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Sirnaomics: Two Is Better Than One
Current treatments for wound healing after surgery do not adequately address reduction in scar formation, and compounds in development may not address enough of the targets involved in the process, according to Sirnaomics Inc. The biotech hopes that by using siRNA to inhibit two proteins involved in scar formation, it will have an advantage.
According to co-founder and VP of Discovery Research David Evans, compounds in development to reduce scarring after surgery focus on the role of a single protein, which may not adequately reduce scar formation.
Sirnaomics’ lead compound, STP705, is a histidine-lysine polymer (HKP) nanoparticle encapsulation of siRNA targeting two proteins involved in scar formation: transforming growth factor (TGF) beta 1 (TGFB1) and cyclooxygenase-2 (COX-2).
Sirnaomics selected TGFB1 and COX-2 based on their roles in wound healing in embryonic and adult tissue.
“We spent considerable time identifying the optimal combinations of targets that provided the benefit of wound healing seen in the fetus, and these two genes were identified to provide the required improvement upon treatment of wounds in both mouse and pig models,” Evans said.
Wounded embryonic tissue expresses high levels of TGFB3 and low levels of TGFB1, TGFB2, and platelet derived growth factor (PDGF). In contrast, adult wounds contain predominantly TGFB1, TGFB2 and PDGF.
There also is an absence of an inflammatory response in wounded fetal tissue. But in wounded adult tissue, COX-2 is a known mediator of the inflammatory response. It is up-regulated in response to a wound and produces prostaglandins, resulting in inflammation and scar formation.
Because of these differences, new dermis that is formed during the healing of embryonic wounds is normal, consisting of bundles of collagen arranged in a basket-weave pattern. In adults, healed dermis contains abnormally patterned collagen bundles, producing a scar.
Sirnaomics tested multiple combinations of growth factors and other proteins up-regulated in fetal tissue but downregulated in adult tissue to arrive at the combination of TGFB1 and COX-2 as its targets.
The company hopes that by blocking TGFB1, it can reduce the formation of abnormally patterned collagen bundles. Similarly, the biotech expects that the blockade of COX-2 will minimize the role of inflammation in the wound repair process and further reduce scarring.
In a preclinical porcine model, STP705 reduced the time to wound closure to about 20 days vs. 45 days for silver sulfadiazine, which is considered the standard of care for wound therapy. STP705 also resulted in reduced scarring and more normal skin morphology compared to placebo.
Sirnaomics is developing the therapeutic as a once-daily HKP nanoparticle topical formulation based on its ability to deliver the optimal dose to the wound site.
“By using siRNAs delivered with the nanoparticle, we can control the relative dosing of each. Both are delivered to the same cells within the tissue at the appropriate concentration for maximal efficacy,”
Evans told BioCentury.
According to co-founder, President and CEO Patrick Lu, the HKP vector also has antimicrobial properties, which can help fight infection and improve time to healing.
Sirnaomics has exclusive rights to the HKP vector for siRNA delivery to treat wounds and ocular diseases from the University of Maryland School of Medicine.
The company is seeking a partner to help it advance the STP705 program, which it hopes to get into the clinic in the next 12 months.
Sirnaomics also hopes to use its combinatorial siRNA approach for other indications, including ophthalmology and infectious disease, for which it has preclinical programs.
Other compounds in development to prevent and reduce scarring after surgery include Juvista, an intradermal injection of human recombinant TGFB3 from Renovo Group plc.
Juvista is delivered via an intradermal injection to the wound site. A Phase III trial is testing two doses administered once following wound closure and again 24 hours later. Data are expected in 1H11.
Shire plc has rights to Juvista in North America.
COMPANIES AND INSTITUTIONS MENTIONED
Renovo Group plc (LSE:RNVO), Manchester, U.K.
Shire plc (LSE:SHP; NASDAQ:SHPGY), Basingstoke, U.K.
Sirnaomics Inc., Gaithersburg, Md.
University of Maryland School of Medicine, Baltimore, Md.
