Oral Enzymatic Management of Phenylketonuria

PhenylketonuriaPKUis a genetic disorder of metabolism characterized by a pathological elevation of phenylalaninePhein the body stemming from a dysfunctional phenylalanine hydroxylase enzymePAHThe resulting high concentrations of Phexcan result in severe intellectual disabilitybehavioral problemsand neurological deficitse gseizuresStrict control of dietary Phe is the primary treatment for PKU current guidelines require diet therapy to be continued for lifewhich markedly exacerbates the problem of non complianceespecially in older children and adultsAn alternative treatment for PKU involves thereplacementof the endogenous PAH with a different Phe metabolizing enzyme such as phenylalanine ammonia lyasePALOrally administered PAL reduced plasma Phe levelsbut this effect was transient as the destruction of PAL by harsh environment of the gastrointestinal tractg i tnecessitated huge doses of the enzymeWe have designed a novel technology to reduce dietary Phe levels in the g i tby oral administration of microencapsulated PALPreliminary studies have demonstrated that we can successfully encapsulate PALPALEin ethyl cellulose using a patented emulsion dispersion techniqueHoweverPALE exhibitsof the activity of unencapsulated enzymePALUin solution limiting its implementation in its current formThe goal of this proposal is to optimize the formulation parameters to encapsulate PAL and characterize its properties in vitro enabling future development efforts Phenylketonuria is an inborn error of metabolismcharacterized by mutations in the enzyme phenylalanine hydroxylase causing a pathological elevation of phenylalanine in the bloodOrally active enzyme replacement therapy has shown initial promise but limited efficacy as native processes break down the exogenous enzymes resulting in a transient reduction in phenylalanine levelsMicroencapsulation of enzymes in a porous and non toxic membrane represents an innovative way to prolong stability and functionality in the destructive environment of the gastrointestinal tract and has the potential to help alleviate the enormous burden experienced by patients