RXi Pharmaceuticals Corporation, a biotechnology company focused on discovering, developing and commercializing innovative therapies addressing major unmet medical needs using RNA-targeted technologies, announced results from the assessment of connective tissue growth factor (CTGF) protein levels following intravitreal injection, of RXI-109 in the eyes of cynomolgus monkeys, as part of a dose-range finding study to build the company's ophthalmology franchise.
CTGF protein levels were determined by immunohistochemistry methods seven days following injection and quantified by digital image analysis of stained slides. Intravitreal administration of RXI-109 resulted in a reduction of CTGF protein levels in a dose-dependent manner in the retina. Whole eye sections were collected in this study and the company was also able to determine CTGF protein levels in the cornea, and noted that these protein levels were also reduced in a dose-dependent manner in the cornea tissue.
"These remarkable results constitute a major boost to the value of our newly formed ophthalmology franchise," said Dr. Geert Cauwenbergh, president and CEO of RXi Pharmaceuticals. He added that, "Not only do these data confirm that RXI-109 lowers CTGF protein levels in a dose dependent manner in the retina of non-human primates, but it also demonstrates that, with an intravitreal injection of RXI-109, sufficient compound migrates to the cornea to lower CTGF protein levels in that eye tissue as well. This finding opens up an avenue to possibly develop topical forms of RXI-109 to combat corneal scarring which often occurs secondary to trauma or infection and can lead to visual impairment, including blindness."
Retinal scarring is the development of scar tissue on the retina as a result of injury or as a consequence of disease. During injury many critical cellular pathways become active including proliferation, adhesion, migration, angiogenesis and scar tissue remodeling. CTGF modulates signals from a wide range of factors in the cell and in this way impacts some of these critical cellular pathways. Overproduction of CTGF is implicated in fibrotic disease and scarring in many tissues including the retina. Specifically, CTGF has been found to be upregulated in proliferative vitreoretinopathy membranes of both human and rabbit (He, Chen et al., 2008) and has been shown to be expressed by Müller cells and RPE cells, two cell types that undergo proliferation in the presence of injury and contribute to retinal scarring.
The cornea is a transparent tissue at the front of the eye that plays two key roles in the health of the eye. First, it provides a physical barrier to protect the inner eye from environmental factors. Second, the cornea is instrumental in directing incoming light to the lens and retina. Scarring of the cornea resulting from injury, disease, or vision correction surgery can have a dramatic impact on vision. In some cases, a corneal transplant may be needed. Importantly, CTGF expression levels have been found to be increased during corneal wound healing in rat corneas and in human corneal fibroblasts and it has been proposed that a reduction of CTGF may be an important step towards reducing corneal scarring (Blalock et al., 2003).
RXI-109 is an sd-rxRNA that targets the mRNA of connective tissue growth factor (CTGF), a gene known to modulate fibrosis and scar formation. RXI-109 is initially being developed to reduce or inhibit scar formation in the skin following surgery. The first clinical trials with RXI-109 (RXI-109-1201 andRXI-109-1202) showed excellent safety and tolerability, with ascending single and multiple doses respectively, as well as dose dependent effects on the CTGF protein and on the mRNA that controls production of this protein.
Two phase 2 clinical trials are currently underway to evaluate the effectiveness and safety of RXI-109 on the outcome of scar revision surgeries performed on hypertrophic scars resulting from lower abdominal surgeries (RXI-109-1301) and to evaluate the effectiveness and safety RXI-109 in healthy subjects who undergo an elective surgical excision of two similarly sized and placed keloids (RXI-109-1401).