Investing in vision: Innovation in retinal therapeutics and the influence on venture capital investment.

Since the groundbreaking approval of the first anti-VEGF therapy in 2004, the retinal therapeutics field has undergone a remarkable transformation, witnessing a surge in novel, disease-modifying therapeutics for a broad spectrum of retinal diseases, extending beyond exudative VEGF-driven conditions. The surge in scientific advancement and the pressing, unmet, medical need have captured the attention of venture capital investors, who have collectively invested close to $10 billion in research and development of new retinal therapeutics between 2004 and 2023. Notably, the field of exudative diseases has gradually shifted away from trying to outcompete anti-VEGF therapeutics towards lowering the overall treatment burden by reducing injection frequency. Simultaneously, a new era has emerged in the non-exudative field, targeting prevalent conditions like dry AMD and rare indications such as Retinitis pigmentosa. This has led to promising drug candidates in development, culminating in the landmark approval of Luxturna for a rare form of Retinitis pigmentosa. The validation of new mechanisms, such as the complement pathway in dry AMD has paved the way for the approvals of Syvovre (Apellis) and Izervay (Iveric/Astellas), marking the first two therapies for this condition. In this comprehensive review, we share our view on the cumulative lessons from the past two decades in developing retinal therapeutics, covering both positive achievements and challenges. We also contextualize the investments, strategic partnering deals, and acquisitions of biotech companies, pharmaceutical companies venture capital investors in retinal therapeutics, respectively. Finally, we provide an outlook and potentially a forward-looking roadmap on novel retinal therapeutics, highlighting the emergence of potential new intervention strategies, such as cell-based therapies, gene editing, and combination therapies. We conclude that upcoming developments have the potential to further stimulate venture capital investments, which ultimately could facilitate the development and delivery of new therapies to patients in need.

Gap junctions modulate interkinetic nuclear movement in retinal progenitor cells.

During early retinal development, progenitor cells must divide repeatedly to expand the progenitor pool. During G(1) and G(2) of the cell cycle, progenitor cell nuclei migrate back-and-forth across the proliferative zone in a process termed interkinetic nuclear movement. Because division can only occur at the ventricular surface, factors that affect the speed of nuclear movement could modulate the duration of the cell cycle. Gap-junctional coupling and gap junction-dependent Ca(2+) activity are common features of proliferating cells in the immature nervous system. Furthermore, both gap-junctional coupling and changes in [Ca(2+)](i) have been shown to be positively correlated with the migration of a number of immature cell types. Using time-lapse confocal microscopy, we describe the nature and rate of progenitor cell interkinetic nuclear movement. We show that nuclear movement is usually, but not always, associated with Ca(2+) transients and that buffering of these transients with BAPTA slows movement. Furthermore, we show for the first time that gap-junctional communication is an important requirement for the maintenance of normal nuclear movement in retinal progenitor cells. Conventional blockers of gap junctions and transfection of cells with dominant-negative constructs of connexin 43 (Cx43) and Cx43-specific antisense oligodeoxynucleotides (asODNs) all act to slow interkinetic nuclear movement. The gap junction mimetic peptide Gap26 also acts to slow movement, an effect that we show may be attributable to the blockade of gap junction hemichannels.

Ca(2+) signalling and gap junction coupling within and between pigment epithelium and neural retina in the developing chick.

Development of the neural retina is controlled in part by the adjacent retinal pigment epithelium (RPE). To understand better the mechanisms involved, we investigated calcium signalling and gap junctional coupling within and between the RPE and the neural retina in embryonic day (E) 5 chick. We show that the RPE and the ventricular zone (VZ) of the neural retina display spontaneous Ca(2+) transients. In the RPE, these often spread as waves between neighbouring cells. In the VZ, the frequency of both Ca(2+) transients and waves was lower than in RPE, but increased two-fold in its presence. Ca(2+) signals occasionally crossed the boundary between the RPE and VZ in either direction. In both tissues, the frequency of propagating Ca(2+) waves, but not of individual cell transients, was reduced by gap junction blockers. Use of the gap junction permeant tracer Neurobiotin showed that neural retina cells are coupled into clusters that span the thickness of the retina, and that RPE cells are both coupled together and to clusters of cells in the neural retina. Immunolabelling for Cx43 showed this gap junction protein is present at the junction between the RPE and VZ and thus could potentially mediate the coupling of the two tissues. Immunolabelling for beta-tubulin and vimentin showed that clusters of coupled cells in the neural retina comprised mainly progenitor cells. We conclude that gap junctions between progenitor cells, and between these cells and the RPE, may orchestrate retinal proliferation/differentiation, via the propagation of Ca(2+) or other signalling molecules.