacerbated, with the therapy restoring functional blood flow to the eye. The use of the systems and methods of treatment as part of a therapy, either alone as a single therapy or as primary combination or secondary combination therapy, will restore functional perfusion to the eye and positively affect retinal disease symptoms to produce an improved treatment result as compared to the currently approved retinal therapies.

[0079] Retinal diseases for which use of the method of treatment as part of a single therapy, a primary combination therapy, or a secondary’ combination therapy may be applicable include, but are not limited to, the following: Wet Age Related Macular Degeneration (WAMD), Dry Age Related Macular Degeneration (DAMD), Primary Glaucoma (Open Angle Glaucoma, Normal Tension Glaucoma, Angle Closure Glaucoma. Congenital Glaucoma). Secondary Glaucoma (Neovascular Glaucoma, Pigmentary Glaucoma, Exfoliation Glaucoma, Uveitic Glaucoma), Retinitis Pigmentosa (RP), Diabetic Retinopathy (DR), Macular Edema (ME), Diabetic Macular Edema (DME), Optic Atrophy, Pathologic Myopic Choroidal Neovascularization (pmCNV), Branch Retinal Vein Occlusion (BRVO), Central Retinal Vein Occlusion (CRVO), Branch Retinal Artery Occlusion (BRAO), Central Retinal Artery Occlusion (CRAO). Arteritic and non-Arteritic Anterior Optic Ischemic Neuropathy (AION), Posterior Ischemic Optic Neuropathy (PION), Amaurosis Fugax, and Central Serous Retinopathy.

[0080] Therapies and therapeutic compound families for which the systems and methods of treatment of the present disclosure may be used as part of a single, primary’ combination, or secondary combination therapy include, but are not limited to:1. Anti-VEGF primary drugs or compound families and targeting therapies (or equivalents) such as, but not limited to: Intravitreal injections of anti-VEGFVEGF-A), Bevacizumab (full antibody - all forms of VEGF -A). Aflibercept (recombinant fragment crystallizable (Fc) fusion protein - VEGF-A. VEGF-B). Placental Growth Factor (PIGF), Conbercept (recombinant fragment crystallizable (Fc) fusion protein - VEGF-A, VEGF-B), placental growth factor (PIGF), Brolucizumab (single chain variable fragment antibody) - VEGF-A, Ziv- Aflibercept (VEGF), Conbercept (VEGF). and Abicipar pegol (based on the designed ankyrin repeat proteins (DARPins) against VEGF-A). Eye drop formulations of ty rosine kinase inhibitors (TKI) (Pazopanib), statins (Atorvastatin) and corticosteroid. In general, compounds including monoclonal antibodies (MABs) and non-MABs would be useful in this application. Biosimilar AntiVEGF (not listed, but including generics) such as, but not limited to: Ranibizumab Biosimilar - SB11, Ranibizumab Biosimilar - FYB201, Aflibercept Biosimilar - ABP938, Aflibercept Biosimilar - FYB203, Aflibercept Biosimilar - SB 15, as well as non-MAB compounds. Complement cascade therapies for the classical, lectin and alternative pathways such as, but not limited to: Lampalizumab - Anti-factor D antibody, Avacinacaptad - C5 inhibitor or CS inhibitor, Pegcetacoplan - C3 inhibitor, Eculizumab - anti C5 antibody or anti-CS inhibitor, LFG316 - C5 Antibody or CS antibody, Combination - Avacinacaptad + ranibizumab, Therapies directed to specifically treat complement factors H, B and I, complement components 3 and 2, susceptibility' 2 / high temperature requirement protein Al (ARMS2 / HTRA1) gene regions or any combination thereof. Dual Target Therapeutics such as, but not limited to: Faricimab - Anti VEGF and angiopoiten-2 (Ang-2) agonist / antagonist TIE2 receptor tyrosine kinase context dependent, Pegpleranib - DNA aptamer bonds to platelet derived growth factor (PDGF) binds to receptors on pericytes added to aflibercept or bevacizumab. Multiple Target Therapeutics (3+): This approach would combine 3 or more therapeutics with the goal of achieving a synergistic action to improve outcomes. A synergistic effect is observed w hen two or more drugs interact and produce an enhanced effect when compared to the sum of their individual effects. A synergetic interaction allow s for a lower dose of individual drugs, which may reduce adverse effects. Combination therapies such as anti-VEGF agents togetherwith photodynamic therapy, and anti-VEGF agents along with corticosteroids have been used previously and are known to be effective. Technology Based Delivery Systems such as, but not limited to: Port delivery system - ranibizumab (refillable reservoir) encapsulated in membrane genetically engineered cell line with encapsulated cell technology NT-501 - Ciliary neurotrophic factor (CNTF) — genetically modified human RPE cell line, laser photocoagulation, photo biomodulation (stimulates response, does not destroy tissue), photodynamic therapy (destroys cells) and photopharmacology. Gene Therapies such as, but not limited to: a. Adeno associated virus-based gene therapy NON-AMD - Retinoid isomerhydrolase RPE65 - encoded protein bilateral subretinal vortigene neparvovecrzyl AAV2-hRPE65v2 - gene replacement, CHM gene encodes RAB escort protein 1 (REP1) - facilitates intracellular protein trafficking via preny lation and membrane expression of the RAB protein. b. Adeno associated virus-based gene therapy AMD - AAV8 vector encoding a fragment of a monoclonal targeting VEGF (RGX-314 antibody targeting VEGF), ADVM-022 AAV.7m8 vector, GT005 recombinant non-replicating AAV encoding human complement factor I (CFI). Non-viral vector gene therapies such as, but not limited to: 17-mer antisense RNA-based oligonucleotide named sepofarsen. Stem Cell Based Therapies such as, but not limited to: Human embryonic stem cells (hESCs), Induce pluripotent stem cells (iPSCs), Somatic stem cells (derived from bone marrow, adipose tissue, central nervous system cells), RPE transplantation (hESC derived RPE cells) into subretinal space, PR transplantation (hESC derived PR cells) into subretinal space. Artificial Vision Therapies such as, but not limited to: Multi characteristic opsin - intravitreal injection of virus encoding a light sensitive ion channel that targets bipolar cells vMCO-010, Optogenetic vector GS030 drug product - real time activation of optogenetically transduced retinal ganglion cells. Mitochondrial Dysfunction Therapies such as, but not limited to: Ampk -AMP activated protein kinase, Mitochondrial fusion / fission inhibitor / enhancement, Suppression of chronic oxidative stress and inflammation in RPE.12. Retinal Prostheses Therapies such as, but not limited to: Epiretinal, Subretinal or Suprachoroidal device placement.

[0081] In one embodiment, a system for primary therapy via femoral or radial access may include a micro-balloon angioplasty catheter, a microcatheter, and a guidewire (GW). However, in one or more alternative embodiments, another treatment device may be used in place of the micro-balloon angioplasty catheter. The system may be configured to work with devices and procedures normally associated with interventional neuro procedures performed by an interventional neuroradiologist. The system may also be configured to specifically navigate and access the anatomy associated with the OA. With reference to FIG. 15, a method 1500 according to one embodiment may include, under neuro interventional imaging, a step 1505 of placing the GW inside the microcatheter and a step 1510 of advancing or navigating the GW through an access site in a subject to the ostium of the OA via the ICA. The access site may be a femoral artery or a radial artery. Then, in step 1515, the microcatheter may be advanced to the ostium of the OA. and, in step 1520, the GW may be pulled back or retracted into the microcatheter. As a result of retraction of the GW in step 1520, the distal tip of the microcatheter may then assume a pre-shaped configuration, which may be specifically formed to allow easy access into the short limb (SL) of the OA. Then, in step 1525, the microcatheter may be advanced to cannulate the SL of the OA, and in step 1530, the GW may be advanced to a position approximately at or beyond the central retinal artery (CRA) branch of the OA. The microcatheter may then be removed in step 1535, and, in step 1540, the micro-balloon angioplasty catheter may be positioned over the GW and advanced or navigated to a lesion site. As a step 1545 of performing treatment with the device, the micro-balloon angioplasty catheter may be inflated to a predetermined pressure over a predetermined time, to. for example, dilate a lesion at the lesion site in the OA. This step may be repeated one or more times, as necessary, to treat any narrowing of the lumen of the OA, such as narrowing caused by a lesion. Once the dilatation of the lesion is complete, in step 1550, the micro-balloon angioplasty catheter and the GW may be removed, and the method 1500 may end. Although the method 1500 is described as including steps 1505 to 1550, the method 1500 may include additional steps or a subset of these steps.

[0082] Other interventional therapies (including other treatment devices) may be substituted for the micro-balloon angioplasty catheter as part of the system and the method to provide treatment to an affected area. These other interventional therapiesmay include, but are not limited to, angioplasty balloons of various shapes and compliances, delivery of energy (i.e., heat, ultrasound, radio frequency), delivery of antirestenosis compounds via drug coated balloon (i.e., sirolimus, paclitaxel, luten). lesion debulking devices (i.e., directional atherectomy, Optical Coherence Tomography (OCT) guided atherectomy, laser excimer atherectomy, Chronic Total Occlusion (CTO) devices), cutting or scoring angioplasty balloons, intra-arterial brachytherapy, and stenting.

[0083] The system and method described herein as a primary therapy may provide a primary treatment for DAMD. The system and method also have the potential to provide a primary treatment for WAMD. Currently, the primary treatment for WAMD consists of injections of an anti-VEGF compound directly into the globe of the eye. The anti- VEGF compound is typically suspended in the vitreous and from there diffuses into the retina. While anti-VEGF therapy can effectively treat WAMD, there are several serious potential complications related to use of the drug. These include, but are not limited to, repeated injections may cause structural changes (thinning) to the sclera, reduction in diameter of retinal and choroidal vessels, significant reduction in choroidal thickness, decrease in capillary density, decrease in choroidal blood flow and velocity, hemorrhage, retinal detachment, degeneration of photoreceptors (PRs), cataract formation, increase in geographic atrophy (GA) progression of up to 1.35 times greater than without, persistent intraocular pressure (IOP) increases, retinal pigment epithelium (RPE) tears, high costs, limited efficacy, and patient compliance issues.

[0084] In another embodiment, a system and a method may be used as part of a primary7combination therapy via femoral or radial access. In such an embodiment, the system is used as described above, and as in the method 1500 described above, as a primary treatment method, but with changes incorporated that provide for the ability to superselecli vely deliver an additional therapeutic modality7directly to the back of the eye via the OA. Specifically, a therapeutic modality may be a pharmaceutical composition intended to treat a particular retinal disease. It may be appreciated that in the pharmaceutical treatment paradigm of treating retinal diseases such as, but not limited to, AMD. drug delivery7for the treatment of AMD is typically performed via intravitreal inj ection in the inferotemporal quadrant of the eye, as seen in the image of FIG. 16.

[0085] In the example of intravitreal injections, these injections place specifically fonnulated compounds (i.e., anti-VEGF, CS inhibitors, gene therapies) directly into the vitreous area to allow drug diffusion into the retinal tissue. These compounds arespecially formulated with a particular carrier and a particular active concentration to provide therapy. In addition, there are various other methods of delivering drug(s) (or pharmaceutical compound(s)) to the retina. These include, with reference to FIG. 17, suprachoroidal delivery with a needle 1700, port delivery systems 1705, topical (drops) 1710, subconjunctival delivery 1715, subretinal delivery 1720, and suprachoroidal delivery with a cannula 1725, in addition to intravitreal delivery 1730.

[0086] Delivering a specially formulated drug via super selective cannulation of an artery allows for precise delivery in such a manner as to optimize the treatment of a target tissue in an immediate fashion. A similar method is used to deliver chemotherapy drugs in the treatment of retinoblastoma. In the retinoblastoma example, superselective OA chemotherapy is used to deliver 90% less of the chemotherapy drug directly to the eye as compared to the amount needed for systemic treatment. This provides a much safer technique with minimum systemic toxicity and a very low complication rate. Typical sy stemic dosing rates for Bevacizumab range from 5 to 15 mg / kg every’ 2 or more weeks, while intravitreal Bevacizumab dosing rates are 1.25 mg / 0.05 ml per injection with a typical injection time frame of every 3 w eeks. In the case of AMD, delivering drugs via a superselective method places the drugs in an artery7that directly supplies the choroid. FIGs. 18A and 18B depict an example of delivery of superselective drugs to the short posterior ciliary artery (SPCA). In particular, FIG. 18A shows a choroid 1800 of an eye. RPE cells 1805, Bruch’s membrane 1810, PRs 1815, Drusen 1820, fluid accumulation and vascular leakage 1825, neo-vascul arization 1830, and a treatment target 1835. FIG. 18B shows a short posterior ciliary artery (SPCA) 1840. The SPCA 1840 is cannulated via the OA 1845, and drugs are delivered into the SPCA 1840, from which they flow directly into the choroid 1800. This pathway is not subject to the same drug transfer restrictions of the blood retinal barrier (BRB) as seen with intravitreal injections.

[0087] In addition to delivering a drug via superselective delivery’ to the SPCA, there are other OA branches that are also suited for superselective delivery of drug therapies. Several of these branches provide pathw ays to the inner and outer retinal layers via the OA 1900. With reference to FIG. 19, these branches include, but are not limited to, dorsal nasal artery 1905, supratrochlear artery 1910, supra-orbital artery71915, central retinal artery 1920, and short posterior ciliary arteries 1925.

[0088] In another embodiment in which the system and method of the present disclosure are used as part of a primary combination therapy, balloon angioplasty may beperformed, as previously described, as a primary therapy. Once complete, a GW may be used to navigate to the desired distal segment of the OA, such as the central retinal artery (CRA). intended for drug treatment, as a secondary treatment target. This example is not limiting, and other arteries as mentioned previously could be the target. A specially designed microcatheter may be placed over the GW and navigated to the origin of the CRA. The microcatheter may be advanced into the ostium of the CRA and a specially formulated drug compound may be injected into the microcatheter so that the drug exits the distal tip of the microcatheter and enters the CRA. Once in the CRA, the drug may then be carried by blood flow to the inner retina target. This direct delivery’ of the compound to the arteries undergoing a disease process will result in an immediate response to the delivered compound.

[0089] FIG. 20 is a cone beam computed tomography (CBCT) image showing an overlay ed example of a GW 2000 advanced down an OA 2005 to an ostium of the OA 2005 and a CRA 2010, with a microcatheter 2015 advancing over the GW 2000, down the distal part of the OA 2005. The inset (left side of FIG. 20) shows the microcatheter 2015 positioned in the ostium of the OA 2005 and the CRA 2010 ready to deliver therapy.

[0090] An important consideration in the use of the system and method of the present disclosure is the design and formulation of drugs that are optimized to work when administered via superselective delivers’. These drugs must consider bioavailability, dosage, and viscosity as examples of a few, but not all, design parameters to maximize the therapeutic results while minimizing side effects. One of the most severe side effects of intravitreal injections is endophthalmitis, which is an inflammation of the interior cavity of the eye and can result in loss of vision or loss of the eye itself. In a recent study, the rate of infection was 0.185% over a 9- year period. The use of superselective delivery of a therapeutic, such as Bevacizumab, will have an immediate and significant effect on the target tissue while eliminating the possibility of endophthalmitis. This approach may be combined with subsequent intravitreal injection as well, to maximize the benefit to the patient.

[0091] In another embodiment in which the system and method of the present disclosure is used as a secondary combination therapy via femoral or radial access, the system is used as described above, and as in the method described above, but with changes incorporated that provide for treatment of retinal disease by superselective deliveiy asthe primary therapy. In this embodiment, the need to treat intralumenal stenosis in the OA may not be necessary, but the delivery of therapeutic to various segments of the retina is desired. The system may incorporate, but is not limited to. specialized devices designed to access distal anatomy of the OA via an intravascular approach from the ICA, such as a GW, a microcatheter, and micro-balloon catheter.

[0092] In the case of the GW, it is designed to consider the unique anatomy of the OA as it branches from the ICA and to facilitate access to the OA, placement in the distal OA for purchase, and support to allow for various intravascular instruments to be delivered over it. Features of such design of the GW may include, but are not limited to, materials, processing, coatings, taper placement, diameters, coil placement, tip shape, radiopacity profile and overall device construction. The GW may function as a typical GW, but also may have a provision to allow for placement in a distal OA branch and to allow for the delivery of drugs through the GW and out of the tip segment, so that medication can be delivered superselectively. FIG. 21 depicts a non-limiting example of a GW designed specifically for OA access and subsequent delivery of a drug via the distal segment of the GW. In particular, FIG. 21 shows a GW 2100 having a distal tip 2105, a first segment 2110 having a diameter of, for example, about 0.0254 cm (about 0.010 inch) and a length of, for example, about 2 cm (about 0.787 inch), a plurality of marker bands 2115, a shaping segment 2120, a distal coil segment 2125, having a length of about 7 cm (about 2.756 inches) and. for example, being formed of a radioopaque (RO) material, a second segment 2130 having a diameter of, for example, about 0.030 cm (about 0.012 inch) and a length of, for example, about 5 cm (about 1.969 inches), a hypotube 2135 having a diameter of, for example, about 0.0356 cm (about 0.014 inch), and one or more openings or holes 2140 for injections, for example. The GW may also have a polymer coating 2145 over the distal coil segment 2125.

[0093] In the case of the microcatheter, it is designed to work with the GW to allow for specific placement within the OA, particularly' the distal branches including, but not limited to, short and long posterior ciliary, lacrimal, and central retinal arteries. Features of such microcatheter design may include, but are not limited to, materials, processing, coatings, polymer design, diameters, tip shape, radiopacity' profile and overall device construction. The microcatheter may function as a typical microcatheter, but, in one or more alternative embodiments, the microcatheter also may have design provisions to allow for specific placement in a distal OA branch and to allow for the delivery of drugs through the microcatheter and out of the tip segment so that medication can be deliveredsuperset ectively. FIG. 22 depicts anon-limiting example of a microcatheter 2200 designed to work with the above-mentioned GW and to allow for positioning in the distal OA or previously mentioned branches thereof. In this embodiment, the microcatheter 2200 may have a radioopaque tip 2205, and a diameter of the top may be about 0.0508 cm (about 0.020 inch).

[0094] The micro-balloon catheter may be designed to work with the GW to allow for specific placement within the OA. particularly the distal branches including, but not limited to, short and long posterior ciliary, lacrimal, and central retinal. Features of such micro-balloon catheter design may include, but are not limited to, materials, processing, coatings, polymer design, balloon design, diameters, tip shape, radiopacity profile, and overall device construction. In addition, the micro-balloon catheter may be designed with one or more balloons, some of which may be used to dispense medication. As a non-limiting example, the micro balloon catheter may be designed such that one balloon may be used to perform angioplasty’ and / or aid in directing the flow of medication, w hile another balloon is used to dispense pharmaceutical compounds or drugs out through micro-holes or fenestrations. The balloon catheter design may be available in coaxial or rapid exchange designs. In the case of the coaxial design, it may7also be possible to deliver therapeutics via the inner lumen to the target anatomy. FIG. 23 depicts a nonlimiting example of a rapid exchange micro-balloon catheter 2300 with a dual balloon design to facilitate use as described. In particular. FIG. 23 shows the rapid exchange micro-balloon catheter 2300 having a drug delivery balloon 2305 and an angioplasty' balloon 2310.

[0095] In another embodiment in which the system and method of the present disclosure are used as part of a secondary combination therapy, a dedicated drug delivery device may be used in combination with the system and the method described above. In one non-limiting example, a micro-balloon, as part of a dedicated drug delivery' device, may' be specifically designed deliver drugs to a target artery by inflating the micro-balloon and pushing the drugs out through micro-holes or fenestrations in the micro-balloon, as depicted in FIG. 24. In particular, FIG. 24 show s a drug delivery device 2400 including a micro-balloon 2405, with micro-holes 2410 therein.

[0096] Photopharmacology has recently been used to irradiate and trigger photoactivable nano system based anti-VEGF drugs administered intravenously (IV) for the treatment of AMD. A photopharmacology drug was developed by combining the base treatmentdrug with a photosensitizer. This combination drug was administered via IV and activated by irradiating the eye with a 690 nm light source.

[0097] In another embodiment, photopharmacology may be combined with drug delivery via the system and method of the present disclosure. In this embodiment, the drug may be delivered to a specific site via superselective catheterization, dispensed to the target, and activated via an external light source. This method would provide an improved result, with a smaller drug dose and less systemic toxicity as compared to the IV method. FIG. 25 depicts a process of activating a drug 2505 dispensed to a target, and using an external light source 2500 to prevent survival, migration, and vessel sprouting related to neo genesis.

[0098] In yet another embodiment, the system and method according to the present disclosure may, by avoiding femoral or radial access, reduce procedural time and related complications. In this embodiment, access to the target areas of the OA and branches is provided via frontal facial access. This route allows for access using very low-profile, short length devices through terminal branches of the OA including, but not limited to, the supratrochlear, supraorbital, and dorsal nasal arteries. These branches provide access to the CRA and posterior ciliary arteries via retrograde OA travel. Therapeutic treatment to the inner retina and choroid may be provided as previously discussed using these approaches. FIG. 26 demonstrates the approach of a microcatheter 2600 entering the supratrochlear artery 2605, and advancing in a retrograde fashion down the OA 2610 to the posterior ciliary artery 2615, and cannulating the posterior ciliary artery' 261 for drug or therapeutic delivery'.

[0099] In the above embodiment, the drug or therapeutic may be specifically formulated to enable delivery through a small gage device and into the target location. This methodology would greatly simplify the interventional procedure such that the treatment may be performed as an outpatient procedure with a minimal wound entry site.

[0100] In another embodiment, the system and method according to the present disclosure may be used with frontal facial access, as previously described, to provide direct choroidal and / or retinal delivery of a therapeutic compound. FIG. 27 shows a method 2700 according to this embodiment, in which, in step 2705, a small caliber device, including a guidewire and a catheter, may be used to cannulate the selected artery and, in step 2710, a compound may be injected into the cannulated artery'. This injection would induce retrograde blood flow in that artery, such that the compound would form a column in the artery. Using an injector, the column may be pushed in aretrograde fashion past the desired branches for delivery. Then, in step 2715, the injector may then be removed, antegrade flow may resume, and the compound may be carried to the desired retina and / or choroidal location via natural circulation. The cannula may be left in place for additional injections. FIGs. 28 and 29 depict this approach, with FIG. 28 showing retrograde induced flow w ith arrows, and delivery of a compound 2800 past the branches for delivery, and FIG. 29 showing antegrade flow with arrows, and delivery of the compound 2900 to targets via the branches for delivery .

[0101] In one or more of the embodiments described above, the use of a specifically designed syringe or inflation device may be included for dispensing medication and a carrier in an appropriate concentration. In such a modified embodiment, the drug and saline (or other carrier) may be placed in separate chambers of a combination chamber device. FIG. 30 shows a dual chamber syringe 300, in a closed state B and in an open state C, as an example, which may be used with the drug being preloaded into one chamber of the dual chamber syringe 300, such that the proper concentration and amount of the drug may be dispensed from the syringe 300, through the devices of the system, to a target location, according to embodiments of the present disclosure.

[0102] Other embodiments of the disclosure will be apparent to those skilled in the art from consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

Claims

CLAIMSWe claim:

1. A method for providing primary therapy to restore functional blood flow to a back of an eye, using a system comprising a guidewire, a microcatheter, and a treatment device, the method comprising: advancing the guidewire through an access site in a subject to an ostium of an ophthalmic artery (OA) via an internal carotid artery (ICA); advancing the microcatheter to the ostium of the OA; retracting the guidewire into the microcatheter, such that a distal tip of the microcatheter assumes a pre-shaped configuration; advancing the microcatheter to cannulate a short limb of the OA; advancing the guidewire to a position approximately at or beyond a central carotid artery (CRA) branch of the OA; removing the microcatheter; advancing the treatment device over the guidewire to a lesion site in the OA of the subject; performing a treatment with the treatment device; and removing the treatment device and the guidewire from the subject.

2. The method according to claim 1, wherein the treatment is performed two or more times.

3. The method according to claim 1, wherein the treatment device is a micro-balloon angioplasty catheter device.

4. The method according to claim 3, wherein the step of performing the treatment includes inflating a micro-balloon of the micro-balloon angioplasty catheter device to a predetermined pressure.

5. The method according to claim 4, wherein the micro-balloon is inflated for a predetermined amount of time.

6. The method according to claim 1, wherein the treatment device is one of a heatdeliver}' device, an ultrasound deliver}' device, or a radio frequency device.

7. The method according to claim 1, wherein the treatment device is a device configured to delivery anti-restenosis compounds via a drug-coated balloon.

8. The method according to claim 1, wherein the treatment device is a lesion debulking device.

9. The method according to claim 1, wherein the treatment device is a cutting or scoring angioplasty balloon device.

10. The method according to claim 1, wherein the treatment device is a stent.

11. The method according to claim 1 , wherein the access site is one of a femoral artery and a radial artery.

12. A primary combination method for providing pnmary combination therapy to a subject, using a system comprising a guidewire, a microcatheter, and a treatment device, the primary combination method comprising: performing the method of claim 1. as a primary treatment method; and delivering a therapeutic modality directly to the back of the eye of the subject via an ophthalmic artery (OA) of the subject, after performing the method of claim 1.

13. The primary combination method according to claim 12, wherein the therapeutic modality comprises a pharmaceutical composition configured to treat age-related macular degeneration (AMD).

14. The primary combination method according to claim 13, wherein the pharmaceutical composition is delivered via intravitreal injection in an inferotemporal quadrant of the eye.

15. The primary combination method according to claim 12, wherein the therapeutic modality comprises delivering a pharmaceutical compound to a retina of the eye using one of: suprachoroidal delivery with a needle, a port delivery system, topical drops, subconjunctival delivery, subretinal delivery, and suprachoroidal delivery with a cannula.

16. A secondary combination method for providing secondary combination therapy to a subject, using a system comprising a guidewire, a microcatheter, and a treatment device, the secondary combination method comprising: delivering a therapeutic modality directly to the back of the eye of the subject via an ophthalmic artery’ (OA) of the subject; and performing the method of claim 1. as a secondary treatment method after delivering the therapeutic modality to the back of the eye.

17. The secondary combination method according to claim 16, wherein the therapeutic modality comprises a pharmaceutical composition configured to treat age-related macular degeneration (AMD).

18. The secondary combination method according to claim 17, wherein the pharmaceutical composition is delivered via intravitreal injection in an inferotemporal quadrant of the eye.

19. The secondary’ combination method according to claim 16, wherein the therapeutic modality comprises delivering a pharmaceutical compound to a retina of the eye using one of: suprachoroidal delivery with a needle, a port delivery system, topical drops, subconjunctival delivery, subretinal delivery, and suprachoroidal delivery with a cannula.

20. A method for providing direct choroidal and / or retinal delivery of a therapeutic compound using a system comprising a guidewire, a microcatheter, and a treatment device, the method comprising: advancing a cannulating device through a frontal facial access site in a subject to an artery; delivering a pharmaceutical compound, via an injector and the cannulating device, to a location in the artery, thereby forming a column within the artery of the pharmaceutical compound and inducing retrograde blood flow to branches of the artery; and removing the injector, thereby allowing antegrade blood flow to resume and the pharmaceutical compound to be delivered via natural circulation of blood.

Images