What is choroidal neovascularization?
Choroidal neovascularization (CNV) is a serious ocular condition in which new, abnormal blood vessels form from the choroid layer beneath the retina. These new blood vessels break through the Bruch’s membrane and invade the subretinal space, causing significant vision impairment or even loss if not treated. CNV is most commonly associated with age-related macular degeneration (AMD), but it can also occur as a result of pathological myopia, ocular histoplasmosis syndrome, or angioid streaks.
Patients with CNV frequently experience symptoms such as blurred or distorted vision (metamorphopsia), dark spots in their vision (scotomas), and reduced visual acuity. These symptoms occur because abnormal blood vessels can leak fluid and blood into the retina, causing swelling, scarring, and damage to the retinal cells that are responsible for clear central vision. A comprehensive eye examination is usually required to diagnose CNV, which includes imaging techniques such as fluorescein angiography, optical coherence tomography (OCT), and, in some cases, indocyanine green angiography to visualize abnormal blood vessels and assess the extent of retinal damage.
Understanding the underlying mechanisms of CNV and their potential impact on vision is critical for successful management. While traditional treatments have been the mainstay for managing CNV, ongoing research and technological advancements have resulted in the development of novel therapies aimed at improving patient outcomes in this difficult condition.
Standard Treatments for Choroidal Neovascularization
The traditional management and treatment of choroidal neovascularization focuses on halting or slowing the growth of abnormal blood vessels, reducing leakage and bleeding, and maintaining vision. CNV treatment has traditionally relied on anti-vascular endothelial growth factor (anti-VEGF) therapy, photodynamic therapy (PDT), and laser photocoagulation.
Anti-VEGF Therapies:
Anti-VEGF therapy is currently the most effective treatment for CNV. VEGF is a protein that stimulates the development of new blood vessels. These therapies, which inhibit VEGF, aim to prevent the formation of new abnormal vessels while also reducing leakage from existing ones. The most widely used anti-VEGF drugs are:
- Ranibizumab (Lucentis): An antibody fragment that binds to and inhibits VEGF-A when injected intravitreally.
- Bevacizumab (Avastin): Although originally approved for cancer treatment, bevacizumab is now used off-label for CNV due to its similar mechanism of action to ranibizumab.
- Aflibercept (Eylea): A fusion protein that functions as a decoy receptor for VEGF-A, VEGF-B, and placental growth factor (PlGF), providing a broader inhibition of neovascular growth.
These drugs are typically administered as intravitreal injections at regular intervals, beginning with monthly injections and progressing to a treat-and-extend approach based on the patient’s response.
Photodynamic Treatment (PDT):
PDT is another well-established treatment for CNV, especially when anti-VEGF therapy is not appropriate or effective. PDT involves the intravenous administration of verteporfin, a photosensitizing agent. After the drug accumulates in the abnormal blood vessels, the eye is exposed to a non-thermal laser light, which activates the drug and selectively damages the neovascular tissue while sparing the surrounding healthy retinal cells. PDT can effectively reduce leakage and prevent further vision loss, but it is less widely used today due to the efficacy of anti-VEGF therapies.
Laser photocoagulation:
Laser photocoagulation was among the first treatments for CNV. This technique uses a high-energy laser to burn the retina and choroid, sealing leaking blood vessels and destroying abnormal neovascular tissue. While effective in some cases, laser photocoagulation is frequently limited to extrafoveal CNV (CNV that is not directly beneath the central macula) due to the risk of damaging central vision. Anti-VEGF therapies have largely replaced laser photocoagulation as a treatment for CNV.
Supportive care:
In addition to these specific treatments, supportive care is essential for managing CNV. Patients are frequently advised to monitor their vision on a regular basis using tools such as the Amsler grid, as well as to live a healthy lifestyle that includes quitting smoking and managing cardiovascular risk factors, which can influence the progression of CNV and AMD.
While conventional treatments have significantly improved the management of CNV, ongoing research is looking into new and innovative approaches to improve treatment outcomes and address current therapies’ limitations.
Recent Advances in Choroidal Neovascularization Management and Treatment
The management and treatment of choroidal neovascularization are rapidly changing, with numerous novel therapies and technologies being developed to improve patient outcomes. These advancements include novel pharmacological agents, cutting-edge drug delivery systems, advanced imaging techniques, and emerging therapies that target the molecular mechanisms of CNV.
- New Anti-VEGF Agents:
a. Brolucizumab (Beovu): A newer anti-VEGF agent that has longer dosing intervals than other therapies. Brolucizumab is intended to be administered less frequently, potentially lowering the treatment burden on patients while maintaining efficacy in controlling CNV.
b. Abicipar Pegol: Abicipar pegol, another promising anti-VEGF drug under investigation, has shown potential for extended dosing intervals and improved treatment effect durability, making it a viable alternative to current anti-VEGF therapies.
2. Combined Therapies:
Combining anti-VEGF agents with other therapeutic approaches is an emerging strategy for improving treatment efficacy and addressing the complexities of CNV.
a. Anti-VEGF and Anti-Angiopoietin 2 (Ang-2) Treatments: Ang-2 is another important regulator of angiogenesis. In clinical trials, combining anti-VEGF therapy with anti-Ang-2 agents, such as faricimab, yielded promising results. This dual approach targets multiple neovascularization pathways, with the potential to provide more comprehensive CNV control.
b. Anti-VEGF and Steroid Treatments: Combining anti-VEGF injections with corticosteroids such as dexamethasone can help reduce inflammation and improve anti-angiogenic effects, resulting in better outcomes for some CNV patients.
- Gene Therapy:
Gene therapy is a novel approach to providing long-term treatment for CNV by delivering genes that produce therapeutic proteins directly to the retina.
a. RGX-314: A gene therapy candidate that employs an adeno-associated virus (AAV) vector to deliver a gene that encodes a therapeutic protein similar to ranibizumab. Early trials have shown that a single injection of RGX-314 can reduce the need for subsequent anti-VEGF injections, suggesting a potential one-time treatment for CNV.
b. ADVM-022: Another gene therapy in development, ADVM-022, employs an AAV vector to deliver a gene encoding an anti-VEGF protein. According to preliminary findings, ADVM-022 can provide sustained VEGF suppression, reducing the treatment burden for patients with CNV.
- Novel Drug Delivery Systems:
Advances in drug delivery systems aim to improve the efficacy and convenience of CNV treatment.
a. Port Delivery Service (PDS): The PDS with ranibizumab is an implantable device that continuously delivers the anti-VEGF drug to the eye. The PDS can be refilled every few months, potentially reducing the number of intravitreal injections while also providing more consistent drug levels.
b. Microneedle Technology: Microneedles are being investigated as a minimally invasive method for delivering drugs directly to the retina. This method could improve drug delivery efficiency while reducing the discomfort associated with traditional intravitreal injections.
- Advanced Imaging Techniques:
New imaging technologies improve the diagnosis and monitoring of CNV, allowing for more precise and personalized treatment.
a. Optical Coherence Tomography Angiogram (OCTA): OCTA is a non-invasive technique for obtaining high-resolution images of the retinal and choroidal vasculature. It enables detailed visualization of CNV without the use of dye injections, making it an important tool for tracking treatment response and disease progression.
b. Adaptive Optics Imaging: This advanced imaging technology provides cellular-level resolution of the retina, allowing for a more detailed assessment of the structural changes associated with CNV. Adaptive optics imaging can aid in the early detection of CNV and the more accurate assessment of treatment efficacy.
- Emerging Molecular Targets:
Research into the molecular mechanisms underlying CNV has revealed new therapeutic targets.
a. Integrin Inhibitors: Integrins are proteins that regulate cell adhesion and angiogenesis. Targeting integrins with inhibitors such as risuteganib can prevent the formation of abnormal blood vessels, providing a novel approach to treating CNV.
b. Inhibitors of Platelet-Derived Growth Factor (PDGF) PDGF promotes the maturation and stability of new blood vessels. Combining PDGF inhibitors with anti-VEGF therapies, such as rinucumab, may improve treatment efficacy by addressing multiple stages of neovascularization.
7. Stem cell therapy:
Stem cell therapy is being studied as a potential treatment for CNV, with the goal of regenerating damaged retinal tissue and restoring vision.
a. Transplantation of the Retinal Pigment Epithelium (RPE) Transplanting healthy RPE cells derived from stem cells can help replace damaged RPE cells and promote retinal health. Early clinical trials are looking into the safety and efficacy of RPE transplantation for CNV.
b. Mesenchymal Stem Cells (MSCs): MSCs have immunomodulatory and regenerative properties, which could help repair damaged retinal tissues. MSCs are being studied for their effectiveness in treating CNV, with the hope that they will reduce inflammation, promote tissue repair, and improve visual outcomes.
- Artificial Intelligence (AI) and Machine Learning:
AI and machine learning technologies are transforming CNV management by improving diagnostic accuracy and personalizing treatment plans.
a. Predictive Analysis: AI algorithms can analyze large datasets to find patterns and predict disease progression. Predictive analytics can help ophthalmologists predict the development of CNV in at-risk patients and tailor treatment strategies accordingly.
b. Treatment Optimisation: Machine learning models can evaluate patient responses to various treatments and recommend the most effective treatment plans. This personalized approach can improve treatment efficacy while reducing unnecessary interventions.
9. Pharmaceutical Advancements:
New pharmacological agents and formulations are being developed to improve the treatment of CNV.
a. Bispecific Antibodies: Bispecific antibodies, like faricimab, target two distinct pathways involved in angiogenesis. Faricimab inhibits both VEGF and Ang-2, providing a more comprehensive approach to controlling CNV and potentially reducing treatment frequency.
b. Formulas for Sustained Release: Researchers are creating sustained-release formulations of existing drugs to increase their duration of action. These formulations can reduce the number of intravitreal injections required, which improves patient compliance and convenience.
