Nanoparticle Distributed Intravenous Enzyme Replacement Therapy (NanoDIVERT)
Nanoparticle Distributed Intravenous Enzyme Replacement Therapy (NanoDIVERT)
批准号:
10723846
负责人:
Jessica Marie Larsen
金额:
$40.46万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-07-01 至 2025-06-30
关键词:
AdjuvantAffectAgeAnimal ModelAnimalsApolipoprotein EApolipoproteinsAreaAutopsyBiodistributionBloodBlood - brain barrier anatomyBrainBrain DiseasesCOVID-19 vaccineCellsCentral Nervous SystemClinicClinicalClinical TrialsDataDevelopmentDiseaseDoseDyesEncapsulatedEnzymesFamilyFamily FelidaeForelimbFutureGLB1 geneGangliosidosis GM1Genetic DiseasesGoalsHalf-LifeHourHumanInflammationInjectionsIntravenousIntravenous infusion proceduresLaboratoriesLow-Density LipoproteinsLysosomal Storage DiseasesLysosomesMarketingMediatingModelingMonitorMusNeurologicNeuropathyOrphanOutcome StudyPatientsPerformanceProductionProteinsRecombinantsRegimenSeverity of illnessSpecificitySpinal CordSurfaceSymptomsSystemTestingTherapeuticTherapeutic EffectTimeTissuesTreatment EfficacyVariantVesicleadeno-associated viral vectorappropriate dosebeta-Galactosidaseclinically relevantcommon symptomenzyme activityenzyme replacement therapyflexibilitygene therapyimprovedin vivoin vivo imaging systeminfancyintravenous injectionmortalitymouse modelnanoparticlenear infrared dyeneuralneurotoxicitypreventreceptorreduce symptomsscale upsuccessvector
中文摘要
项目摘要
英文摘要
PROJECT ABSTRACT
Enzyme replacement therapy (ERT) has been successful in ameliorating symptoms of patients with non-
neuropathic lysosomal storage disorders (LSDs), making it a viable therapeutic approach for these rare, orphan
genetic diseases. Essentially, patients receive intravenous (IV) infusions of endogenous enzymes that are either
present at low concentration, missing entirely, or misfolded, and therefore dysfunctional due to their genetic
disease. Despite its promise in the clinic, ERT cannot be used to treat 50-70% of LSDs with central nervous
system manifestation due to the blood-brain barrier (BBB) which prevents the passage of recombinant enzymes
from the blood into the brain. One of these diseases and the focus of this proposal, GM1 gangliosidosis, arises
from variants in GLB1 that leads to decreased production of lysosomal β-galactosidase (βgal). Its most common
form results in mortality between the ages of 2 and 4. Recently, our laboratory has created nanoparticle vesicles,
called polymersomes, capable of encapsulating and delivering βgal to lysosomes of GM1-affected cells, where
the delivered enzyme maintains its activity. Preliminary data in a feline model of GM1 gangliosidosis shows that
with the addition of an apolipoprotein on the surface, polymersomes transport active βgal across the BBB within
48 hours after an intravenous forelimb injection. This approach to treatment, titled nanoparticle distributed IV
ERT (NanoDIVERT), can potentially extend ERT into the central nervous system, which could impact not only
GM1 gangliosidosis but also other orphan neuropathic LSDs. To further test the applicability of the nanoparticle-
mediated approach to IV ERT, we will optimize in vivo performance. Specifically, we aim to increase delivery to
the brain and determine the most appropriate dosing for therapeutic effects. We aim to initially optimize
NanoDIVERT in a murine model of GM1 gangliosidosis, for testing in greater animal numbers, before scaling up
to large animal models. The outcome of these studies could enable the development of a clinically relevant ERT
for GM1 gangliosidosis and other neuropathic LSDs for the first time.
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