The era of anti-VEGF agents started with pegaptanib, which blocked the VEGF-A splice variant 165 and no other isoforms. This was quickly supplanted by ranibizumab and bevacizumab, which blocked all splice variants of VEGF-A, including the most pathologic, being 165. The VEGF family consists of VEGF-A, VEGF-B, VEGF-C, VEGF-D, and placental growth factor (PlGF). Aflibercept was designed as a fusion protein with key domains of VEGF receptors (VEGFR) 1 and 2; therefore, it blocked VEGF-A, VEGF-B, and PlGF. This multitarget approach was also used with faricimab, which blocked VEGF-A as well as Angiopoietin 2, a competitive antagonist to Ang1, which prevents Tie2 receptor activation.
The key feature of all these molecules was blockage of VEGF-A in the extracellular space. This prevented activation of VEGFR2 and the resulting leakage, inflammation, and angiogenesis. But very little has been discussed about VEGF-C and VEGF-D, largely because until recently there were no anti-VEGF agents that blocked these members of the VEGF family.
Historically, VEGF-C was known to be very important for lymphangiogenic development via VEGFR3. More recently, it has been also shown to play a role in angiogenesis through weaker binding to VEGFR2. Similarly, VEGF-D has also been shown to be a potent inducer of angiogenesis through VEGFR2. Interestingly, studies have shown upregulation of the other VEGF members when VEGF-A is blocked. This has led to several companies targeting VEGF-C combined with VEGF-A to improve the outcomes in retinal vascular diseases. This technique is explored in detail in this issue. Early studies have shown better visual results than our current generation of anti-VEGF agents, which leaves us excited to see the results of the phase 3 studies.
Gene therapy to produce different anti-VEGF proteins by our retinal cells is explored in this issue. Adverum is infecting cells with AAV.7m8 delivering cDNA of aflibercept through an intravitreal injection. Similarly, Vanotech is using AAV8 to a produce an aflibercept-like protein. 4D Molecular Therapeutics is delivering VEGF-C interfering RNA through an AAV capsid that also produces an aflibercept-like protein that blocks VEGF-A, VEGF-B, and PlGF. Furthest along is RegenxBio, which is using AAV8 to deliver a VEGF-A inhibiting protein through subretinal surgery. These are very exciting programs that may offer sustained anti-VEGF delivery.
The VEGF family members activate VEGF receptors that are all tyrosine kinase receptors that activate cytoplasmic signaling molecules. Activated signaling pathways lead to cell proliferation, protein translation, inflammation, and increased vascular permeability. Tyrosine kinase inhibitors (TKIs) work intracellularly to block the downstream activation of the VEGF receptors. Several companies are delivering TKIs via various polymers as well as to the suprachoroidal space to effectively block all VEGF family members.
It is certainly an exciting time in VEGF inhibition for retinal vascular diseases. We hope you enjoy this issue where we take a deep dive into all these technologies. RP
