Development of Human Recombinant Decorin Core Protein as an Anti-Scarring Therapeutic for Dystrophic Epidermolysis Bullosa
Abstract
Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited skin disease caused by a deficiency or dysfunction in collagen type VII, a key structural protein that anchors the outer layer of skin, the epidermis, to the inner layer of skin, the dermis. The disease is usually detected at childbirth because the infant is born with a significant portion of their epidermis missing, making them look like a burn victim. Children with RDEB are known as “butterfly children” because of their fragile skin. They suffer from severe blistering on their skin, in their mouths, esophagus, urethra, and anus because the missing or dysfunctional collagen VII “super glue” between their epidermis and dermis results in easy separation of these two layers of skin with activities of daily life, e.g., walking, writing, eating, defecating. There are no Food and Drug Administration (FDA)-approved treatments for DEB. Palliative treatments focus on wound care to avoid infection (bursting blisters, wound cleaning, bandaging antibiotics), relieving pain, and surgical procedures that burden caused by the excessive buildup of scar tissue from repeated injuries. Patients with RDEB have chronic wounds that heal with extensive scarring. For example, the majority of children aged 10 or older have mitten deformity, where webbed scar tissue builds up between the fingers and toes and covers them fusing the digits together. A common surgery is thumb release surgery to correct the mitten deformity, so the patient can hold a pencil or a fork. Unfortunately, this is just a temporary measure because scar tissue re-builds post-surgery, and the surgery must be repeated. Therefore, there is an urgent need to identify anti-scarring treatments for RDEB. We are developing a gel that may be applied to the skin (i.e., topical application) that we believe will accelerate wound healing and significantly reduce scarring. This gel contains an engineered form of a naturally occurring anti-scarring human protein called decorin as its active ingredient. The engineered form of decorin in known as human recombinant decorin (hrDecorin). In a remarkable case study of identical twins with RDEB, there was twice as much decorin in the skin of one twin, whose skin had significantly lower scarring, compared to his identical twin brother who had severe scarring. This is despite the fact that the brothers had the same, low levels of collagen VII. We hypothesize that the anti-scarring properties of decorin were responsible for the mild appearance of the RDEB twin with elevated decorin levels. Decorin is widespread throughout the body and plays a key anti-scarring role by binding to collagens and maintaining their structural integrity, inhibiting the main growth factors that cause scarring, and reducing inflammation. Data from multiple animal studies show that hrDecorin not only slows the rate of scarring but also can reverse scarring, not just in the skin but in other organs (the eye, brain and spinal cord, liver, and kidney). We are seeking funding to develop a topical gel that contains hrDecorin that could be applied to the skin of RDEB patients to improve wound healing and reduce scarring. We will manufacture hrDecorin using an existing process, develop a topical gel containing hrDecorin and other ingredients that are soothing to the skin, and test our hypothesis that our topical hrDecorin gel will improve wound healing and reduce scarring in a mouse model of RDEB. This mouse model develops blisters and scarring, similar to patients with RDEB. In addition, we will evaluate the safety and tolerability of our topical hrDecorin gel in toxicology studies that the Food and Drug Administration (FDA) requires before we can file an Investigational New Drug (IND) application, which will support clinical trials of our topical drug in RDEB patients. A safety and efficacy study using the topical hrDecorin gel in a clinical trial with RDEB patients would be the next step
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Nov 19, 2019
- Source ID
- W81XWH1910834
Entities
People
- Jean Tang
Organizations
- United States Army