Dermal Fibrosis

Dermal Fibrosis

Derm 3

Connective Tissue Growth Factor (CTGF) and Scarring

 CTGF
CTGF is an extracellular matrix protein that plays a key role in tissue regeneration and repair.  During wound healing, CTGF modulates signals from a wide range of factors in the cell and in this way controls critical cellular pathways including scar tissue deposition and remodeling.  CTGF is involved in the differentiation of fibroblasts to contractile myofibroblasts which are the main cells responsible the deposition of collagen, a major structural protein of a scar.  Elevated levels of CTGF-dependent signaling can prolong the tissue repair process and lead to pathological scarring, fibrosis, and cancer.  For example, CTGF levels are increased in fibrotic tissue, scleroderma lesions, as well as in fibroblasts isolated from hypertrophic and keloid scars.

Scar Prevention is a High Unmet Medical Need

 

RXI-109 is initially being developed to reduce fibrosis or scarring of the skin at a post-surgical wound site.  Scarring represents a high unmet medical need as there are currently no FDA-approved therapies in the U.S. for the treatment and prevention of scars in the skin.  In the U.S. alone, there are over 35 million surgical procedures annually1, and 234 million major surgeries worldwide2.  If approved, RXI-109 would be a “first-in-class” RNAi treatment for the prevention or reduction of dermal scarring.

Together with leading scientists in the field of scarring, RXi Pharmaceuticals believes that reducing the level of CTGF during the wound healing process will result in a reduced level of scarring.  A therapeutic of this type could have great benefit for trauma and surgical patients (especially relating to raised or hypertrophic scarring), burn patients (including potential burn contractures), surgical revision of existing unsatisfactory scars, and in the treatment, removal and inhibition of keloids (scars which extend beyond the original skin injury).

Types of Scars

hyper

Image of a hypertrophic scar (Courtsey of RXi Pharmceuticals)

While scar formation is the normal result of wound healing, in some cases the healing process goes awry. Hypertrophic scars are abnormal scars that are raised above the normal skin surface and can be reddened or darker than the existing skin tone.  These scars result in part from an increased level of collagen and are less ‘elastic’ than the surrounding skin.  Hypertrophic scars remain confined to the original surgical incision line or site of injury.  The incidence of hypertrophic scarring (raised, thickened scars) following surgery is reported to be at least 40%in the general population3 and up to 70% in certain Asian populations4.

Keloids are also raised and reddened or darkened scars resulting from increased collagen production.  However, keloids often spread beyond the original site of skin injury and may continue to expand in size.  Keloids can result from skin ‘trauma’ as common as an ear piercing or vaccination and may grow to cover large areas.  Keloids are sometimes removed by surgical revision, but recurrence rates are as high as 50-80%.  Keloids are most prevalent in darker skinned individuals, up to 16% in people of African ancestry, and 50% of all keloid patients have a family history of keloids.

Scars resulting from burns are very difficult to treat, especially for deeper burns where >50% result in hypertrophic scarring.  Over production of collagen is also a main feature of scleroderma, a rare but debilitating disease of the connective tissue in which the skin becomes thickened and stiffens, a result of overproduction of collagen and other connective tissue proteins.  In severe cases, internal organs are also involved.

Effects of Scars

In humans, scarring of the skin after surgery, trauma, or burns can cause debilitating aesthetic, functional and psychological effects.  Unfavorable skin scarring occurs despite the best surgical technique and post-operative wound care.  Predisposition to hypertrophic scarring is a factor leading to a negative outcome.  In addition to the aesthetic considerations, excessive scarring in certain regions of the body can result in a marked loss of function due to reduced flexibility.  For example, scars across joints can impede movement and restrict normal daily activity.  For severe scars resulting from burns or trauma, contractures of the scarred area can occur which shorten the scarred tissue and result in permanent loss of mobility of the affected area or joint.

Scar reduction and prevention is a therapeutic area of high unmet medical need, with no universal standard of care and no approved drugs for the prophylactic reduction of scarring.  For the skin, prophylactic treatments involving agents that are administered locally at the time of surgery or injury may lead to long-term improvements in scarring.  Scar revision surgery is an option, with over 177,000 being conducted per year in the U.S., but often the scar recurs.  Given the large number of surgical procedures and the negative effect of abnormal/hypertrophic scarring on health and quality of life, there is a significant market for a scar prevention therapeutic such as RXI-109.

Dermatology


Wound Architecture

Wound

As shown in this example of rat skin, the wound area has a different ‘architecture’ and a thicker epidermis than the healthy surrounding skin. In normal healing, the wound heals and regains a more normal appearance. In humans, aberrant healing can lead to hypertrophic scarring and keloids.

Keloids

Images of single and multiple keloids, and disfiguring keloid scars on the face resulting from inflammatory cystic acne (Courtesy of the Department of Dermatology, University of Leuven)

Burn Scars

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Keloidal scars and contractures resulting from burns on the hands (Courtesy of the Department of Dermatology, University of Leuven)