Quark Biotech links gene to AMD development

The results revealed that in an animal model of CNV, disruption of RT801 expression through siRNA, reduced CNV by almost 58 per cent compared to the control. In addition, in RTP801-knockout mice, CNV was inhibited by 32 per cent.

The news also raises the prospect of using siRNA as a viable treatment, not only for wet AMD but also diseases caused by inappropriate activity of specific genes. The ability to silence and regulate such genes selectively through siRNA could provide an essential tool for drug discovery and therapeutic development.

"We believe that our program's focus on RTP801 is a novel therapeutic strategy because the majority of emerging therapies are currently focusing on the inhibition of VEGF-VEGFR1 axis. Our study of RTP801 forms the basis of our discovery programs in diabetic retinopathy, AMD and chronic obstructive pulmonary disease,"​ said Dr Daniel Zurr, chief executive officer of Quark Biotech.

AMD is the leading cause of vision loss and blindness in Americans age 65 and older, with over 200,000 news cases every year in the US. According to the eye-health organisation Macular Degeneration Partnership, around 15m Americans have evidence of macular degeneration and the incidence is increasing with time.

In AMD, abnormal blood vessels gain access to the macula, a key retinal area where central vision resides, leading to irreversible damage and loss of central vision by the growth of scar tissue. To date, the key to therapies is to stop or prevent the growth of the abnormal blood vessels and slow down the progression of scar tissue formation.

"Molecular therapies are urgently needed to help treat patients with AMD. As part of our program in ischemic diseases, we plan to further develop the RNAi-based drug candidate using the RTP801 target,"​ Zurr added.

Quark​ had reported the discovery of RTP801 in 2002 and was recently granted three broad US patents for covering the gene, its encoded protein and their inhibition. Quark has demonstrated in a model of retinopathy of prematurity (ROP) that knockout mice deficient of RTP801 are protected from the three major pathological hallmarks of this model of retinopathy: hyperoxia- associated vasoobliteration, hypoxia-induced apoptosis of neuroretina and retinal neovascularisation (angiogenesis).

This is not the only work of its kind to appear in this field. In November last year, Acuity announced it had initiated a Phase 1 clinical trial of its lead compound Cand5 in patients with age-related macular degeneration (AMD). The ophthalmic pharmaceutical company, also announced it had signed a long-term manufacturing agreement with Avecia Biotechnology for pharmaceutical grade supplies of Cand5.

Cand5's mechanism of action shuts down the production of vascular endothelial growth factor (VEGF), the central stimulus in the development of wet AMD. This is achieved by using short nucleic acid sequences that bind to and inactivate the machinery in the cell that leads to protein transcription. This is also known as gene silencing and its manner is similar to that achieved using antisense oligonucleotides.

Alnylam, in collaboration with Merck, is developing RNAi therapeutics for the treatment of ocular microvascular diseases. This collaboration, initiated in June 2004, includes Alnylam's most advanced program, to develop a direct RNAi therapeutic targeting VEGF for the treatment of wet AMD.

Last month, the company demonstrated in preliminary pre-clinical studies, its lead candidate RNAi therapeutic reduced pathological vascular leakage compared with placebo control. Currently Alnylam are involved in ongoing pre-clinical studies to confirm this finding, determine the optimal drug dose and delivery regimen.

There are limited treatments currently available for AMD. QLT and Novartis have the leading treatment, a US FDA-approved therapy called Visudyne, which is the current standard of care for treating AMD. However, Visudyne does not address the root cause of these diseases and its efficacy is limited.

According to the US Census Bureau, National Eye Institute, over 1.7m people in the US are estimated to have the advanced form of wet AMD, and approximately 30m individuals are estimated to have some form of AMD worldwide.

By 2030, an estimated 2.8m Americans will suffer from visual impairment as a result of AMD. US market for AMD therapies is forecast to grow to $7.5 bn (€5.6 bn ) by 2010.