Dystrophic epidermolysis bullosa (DEB) is a rare and severe disease that affects the skin and mucosa and is caused by one or more mutations the COL7A1 gene. COL7A1 encodes the type VII collagen (COL7) protein that forms anchoring fibrils and hold skin layers together. The lack of functional anchoring fibrils in DEB patients leads to extremely fragile skin that blisters and tears from minor friction or trauma. DEB patients suffer from frequent and recurring open wounds, which leads to skin infections, fibrosis which can cause fusion of fingers and toes, and are ultimately at an increased risk of developing aggressive forms of squamous cell carcinoma which can be fatal.

First approved in the United States in 2023, VYJUVEK is a topical, redosable genetic medicine built using Krystal’s HSV-1 platform to treat DEB at the molecular level by providing the patient’s skin cells the template to make normal COL7 protein.

Building on the success of VYJUVEK and the strengths of our HSV-1 platform in skin gene delivery, we are advancing additional gene therapy candidates targeting diseases of skin, including rare genetic diseases for which no FDA approved treatments are available. One such disease is Hailey-Hailey disease (HHD), a serious and rare monogenic skin disorder characterized by painful rash and blistering in skin folds and linked to mutations in the ATP2C1 gene and low expression levels of the ATP2C1-encoded calcium transporter in keratinocytes. Patients with HHD report debilitating symptoms of pain, itch, burning, infections, and body odor, as well as severe, negative impacts on quality of life and psychological distress.

We are also exploring the potential of our HSV-1 platform to deliver genetic cargo and treat rare genetic diseases of the lung. Our initial focus is on the treatment of cystic fibrosis (CF) and alpha-1 anti-trypsin deficiency (AATD) lung disease, two genetic diseases characterized by progressive lung decline and for which new therapeutic options are urgently needed.

Cystic Fibrosis

Cystic fibrosis (CF) is a rare and life-shortening genetic disease caused by mutations in the CFTR gene encoding the cystic fibrosis transmembrane conductance regulator (CFTR) protein. Lack of functional CFTR in secretory airway epithelia results in defective ion secretion and mucus production, leading to dehydration and acidification of the airway surface liquid. CF is characterized by recurrent chest infections, increased airway secretions, and eventually, respiratory failure. While CF is a multiorgan disease, the primary cause of morbidity and mortality is progressive lung destruction. Approximately 10-15% of CF patients harbor genetic mutations for which there are no available disease-modifying treatment options, representing a significant unmet need.

Alpha-1 Antitrypsin Deficiency

Alpha-1 antitrypsin deficiency (AATD) is a progressive and life-threatening rare lung disease caused by mutations in the SERPINA1 gene that lead to decreased levels and/or decreased functionality of alpha-1 antitrypsin (AAT) protein. Low levels of AAT can allow inflammation to proceed unchecked and damage the lungs. Over time, the deficiency can lead to progressive enzymatic destruction of the lung tissue, ultimately causing life-threatening pulmonary impairment and severe respiratory insufficiency. Current disease management often includes intravenous plasma-derived AAT augmentation therapy, which requires weekly infusions. There is currently no cure for AATD.

Due to rapid cell turnover and protein clearance rates, the cornea has historically been a difficult tissue to target with biologic modalities, limiting treatment options for many corneal diseases. We are evaluating the potential of our HSV-1 platform for repeated gene delivery to the cornea following eye drop administration. Our current focus is on gene therapy candidates for the treatment of neurotrophic keratitis (NK) and corneal complications of dystrophic epidermolysis bullosa (DEB), two corneal diseases that can result in severe ocular complications for which adequate therapeutic options are lacking or burdensome.

Corneal Complications of Dystrophic Epidermolysis Bullosa

Although the skin is the primary affected tissue in DEB, ocular complications – including corneal abrasion, corneal scarring, pannus, eyelid ectropions and blisters – are also common and can lead to progressive vision loss and even blindness in some patients. There are no corrective therapies available for the treatment or prevention of these complications. Current disease management is limited to supportive wound care and in some cases surgical interventions to remove scar tissue.

Neurotrophic Keratitis

Neurotrophic keratitis (NK) is a rare, degenerative corneal disease characterized by damage to or loss of function of the neurons innervating the eye leading to corneal epithelial defects, ulcers, and perforation. Left untreated, NK can result in severe vision loss. Recombinant nerve growth factor eye drops have been shown to significantly improve corneal healing and are approved for the treatment of NK in multiple jurisdictions worldwide including the United States, but the short half-life of recombinant protein results in rapid clearance from the eye, thereby necessitating burdensome administration six times a day, and may lead to suboptimal treatment outcomes. Eye pain during treatment with recombinant nerve growth factor eye drops is also frequently reported.

There remains a major unmet need for new cancer treatment modalities, particularly for those patients with checkpoint refractory solid tumors. We are evaluating the potential of our HSV-1 platform to enable localized and sustained expression of immune boosting cytokines in the tumor microenvironment. Krystal’s lead oncology product candidate is a modified HSV-1 vector designed to deliver genes encoding both human IL-12 and IL-2 to the tumor microenvironment and promote systemic immune-mediated tumor clearance by targeting solid tumors that are accessible via intratumoral injection or inhalation.

Skin undergoes sequential and cumulative alterations with the passage of time leading aged skin to appear wrinkled or generally less elastic and resilient than its youthful counterpart. This aging of the skin occurs as the result of numerous factors and is associated with declining expression of key extracellular matrix proteins including collagen and elastin. Jeune Aesthetics is developing a pipeline of aesthetic products to address these structural skin changes at the source by delivering targeted gene therapy to skin cells to boost the natural expression of key collagen and elastin proteins. This novel technology has the potential to rejuvenate aged skin, restoring youthful beauty. For more information visit Jeune Aesthetics.