Dystrophic Epidermolysis Bullosa
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. DEB can be either dominant (DDEB) or recessive (RDEB) based on inheritance pattern. Both DDEB and RDEB can present with similar dermatologic signs and symptoms, a range in severity, and potential for serious complications. 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.
Krystal’s ability to deliver missing or defective genes to the skin is validated by FDA-approval of VYJUVEK, and we continue to advance a pipeline of candidates targeting unmet needs in the skin.
Autosomal Recessive Congenital Ichthyosis (ARCI) is a lifelong, severe genetic skin disease. The most common cause of ARCI is an inactivating mutation in the TGM1 gene encoding the enzyme transglutaminase-1 (TGM1), a protein essential for the proper formation of the skin barrier. Mutations in the TGM1 gene lead to pronounced dehydration, transepidermal exposure to unwanted toxins and surface microorganisms, and a greatly increased risk of infection. TGM1 deficiency is associated with increased mortality in the neonatal period and has a dramatic impact on quality of life. Patients with ARCI often exhibit life-long pronounced scaling of the skin with increased transepidermal water loss, and frequently suffer from deformities, scarring alopecia, and thickening of the skin on the palms of the hands and soles of the feet. Additional complications include episodes of sepsis, fluid and electrolyte imbalances due to impaired skin barrier function, and failure to thrive. Severe heat intolerance and nail dystrophy are also frequently observed. Currently, there are no FDA-approved treatment options for patients with ARCI.
Netherton Syndrome (NS) is a debilitating autosomal recessive skin disorder causing defective keratinization, severe skin barrier defects, and recurrent infections. NS arises due to mutations in the SPINK5 gene, resulting in loss of activity of its encoded serine protease inhibitor protein SPINK5. T Excessive serine protease activity due to loss of SPINK5 function causes uncontrolled desquamation and a defective skin barrier. Patients with NS often experience chronic skin inflammation, severe dehydration, and stunted growth. A predisposition to allergies, asthma, and eczema is also characteristic. Currently, there are no FDA-approved treatment options for patients with NS.
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 comprises a multiorgan pathology, the primary cause of morbidity and mortality in CF is due to 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 (AATD) is a progressive and life-threatening 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. Also, the clinical benefit of which is debated. There is currently no cure for AATD.
There remains a major unmet need for new cancer treatment modalities, particularly for those patients with checkpoint refractory solid tumors. In the US alone, an estimated 1.6 million tumor cases are expected in 2023, as well as over 450,000 solid tumor deaths. Krystal is leveraging its prior experience in skin and lung tissue for local delivery of immune boosting cytokines to 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.
There are multiple genetic diseases that cause severe ocular complications or blindness, including dystrophic epidermolysis bullosa (DEB). Although the skin is the primary affected tissue in DEB, ocular complication – including corneal abrasion, corneal scarring, pannus, eyelid ectropions and blisters –are common and can lead to progressive vision loss and even blindness. Krystal is evaluating the potential of its platform to address ocular complications of DEB, as well as compatibility of its HSV-1 platform with other routes of ocular administration to treat additional genetic diseases affecting the eye, including inherited retinal diseases such as Stargardt’s disease.
Skin, like all organs in the human body, 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 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.
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