Category: Research

Month: 02 Mar 2016

Issue: not yet available

New inhibitor against novel inflammatory target in AMD shows potential in experimental models

Research results published in the Journal of Experimental medicine (www.jem.org/cgi/doi/10.1084/jem.20150894) by scientists from Genentech’s research facilities suggest that a new molecular player in AMD may hold considerable promise for the development of novel therapeutics. The research publication claims to be the first report to demonstrate increased expression of interleukin-33 (IL-33) in AMD and additionally proposes a role for the cytokine in the recruitment of myeloid cells in the outer retina resulting in photoreceptor cell loss and vision impairment in preclinical models under-going retinal stress. According to the researchers, the collected data indicates that inhibiting IL-33 may be sufficient to slow or halt myeloid recruitment and thereby prevent the current irreversible loss of photoreceptors. Development of antibody inhibitors, or any number of alternative pharmacological agents targeting IL-33, is likely to be the next step for such research. As Genentech have considerable experience in the development of biologics for AMD it may be likely that patents protecting their approach will appear in due course.

 

The research was conducted on both human donor tissues, with and without AMD, and on experimental model systems of AMD used to investigate the effect of interfering with IL-33 expression. In their report, the researchers identified IL-33 as a key regulator of inflammation following retinal stress or injury. In models under going retinal stress the levels of bioactive IL-33 were increased significantly leading to increased inflammatory chemokine and cytokine expression in activated Muller cells. Removing the receptor for IL-33 or using a soluble IL-33 decoy in models significantly reduced the release of inflammatory mediators and inhibited the accumulation of phagocytes in the outer retina. The employment of such blocking mechanisms clearly provided protection for photoreceptor rods and cones suggesting a clear role for the cytokine in disease progression.

 

IL-33 is a recently discovered cytokine of the IL-1 family and, while a significant amount of knowledge on the biology is yet to be characterized, the basic principle of been able to inhibit its effects were clearly demonstrable. Administration of soluble receptors to mop up IL-33 was achieved through subretinal AAV injections into experimental models. The AAV-soluble receptor were capable of blocking IL-33 from mediating downstream effects and the use of such AAV-soluble receptors in models exposed to light stress resulted in the protection of rods, cones and ganglion cells. Similarly treated controls showed no protective effect. As no side effects were seen in administering the IL-33 inhibitor in rodents the research team are hopeful that a similar strategy may be possible in human eyes however, a significant road of clinical trials will be required before the potential of such an approach can be determined.

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