Tyrosine Kinase inhibitor shows promise for AMD treatment

A new study finds that inhibition of CXCR4 may be useful in preventing neovascularization but does not appear to have an effect on already established angiogenesis, whereas a multiple receptor tyrosine kinase inhibitor (SU14813) reduced the size of previously formed lesions.

Endothelial precursor cells (EPCs) derived from hematopoietic stem cells (HSCs) have been shown to contribute to choroidal neovascularization (CNV) by signaling through the SDF-1 and its receptor, known as CXCR4. Hematopoietic stem cells are implicated in the formation of new pathologic vessels observed in wet AMD. Recruitment of endothelial precursor cells to the site of neovascularization is mediated, in part, by the chemokine SDF-1, and its receptor, CXCR4. CXCR4 is a G-protein-coupled receptor found on lymphocytes, monocytes, hematopoietic, endothelial progenitor cells, and mature endothelial cells.


Methods and Results

CNV in rats was generated by focal rupture of Bruch's membrane with an 810-nm diode laser. In the prevention mode, a CXCR4 antagonist (AMD3100) was delivered via an osmotic pump 1 day after laser induction. In the intervention mode, AMD3100 delivery commenced 14 days after laser induction. Inhibition of CXCR4 was determined through leukocyte and SDF-1 actin polymerization blood biomarker assays. Leakage was assessed by fluorescein angiography, and CNV lesion size was quantified after isolectin B4 endothelial cell staining. SU14813, an anti-VEGFR, PDGFR-beta, KIT, and FLT3 inhibitor, was also assessed in an intervention study protocol.

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Inhibition of CXCR4 was demonstrated by an increase in the number of blood leukocytes, and diminished SDF-1 induced actin polymerization in whole blood. CNV leakage and neovascularization were inhibited when the dose regimen was initiated 1 day after laser-induced CNV induction. AMD3100 did not show efficacy when administered 14 days after lasering. Treatment with SU14813 significantly decreased CNV leakage and lesion size in an intervention modality.

Discussion and Conclusions

In this study, CXCR4 inhibition was efficacious in the prevention of CNV, but failed to reduce choroidal leakage and angiogenesis in the intervention modality. This finding suggests that therapies targeting the SDF-1/CXCR4 axis may be beneficial in blocking the induction of ocular neoangiogenesis, but are unlikely to reduce already established angiogenesis.

There is strong evidence that CXCR4 inhibition disrupts the recruitment of endothelial precursor cells (EPCs) to sites of angiogenesis, most likely the major mechanism leading to efficacy in the prevention model.

In addition to suppressing CNV, CXCR4 inhibition reduced choroidal vascular leakage in the prevention modality (but not in the intervention modality). It is not known whether CXCR4 inhibition decreases leakage directly or as a secondary effect of the reduction of the angiogenic vessel area.

The observation that CXCR4 inhibition did not decrease choroidal leakage or angiogenic lesion size in the intervention modality suggests that after a 2-week generation of laser-induced CNV, there is limited, if any, contribution of EPC cells to the already established vessels

A multiple receptor tyrosine kinase (RTK) inhibitor may still be an effective monotherapy, as SU14813 reduced the size of previously formed lesions. In treatment mode, both leakage and angiogenesis decreased even after the pathologic effect was given 14 days to fully establish before drug intervention. This study suggests that blockade of the VEGF receptor is an effective alternative method of inhibiting the VEGF pathway compared to conventional anti-VEGF strategies.

SU14813 is a small molecule with broad target RTK selectivity, inhibiting the VEGF receptor (VEGFR), PDGFR-β, KIT, and FLT3. Although the primary mechanism that reduces preexisting angiogenesis and leakage is the blockade of the central VEGF pathway, the additional inhibition of PDGFR-β may augment efficacy in this model over single anti-VEGFR agents.

The investigators conclude that inhibition of CXCR4 may be useful in preventing neovascularization but does not appear to have an effect on already established angiogenesis. A multiple receptor tyrosine kinase inhibitor (SU14813) approach shows promise for the treatment of wet age-related macular degeneration.