in vitro and in vivo Assessments of Novel Protein Therapy for Disease Modification in Alzheimer's Mice

Project Summary AbstractStream BiomedicalDementia is estimated to effect nearlymillion people worldwideAlzheimer s DiseaseADis the leading cause of dementia andth leading cause of death in the United StatesThe social and economic impact of AD and related dementias is profoundinpeople over the age ofhave ADandmillion Americans provide unpaid care for friends or family members with AD or related dementiasat a cost of $billion dollarsThis burden is also heavily weighted on womenwho comprise nearlyof all patientsDeath from AD is increasing at a ratefold higher than heart diseaseand early diagnosis and or improved therapeutics for AD could result in projected cost saving of $trillion dollarsThere are no proven therapies for ADand there is a great unmet need for therapies that inhibit the underlying mechanisms or halt disease progressionImportantlyAD is identified as sharing many neurovascular pathologies with vascular dementiasVaDand stroke and other neurovascular conditions are significant risk factors for developing ADStream Biomedical is commercializing a therapeutic proteinrecombinant human perlecan domain VrDVwhich has been shown in vitro and in small animals to be angiogenicantiinflammatoryneuroprotectiveand gliomodulatoryrDV inhibits amyloid induced toxicity and improves cell viability in neurons critically affected by ADas well as in brain microvascular endothelial cellsPost stroke application in rodents results in profound improvements in cellular and functional outcomesPreliminary studies investigating rDV as an anti amyloid agent suggest that rDV may exert powerful therapeutic effects in ADrDV has been shown to protect neurons and endothelial cells from amyloid induced toxicity and modulate the activity of endothelial cells and astrocytes in a synergistic manner that accelerates migration toward locus of injury while reducing chronic inflammation and glial scar formationin vitro studies of isolated brain microvasculature have demonstrated that rDV induces a p gp mediated increase in amyloid transmembrane clearance into the lumenThe next target therapeutic applications for rDV are AD and VaDto investigate its potential as a subchronic intervention for combating cellular and molecular pathologies and improving cognitive functionThe developmental objectives of this translational phaseproposal are to conduct pilot studies to investigate and identify potential therapeutic action and bioactivity in the context of AD and VaDinvestigate age specific variabilityestablish foundation for dose range finding studiesand provide insight on interaction of peripheral systems through parallel ex vivo and in vivo studies Project Narrative Currently there are no approved therapies for Alzheimer s Disease and vascular dementiasand with overmillion cases of Alzheimer s in the US and millions more worldwiderecombinant perlecan domain VrDVwill serve a significant unmet needWhile already an urgent issue facing millions of patientsfamily membersand medical providersthis need will rapidly grow as the elderly proportion of US and world populations is expected to increaseor more byrDV has shown significant promise as an anti amyloid agent in preliminary in vitro studiesand this project will serve as the basis for expanding our knowledge of rDV s therapeutic applicationswith the potential to improve quality of life for millionsand save billions of dollars in annual economic and medical costs