Preventing and Reducing HAND by Using New BDNF Nanoprobes

Human immunodeficiency virusHIVassociated neurocognitive disorderHANDrepresents a major chronic health problem in the US and abroadMagnetic Resonance ImagingMRIstudies have consistently shown brain gray and white matter abnormalities and cognitive deficits in patients with HANDAdvances in treatment of HAND have been made by delivering drugs or viral vectors that can increase brain derived neurotrophic factorBDNFlevels in the brain indirectlyBDNF promotes neuroregeneration and restores brain functionsHoweverBDNF cannot cross an intact blood brain barrierBBBand is unstable in the blood or when delivered orallyIn Phasewe plan to further demonstrate the feasibility of our novel nanotechnology to reverse brain gray and white matter abnormalities associated with HANDand successfully treat learning and memory deficitsIn our Phasestudiesour first preclinical data showediour capabilities to successfully bioengineer novel BDNF nanoparticlesNPsiithe NPs noninvasively passed the BBBiiithe NPs effectively delivered BDNF to the brainandivthe NPs significantly enhanced neurogenesis and synaptogenesis in GT tg bigenic mice induced with doxycyclinedoxto overexpress a toxic HIV transactivator of transcriptiontatproteinThe goal of this Phaseeffort is therefore to more thoroughly test our hypothesis that BDNF nanoparticlesNPsdeliver BDNF to the affected brain regionsreverse gray and white matter abnormalities in these regionsand improve learning and memory in a GT tg mouse model of HANDTo accomplish our Phasegoals we plan a series of studies that will ascertain NP stabilitybrain and body distributionand functionality in dox induced GT tg miceAs in Phasemice will be tested with standard memory testsbut in larger numbers and with an improved treatment planFurtheranatomical MRI and diffusion tensor imagingDTIwill also be used to assess gray mater density and structural connectivity before and after NP saline treatmentsThusour Phaseresults would clear the way to PhaseThis research project will provide new noninvasive nanotechnology tools for early treatment of HANDThe new nanotechnology may be able to enhance brain gray matter densityimprove structural connectivityand restore brain functions more quickly and completely than existing treatment methodswhile using much lower therapeutic drug dosesand causing fewer side effectsThe development of a stablenontoxic nanoparticle may also provide a major new tool for research of biomarkers in HANDThis nanotechnology may serve as the basis for a next generation thernostic that can specifically target relevant brain systemsand also may have utility as an imaging agent to enhance diagnosis and monitor progression of the disease The development of a noninvasivenon toxic nanotechnology for the treatment of human immunodeficiency virusHIVassociated neurocognitive disorderHANDthat will provide a significant therapeutic advance and fill a critical unmet medical needThe new drug would be able to enhance brain gray matter densityimprove structural connectivityas well as restore brain functions quicker and better than existing HAND treatment methodsand with less side effectsThis new nanotechnology would serve as a new drug delivery platform that could target relevant brain systemsand also may have utility as an imaging agent to enhance diagnosisprognosisand monitoring of HAND