 presents a comprehensive discussion of current knowledge regarding the disease state, raises important questions to be addressed in future research, and underscores the idea that AMD is not a single entity but instead represents a disease spectrum with distinct phenotypes that appear to have different underlying risk factors and pathogenic pathways.

 was written by invitation from the journal’s editors and represents joint efforts by an international expert panel organized by Emily Y. Chew, MD, PhD, director of the Division of Epidemiology and Clinical Applications at the National Eye Institute at the National Institutes of Health in Bethesda, Maryland. The paper covers epidemiology; mechanisms/pathophysiology; diagnosis, screening, and prevention; management; and quality of life, and it cites 280 references.

Age-related macular degeneration: treatment overview

Monika Fleckenstein, MD, a professor of ophthalmology at John A. Moran Eye Center at the University of Utah in Salt Lake City, is the first author of the work. She told 

 that there have been several recent review articles on AMD but that she believes the paper stands out for the depth and breadth of the information it contains.

“Although our paper, which is a review article, does not present new original research, we believe it highlights some important new concepts about AMD and topics for future investigations,” she said.

Moreover, Fleckenstein added that her team believes the global overview of AMD provided in their paper will be useful for all ophthalmologists, ophthalmologists in training, and physicians in other fields of medicine in addition to anyone with a special interest in AMD.

“We hope that our emphasis on the idea that AMD comprises diverse pathological conditions will be thought provoking for basic and clinical scientists as they plan new research that ultimately will lead to improved care and better quality of life for patients with AMD,” she added.

Fleckenstein pointed out that when the article was solicited, the journal editors asked that it describe a model of AMD. However, complying with this request challenged the writing group because the exact interactions of pathophysiological events that may culminate in different AMD types remain to be elucidated.

“We know there are different phenotypes and stages in this bucket of AMD, and because of accumulating evidence, we are more and more convinced there are different dominant mechanisms for their development,” Fleckenstein said.

Protecting mitochondria with elamipretide

For example, she noted that current information indicates the risk factors for the development of geographic atrophy differ from those associated with progression of the atrophic lesions. Knowledge of these differences is important for researchers, as it indicates a need to focus on different targets for preventive versus therapeutic interventions.

In discussing neovascularization in AMD, the paper highlights new concepts and terminologies that have emerged thanks to clinico-pathological correlations that have been refined through advances in imaging techniques. First, the paper uses the term macular neovascularization (MNV) rather than choroidal neovascularization based on the fact that not all neovascularization in the area of the macula arises from the choroid.

Gene therapy for nAMD maintains vision with single injection

In addition, the article reviews evidence of different types of MNV, some of which seem to protect against AMD progression.

“This latter concept was first put forth decades ago by histopathologists but has only recently gained full attention because newer imaging technologies have enhanced our ability to visualize different subtypes of MNV in vivo,” Fleckenstein said. “Indeed, several studies implementing high-resolution retinal imaging have shown that rates of dry AMD progression differ depending on the presence of certain MNV subtypes.”

Fleckenstein added that the observations may lead to the identification of new therapeutic targets and also arguments against interventions that aim to eliminate all MNV.

One goal of developing new consensus terminologies for distinct manifestations of AMD is to provide a complete view of pathological changes that occur in the disease.

“The use of common terminology for phenotypic features is important if we want to be able to compare findings from different studies,” Fleckenstein explained.

Laser imaging system may offer early detection, treatment for eye diseases that cause blindness

She noted, however, that it is a task not easily done. For example, although the term MNV recognizes the fact that not all AMD-related neovascularization originates from the choroid, it does not account for the fact that AMD can also be associated with neovascularization in the peripheral retina, Fleckenstein explained.

“It became clear to me while working on this project that it is not always possible to find all-inclusive terms that also reflect the range of experts’ opinions,” she said.

Outlook is bright for telemedicine in ophthalmology

Fleckenstein concluded that even if a group comes to a consensus about a particular classification system or preferred term, other specialists in the field may not agree.

“But it is the open-minded discourse that will advance our field,” she noted. “And we also have to realize that terminologies are always subject to flux as new information emerges.”

Fleckenstein receives grants from Heidelberg Engineering, Genentech/Roche, Novartis, and Optos; personal fees from Bayer, Heidelberg Engineering, Genentech/Roche, and Novartis; and nonfinancial support from Carl Zeiss Meditech, Heidelberg Engineering, and Optos outside the submitted work.

1. Fleckenstein M, Keenan TDL, Guymer RH et al. Age-related macular degeneration. 

2021;7(1):31. https://doi.org/10.1038/ s41572-021-00265-2

2. Fleckenstein M, Mitchell P, Freund KB, Sadda S, Holz FG, Brittain C, Henry EC, Ferrara D. The progression of geographic atrophy secondary to age-related macular degeneration. 

2018;125(3):369-390. doi: 10.1016/j.ophtha.2017.08.038. Epub 2017 Oct 27. PMID: 29110945

Articles

Why investigators are considering AMD to be a disease spectrum rather than a single disease.

Gaining a greater understanding of AMD

Understanding the role of the VEGF pathway in various retinal vascular disorders has been instrumental in understanding common pathologic features among them, and, in turn, directing therapeutic strategies. Although 

 (AMD), and retinal vein occlusion (RVO) with macular edema are distinct clinical entities with differing pathogeneses, they are all characterized by increased vascular permeability, unregulated inflammation, and neovascularization, each of which is mediated, at least in part, by VEGF. 

As a result, targeted VEGF inhibition via intravitreal injection of agents designed to halt activity in the pathway has proven to be a largely successful strategy, often leading to a slowing of progression and preservation of vision, and in some cases, anatomic improvement and gain in visual function.

However, mounting evidence suggests that targeting VEGF alone is an incomplete therapeutic strategy. For example, currently approved agents have to be readministered on a frequent basis, as often as every 1 to 3 months.

 This creates a significant treatment burden, with many patients ultimately receiving fewer than the recommended number of injections, resulting in suboptimal visual outcomes in real-world studies. 

Although less frequent dosing may be effective, patients still require monitoring visits between injections, resulting in a treatment schedule that may be unsustainable for patients and their caregivers. As well, even when administered at recommended intervals, anti-VEGF therapy is insufficient to prevent vision loss in some eyes.

While incomplete response to VEGF targeting is multifactorial, it is highly plausible that additional signaling pathways complement and work in tandem with VEGF to contribute to pathobiology associated with retinal vascular disorders.

Research focuses on anti-VEGF treatment lapses in retinal vein occlusion

Indeed, recent research has identified the role of additional pathways, such as Tie2 signaling, in DR/DME, AMD, and RVO.

 Under normal healthy conditions, Tie2 is highly functional in maintenance of vascular health,

 suggesting that therapeutic targeting to restore or upregulate activity in this crucial pathway might provide conditions favorable to stopping or reversing pathologic changes associated with retinal vascular diseases. 

Novel strategies currently under investigation that offer the prospect of a dual mechanism of action, in which VEGF is inhibited and Tie2 is activated, offer tremendous promise for answering current unmet need in AMD, DR/DME, and RVO.

This article provides a brief overview of Tie2, its relevance to retinal vascular disease, and role as a therapeutic target. Following that is a discussion of the novel agent AXT107 (AsclepiX), focusing on its proposed dual mechanism of action and highlighting features of the peptide that would seem to offer great promise for treatment of retinal vascular disorders.

Role of Tie2 in Retinal Vascular Disorders

Tie2 is a transmembrane protein, expressed primarily on endothelial cells, but also found on some hematopoietic cells. It is primarily associated with two natural ligands: the agonist angiopoietin-1 (Ang1) and the contextual antagonist angiopoietin-2 (Ang2), which is a partial agonist in some situations. Ang1 binding to the Tie2 receptor initiates receptor clustering and activation of a host of provascular activity, including activation of Akt (supports endothelial cell survival and preservation, promotes vascular stability, and suppresses Ang2 production) and the PI3K pathway (promotes endothelial cell migration); suppression of inflammation; and decrease of endothelial cell permeability. 

On the other hand, Ang2 destabilizes vessels, allowing for angiogenesis or remodeling of the vasculature. This activity is unregulated in disease states, leading to formation of abnormal vasculature, increased permeability, and inflammation.

Ang-2/VEGF-A inhibition synergistic effect in DME and AMD (video)

The role of Tie2 in neovascularization is supported by research identifying the antagonistic angiopoietin 2 gene is a susceptibility gene for neovascular AMD

; as well, Ang2 expression is upregulated in highly vascularized regions of surgically excised choroidal neovascular (CNV) membranes.

 Moreover, the Tie2 agonist Ang1 suppresses CNV and vascular leakage.

The function of Tie2 inactivation leading to increased vascular permeability and inflammation occurs via interactions of Ang2 which cannot cause receptor dimerization and activation. 

For example, the potency of VEGF in inducing permeability is increased in the presence of Ang2,

 and Ang2 sensitizes endothelial cells to TNF-α, thereby playing a key role in induction of inflammation.

Meanwhile, Ang2 expression is increased in the setting of hypoxia,

 elevated in the vitreous of eyes with diabetic retinopathy,

 and is released from Weibel-Palade bodies in endothelial cells by VEGF activation

 Ang2 has also been identified as a potentially valuable therapeutic target because of its dual functions in promoting angiogenesis and mediating inflammatory processes.

Integrin receptors play a key functional role in activation of VEGF and Tie2. VEGF binding to VEGF receptor 2 (VEGFR2) is highly dependent on αvβ3 integrin activation. Furthermore, VEGFR2 activation induces release of Ang2 from retinal vascular cells. The role of AXT107 in mediating activity within the VEGF and Tie2 pathways derive from the molecule’s interactions with integrin proteins.

AXT107 is a peptide derived from collagen IV, which is the substrate for integrin receptors. In the presence of AXT107, α5β1 integrin is disrupted, leading to clustering of Tie2 receptor moieties (activation) at endothelial cell-cell junctions. Notably, this Tie2 clustering is analogous to clustering that occurs under physiologic conditions in response to Ang1 exposure; however, as the activity occurring in the presence of AXT107 does not require previous ligand activation, Tie2 is now available for activation by 

Wet AMD treatment burden eased by nonviral gene therapy

Such activity is highly consequential for retinal vascular disorders characterized by elevated expression of Ang2, in that the natural antagonist of Tie2 activity is now converted into a strong agonist and promoter of vascular stability. This conversion also has implications for interrupting the synergism between TNF-α and Ang2, which is typically a crucial component in driving inflammatory processes, as well as activating directly anti-inflammatory signaling through Tie2.

As a second mechanism, AXT107 also disrupts αvβ3 integrin, leaving it unavailable for complex with VEGFR2, thereby blocking downstream signaling activity.

AXT107 is delivered via an intravitreal injection. Post-injection, it self-assembles into a gel depot that settles into the vitreous away from the visual axis and slowly dissipates over several months. Preclinical studies indicate that it may be active for up to a year.

 This unique characteristic suggests the potential to extend the durability of effect and increase the interval between treatment.

The drug’s sponsor (AsclepiX) is expected to initiate phase 1/2 studies of AXT107 in early 2021 based on positive animal models and in vitro evidence demonstrating suppression and regression of CNV and subretinal neovascularization, suppression of VEGF-induced leakage, reduction in inflammation, and good safety.

 As with any investigational molecule, additional study is needed to fully understand safety and efficacy in humans. 

Subretinal gene therapy for neovascular AMD showing efficacy and safety

Nevertheless, exploring therapeutic targets beyond the VEGF pathway is supported by strong rationale, particularly in light of the growing appreciation of Tie2 activity in promoting healthy vasculature. The ability to supplant or complement currently available therapeutic strategies could, therefore, address unmet treatment need for patients deemed unresponsive or less than ideally responsive to anti-VEGF therapy. 

Furthermore, there are limited options to address the role of inflammation in DR/DME, AMD, and RVO. Although intravitreal corticosteroid injections may be used in DR/DME and RVO to address macular edema associated with inflammation, they entail risk of IOP elevation and other complications; there are not additional treatment options for this purpose in AMD.

Faricimab satisfies primary study endpoint in TENAYA and LUCERNE trials

The novelty of AXT107 to form a gel-like depot, and thereby remain available to distribute its active for an extended period of time, represents the potential to reduce treatment burden associated with anti-VEGF injections and monitoring. Additionally, because it mechanistically shuts down VEGF activity while promoting beneficial signaling in Tie2, it is highly likely to be used in a monotherapy approach should it prove safe and effective in human trials. While caution is warranted in interpreting early results, AXT107 potentially represents an important development for improving outcomes for patients with DR/DME, AMD, and RVO.

1. Genentech. Lucentis Prescribing Information. 2017.

3. Novartis. Beovu Prescribing Information. . 2019.

4. Broadhead GK, Hong T, Chang AA. Treating the untreatable patient: current options for the management of treatment-resistant neovascular age-related macular degeneration. Acta Ophthalmol. 2014 Dec;92(8):713-23.

 The Tie2 signaling pathway in retinal vascular diseases: a novel therapeutic target in the eye. 

6. Thurston G, Daly C. The complex role of angiopoietin-2 in the angiopoietin-tie signaling pathway. Cold Spring Harb Perspect Med. 2012 Sep 1;2(9):a006550.

7. Ma L, Brelen ME, Tsujikawa M, et al. Identification of ANGPT2 as a New Gene for Neovascular Age-Related Macular Degeneration and Polypoidal Choroidal Vasculopathy in the Chinese and Japanese Populations. Invest Ophthalmol Vis Sci. 2017 Feb 1;58(2):1076-1083.

8. Otani A, Takagi H, Oh H, et al. Expressions of angiopoietins and Tie2 in human choroidal neovascular membranes. Invest Ophthalmol Vis Sci. 1999 Aug;40(9):1912-20.

9. Lee J, Park DY, Park DY, et al. Angiopoietin-1 suppresses choroidal neovascularization and vascular leakage. Invest Ophthalmol Vis Sci. 2014 Apr 7;55(4):2191-9.

10. Peters S, Cree IA, Alexander R, et al. Angiopoietin modulation of vascular endothelial growth factor: Effects on retinal endothelial cell permeability. Cytokine. 2007 Nov;40(2):144-50.

11. Fiedler U, Reiss Y, Scharpfenecker M, et al. Angiopoietin-2 sensitizes endothelial cells to TNF-alpha and has a crucial role in the induction of inflammation. Nat Med. 2006 Feb;12(2):235-9.

12. Oh H, Takagi H, Suzuma K, et al. Hypoxia and Vascular Endothelial Growth Factor Selectively up-Regulate Angiopoietin-2 in Bovine Microvascular Endothelial Cells. J Biol Chem 1999;274:15732-9

13. Khalaf N, Helmy H, Labib H, et al. Role of Angiopoietins and Tie-2 in Diabetic Retinopathy. Electron Physician. 2017 Aug 25;9(8):5031-5035.

14. Cossutta M, Darche M, Carpentier G, et aI. Weibel-Palade bodies orchestrate pericytes during angiogenesis. Arterioscler Thromb Vasc Biol. 2019 Sep;39(9):1843-1858.

15. Jang C, Koh YJ, Lim NK, et al. Angiopoietin-2 exocytosis is stimulated by sphingosine-1-phosphate in human blood and lymphatic endothelial cells. Arterioscler Thromb Vasc Biol. 2009 Mar;29(3):401-7.

16. Scholz A, Plate KH, Reiss Y. Angiopoietin-2: a multifaceted cytokine that functions in both angiogenesis and inflammation. Ann N Y Acad Sci. 2015 Jul;1347:45-51.

17. Mirando AC, Shen J, Silva RLE, Chu Z, Sass NC, Lorenc VE, Green JJ, Campochiaro PA, Popel AS, Pandey NB. A collagen IV-derived peptide disrupts α5β1 integrin and potentiates Ang2/Tie2 signaling. JCI Insight. 2019 Feb 21;4(4):e122043.

18. Mirando AC, Lima E Silva R, Chu Z, Campochiaro PA, Pandey NB, Popel AS. Suppression of Ocular Vascular Inflammation through Peptide-Mediated Activation of Angiopoietin-Tie2 Signaling. Int J Mol Sci. 2020 Jul 21;21(14):5142.

20. Silva RLE, Kanan Y, Mirando AC, et al. Tyrosine kinase blocking collagen iv-derived peptide suppresses ocular neovascularization and vascular leakage. Sci Transl Med. 2017;9.

Promoting Tie2 signaling activity may complement inhibition of VEGF in addressing pathology in disease states characterized by angiogenesis, vascular permeability, and inflammation.

VEGF and beyond: therapeutic targeting in retinal vascular disorders

Investigators believe a non-contact laser imaging system could help doctors diagnose and treat eye diseases that cause blindness much earlier than is now possible.

 developed by engineering investigators at the University of Waterloo in Waterloo, Ontario, Canada, is designed to detect telltale signs of major blinding diseases in retinal blood and tissue that typically go unseen until it is too late.

With current testing methods, diseases such as age-related macular degeneration, diabetic retinopathy and glaucoma, which have no symptoms in their early stages, are usually diagnosed only after vision is irreversibly affected.

“We are optimistic that our technology, by providing functional details of the eye such as oxygen saturation and oxygen metabolism, may be able to play a critical role in early diagnosis and management of these blinding diseases,” said Parsin Haji Reza, director of the PhotoMedicine Labs at Waterloo University, in a statement.

According to investigators, patented technology at the core of the new system is known as photoacoustic remote sensing (PARS). It uses multicolored lasers to almost instantly image human tissue without touching it.

When used for eyes, the non-invasive, non-contact approach improves both patient comfort and the accuracy of test results, according to the university.

The technology is also being applied by Haji Reza and investigators in his lab to provide microscopic analyses of breast, gastroenterological, skin and other cancerous tissues, and to enable real-time imaging to guide surgeons during the removal of brain tumors.

According to Richard Weinstein, MD, an ophthalmologist and co-founder of the Ocular Health Centre, PARS may move ophthalmology beyond the current gold standard in ophthalmological imaging.

“For the first time, not just in ophthalmology but in the entire medical field, diagnosis and treatment of disease could be made prior to structural change and functional loss,” he said in a statement.

Haji Reza, a professor of systems design engineering and co-founder of startup company illumiSonics, said researchers are working with several ophthalmologists and hope to start clinical trials within two years.

Z. Hosseinaee, N. Pellegrino, et. al; Functional and structural ophthalmic imaging using noncontact multimodal photoacoustic remote sensing microscopy and optical coherence tomography; 

According to investigators, the new technology is designed to detect telltale signs of major blinding diseases in retinal blood and tissue that typically go unseen until it is too late.

Daniel F. Kiernan, MD, a vitreoretinal surgeon at The Eye Associates, Sarasota, Florida, discusses the highlights of his 2021 ARVO virtual presentation on the effect of dexamethasone intracameral drug-delivery suspension on macular thickness based on optical coherence tomography (OCT) testing following vitreoretinal surgery.

Videos

Daniel F. Kiernan, MD, discusses key findings of a clinical study analyzing the effect of dexamethasone intracameral drug-delivery suspension on macular thickness based on OCT testing following vitreoretinal surgery.

Modern Retina, Summer 2021

Gaining a greater understanding of AMD

VEGF and beyond: therapeutic targeting in retinal vascular disorders

Laser imaging system may offer early detection, treatment for eye diseases that cause blindness

Analyzing clinical results of dexamethasone implant effect on macular thickness