Novel therapy for Netherton syndrome

DESCRIPTION provided by applicant Netherton syndrome NS is one of the most severe heritable skin disorders of neonates with life threatening symptoms that result from a defective skin barrier Severe complications in infants include recurrent bacterial infections dehydration and failure to thrive In adults NS is a chronic debilitating condition with no effective treatmet Current therapies anti inflammatory drugs immunosuppressants antibiotics and drugs for symptomatic relief are only modestly effective and often cause unacceptable adverse events particularly with long term use Recently the cause of NS was identified as mutations in an epidermal protease inhibitor LEKTI At neutral pH in the deep stratum corneum SC LEKTI binds and inhibits Kallikrein KLK In normal epidermis LEKTI inhibits KLK through a pH dependent interaction In the superficial SC where the pH is this complex dissociates permitting KLK to proteolytically activate additional epidermal kallikreins KLK and KLK as well as elastase ELA These proteases degrade corneodesmosomal proteins leading to shedding of superficial cells Recent data from human genetic studies animal models and siRNA knockdown of LEKTI in organotypic human tissue culture establish unregulated KLK activity as the underlying cause of NS An inhibitory antibody to KLK can provide an effective treatment for NS by blocking the KLK protease cascade in the SC During this Phase I project we will identify an inhibitory anti KLH human monoclonal antibody humAb We will evaluate inhibitory activity in vitro using an organotypic human skin culture model This work has the potential to result in a new therapeutic for NS by alleviating the life threatening skin barrier deficits in the newborn and reducing skin irritation and inflammation in adults This humAb may also be effective against other dermatological disorders including atopic dermatitis that involve activated KLK PUBLIC HEALTH RELEVANCE Netherton syndrome NS is one of the most severe heritable skin disorders of neonates with life threatening symptoms that result from a defective skin barrier In adults NS is a chronic debilitating condition with no effective treatment There are o approved treatments for NS with current therapies directed only on relief of symptoms We have identified a monoclonal antibody that targets the underlying cause of premature skin shedding in NS This antibody will provide the first specifically targeted mechanism based treatment for NS