Disease progression pathways of wet AMD: opportunities for new target discovery

Wolf, Amber T.; Harris, Alon; Oddone, Francesco; Siesky, Brent; Vercellin, Alice Verticchio; Ciulla, Thomas A.

doi:10.1080/14728222.2022.2030706

Cited by 19 publications

(11 citation statements)

References 52 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…It is a multifactorial, slow progressive, and neural degenerative disease, clinically featured with drusen formation in the early stage; as the disease progresses, about 85% of patients progress toward geographic atrophy (GA), an advanced form of AMD (dry type), and 15% end up with choroidal neovascularization (CNV), leading to subretinal fluid or leakage (wet type), which accounts for 90% of vision loss in AMD [5]. In the past 15-20 years, the success of anti-VEGF therapies, from Macugen, Avastin (off-label) to Lucentis, Eylea, Beovu, and the recent approval of Vabysmo (bispecific Faricimab) [6], has revolutionized retinal specialty care for treating retinal angiogenesis pathologies by removing VEGF to prevent such devastating vision loss, caused by wet AMD, diabetic macular edema, retinal vein occlusion, and CNV secondary to other retinal diseases such as myopia and polypoidal choroidal vasculopathy (Figure 1). However, 1/3 to 2/3 of CNV lesions gradually evolve (switch) to…”

Section: Age-related Macular Degeneration (Amd)mentioning

confidence: 99%

Understanding the Biology in Current Cell and Gene Therapy for Treating Macular Diseases

Guanting Qiu

2023

Macular Diseases - An Update [Working Title]

View full text Add to dashboard Cite

The 21st century ushers us into an information explosive era in modern medicine development. At the cusp of biology and technology convergence, significant advances are being made in the strategic approach toward preventing and treating retinal degeneration and neovascular diseases, in particular of a restoration of macular vision, from new surgical interventions to emerging pharmacotherapies through minimally invasive ocular drug delivery and genetic bio factory, and rapidly evolving retinal gene therapies and cell transplant, which are changing the landscape of retinal therapeutic horizon. Understanding disease physio pathological processes is becoming ever more important for developing and delivering these therapeutic modalities to individual patients with precision; in the light of cell & gene therapy, host-donor interplay is of strategic importance.

show abstract

Section: Age-related Macular Degeneration (Amd)mentioning

confidence: 99%

Understanding the Biology in Current Cell and Gene Therapy for Treating Macular Diseases

Guanting Qiu

2023

Macular Diseases - An Update [Working Title]

View full text Add to dashboard Cite

show abstract

“…Current FDA approved therapies include antibody fragments targeting VEGF-A isoforms such as ranibizumab, brolucizumab, and off-label bevacizumab; a protein decoy for VEGF receptors, aflibercept; and a bispecific antibody targeting VEGF-A and angiopoetin-2, faricimab [4]. There are emerging biosimilars [5] and interest in alternate molecular targets such as other VEGF family proteins, integrins, tyrosine kinase inhibitors, and Tie/Angiopoetin-2 pathway [6]. Despite such active research pipelines, AMD represents a significant and growing burden due to the necessity of frequent treatment [7] and high cost medications [8][9][10].…”

Section: Introductionmentioning

confidence: 99%

Gene therapy for age-related macular degeneration: potential, feasibility, and pitfalls

Berkowitz,

Finn

2024

Current Opinion in Ophthalmology

View full text Add to dashboard Cite

Purpose of review The landscape for age-related macular degeneration (AMD) is rapidly changing with addition of biosimilars and now United States Food and Drug Administration (FDA) approved nonneovascular AMD (nnAMD) treatment options. These developments have inspired a burgeoning pipeline of gene therapy approaches focused on similar antivascular endothelial growth factors (VEGF) and complement related pathways. Historic and more recent setbacks in the gene therapy pipeline, including intraocular inflammatory reactions, have raised important concerns for adverse events related to AMD therapeutics both for gene and nongene approaches. The specific clinical profile of these therapeutics approaching later stage clinical trials are complex and under active investigation; however, these options hold promise to disrupt the current landscape and change management paradigms for one of the leading causes of vision loss worldwide. Recent findings This review covers current gene therapy approaches for neovascular AMD (nAMD) and nnAMD. Intravitreal, suprachoroidal, and subretinal delivery routes are discussed with attention to technical procedure, capabilities for transgene delivery to target tissue, immunogenicity, and collateral effects. Suprachoroidal delivery is an emerging approach which may bridge some of the practical drawbacks for intravitreal and subretinal methods, though with less elaborated immunologic profile. In parallel to delivery modification, viral vectors have been cultivated to target specific cells, with promising enhancements in adeno-associated viral (AAV) vectors and persistent interest in alternate viral and nonviral delivery vectors. Ongoing questions such as steroid or immunosuppressive regimen and economic considerations from a payer and societal perspective are discussed. Summary The present review discusses emerging gene therapy options which could foster new, more durable nAMD and nnAMD therapeutics. These options will need refinement with regards to route, vector, and dosage, and specialists must decipher the specific clinical risk benefit profile for individual patients. Ongoing concerns for immunogenicity or dosage related adverse events could stifle progress, while further vector development and refined delivery techniques have the potential to change the safety and efficacy of currently options in the pipeline.

show abstract

“…Current antibody-based wAMD therapies only target a small number of VEGF ligands (i.e., VEGF-A and VEGF-B.) Small-molecule tyrosine kinase inhibitors (TKIs) such as vorolanib, sunitinib, and axitinib ( Fig 1 ) offer advantages over antibody treatments for wAMD by targeting multiple VEGF receptors (VEGFRs) intracellularly [ 15 ]. Sunitinib capsules and axitinib tablets have been approved by the US Food and Drug Administration for the treatment of certain types of cancer [ 16 , 17 ], and vorolanib tablets in combination with everolimus were approved in 2023 by China’s National Medical Products Administration for the treatment of advanced renal cell carcinoma [ 18 ].…”

Section: Introductionmentioning

confidence: 99%

Vorolanib, sunitinib, and axitinib: A comparative study of vascular endothelial growth factor receptor inhibitors and their anti-angiogenic effects

Bakri,

Lynch,

Howard-Sparks

et al. 2024

PLoS ONE

View full text Add to dashboard Cite

Purpose Pathological angiogenesis and vascular instability are observed in diabetic retinopathy (DR), diabetic macular edema (DME), and wet age-related macular degeneration (wAMD). Many receptor tyrosine kinases (RTKs) including vascular endothelial growth factor receptors (VEGFRs) contribute to angiogenesis, whereas the RTK TIE2 is important for vascular stability. Pan-VEGFR tyrosine kinase inhibitors (TKIs) such as vorolanib, sunitinib, and axitinib are of therapeutic interest over current antibody treatments that target only one or two ligands. This study compared the anti-angiogenic potential of these TKIs. Methods A kinase HotSpot™ assay was conducted to identify TKIs inhibiting RTKs associated with angiogenesis and vascular stability. Half-maximal inhibitory concentration (IC50) for VEGFRs and TIE2 was determined for each TKI. In vitro angiogenesis inhibition was investigated using a human umbilical vein endothelial cell sprouting assay, and in vivo angiogenesis was studied using the chorioallantoic membrane assay. Melanin binding was assessed using a melanin-binding assay. Computer modeling was conducted to understand the TIE2-axitinib complex as well as interactions between vorolanib and VEGFRs. Results Vorolanib, sunitinib, and axitinib inhibited RTKs of interest in angiogenesis and exhibited pan-VEGFR inhibition. HotSpot™ assay and TIE2 IC50 values showed that only axitinib potently inhibited TIE2 (up to 89%). All three TKIs effectively inhibited angiogenesis in vitro. In vivo, TKIs were more effective at inhibiting VEGF-induced angiogenesis than the anti-VEGF antibody bevacizumab. Of the three TKIs, only sunitinib bound melanin. TKIs differ in their classification and binding to VEGFRs, which is important because type II inhibitors have greater selectivity than type I TKIs. Conclusions Vorolanib, sunitinib, and axitinib exhibited pan-VEGFR inhibition and inhibited RTKs associated with pathological angiogenesis. Of the three TKIs, only axitinib potently inhibited TIE2 which is an undesired trait as TIE2 is essential for vascular stability. The findings support the use of vorolanib for therapeutic inhibition of angiogenesis observed in DR, DME, and wAMD.

show abstract

Disease progression pathways of wet AMD: opportunities for new target discovery

Cited by 19 publications

References 52 publications

Understanding the Biology in Current Cell and Gene Therapy for Treating Macular Diseases

Understanding the Biology in Current Cell and Gene Therapy for Treating Macular Diseases

Gene therapy for age-related macular degeneration: potential, feasibility, and pitfalls

Vorolanib, sunitinib, and axitinib: A comparative study of vascular endothelial growth factor receptor inhibitors and their anti-angiogenic effects

Contact Info

Product

Resources

About