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Principal Investigator: MIGUEL S ESTEVES
Organization: NORTHWESTERN UNIVERSITY
Fiscal Year: 2024
Award: $548,624
Funding agency: National Institute of Neurological Disorders and Stroke
Abstract: Real-Time Tracking of Gene Therapy by Bioactivated MR contrast Probes
With mean survival rate of 5 years (and most cases are fatal) lysomal storage diseases (LSD) are among
the most dismal of prognosis in all of medicine. LSD's represent a large number of monogenetic diseases and
while rare the prevalence is to hemophilia. As monogenetic diseases with clearly defined genotype-phenotype
relations, lysosomal storage diseases are excellent candidates for gene therapy. The transformative results
documented in an adeno-associated virus (AAV) gene therapy clinical trial in infants affected by spinal
muscular atrophy demonstrated unequivocally the potential of in vivo gene transfer to treat monogenic
neurological disorder.
However, to date, there is a lack of non-invasive ways to determine biodistribution or activity levels of these
AAV therapies in patients. This is a significant hinderance, leaving investigators guessing which organs or
structures are effectively treated and, due to the lag time associated with clinical disease progression, this
limitation ultimately impacts the evolution of treatment modalities.
In order to overcome these limitations, we propose the development of a new magnetic resonance imaging
(MRI)-based technology to track enzymatic activity in any organ, peripheral nervous system (PNS), or central
nervous system (CNS) over time and thus have the potential to be applicable to any LSD caused by an
enzymatic deficiency. Magnetic resonance imaging is an ideal technique for the study of neurological
disorders. This technique is has become a gold standard in diagnostic radiology as a result of the absence of
ionizing radiation and is capable of true 3D imaging and has been in use for several decades . Detailed
structural information can be obtained in minutes, and single slices in seconds. However, the need to
differentiate regions of tissues or organs that are magnetically similar but histologically distinct has been a
major impetus for the development of contrast enhancement agents. Greater than 40% of all MR procedures
employ contrast agents with more than 450,000 million doses to date have been administered to patients and
Gd(III) based contrast agents are among the safest clinical probes in use.
We pioneered the development of bio-responsive (i.e., conditionally activated) MR contrast agents and
since that time a library of this class of probes has expanded from enzyme activated agents to pH sensitive,
the detection of ions such as Zn(II) and Ca(II), and redox activated. Here, we describe the development of a
platform where the substrate (that prevents access of water to a Gd(III) ion) is removed by an enzyme which
can be substituted to accommodate a number of gene therapy targets.
Terms: <3-D Imaging><3D imaging><Acid Maltase Deficiency Disease><Adeno-Associated Viruses><Affect><After Care><After-Treatment><Aftercare><Alpha-glucosidase><Animal Model><Animal Models and Related Studies><Aran-Duchenne disease><Architecture><Beta-glucuronidase><Biodistribution><Biological Markers><Body Tissues><Brain><Brain Nervous System><CNS Nervous System><Caffey pseudo-Hurler syndrome><Caffey syndrome><Candidate Disease Gene><Candidate Gene><Capsid><Cats><Cats Mammals><Cell Body><Cells><Central Nervous System><Chemicals><Childhood><Clinical><Common Rat Strains><Contrast Agent><Contrast Drugs><Contrast Media><Cruveilhier disease><D-Galactose><DNA Therapy><Darkness><Data><Dependoparvovirus><Dependovirus><Detection><Development><Diagnostic Radiology><Diagnostic radiologic examination><Disease><Disease Progression><Disorder><Domestic Cats><Dose><Encephalon><Engineering / Architecture><Enzyme Gene><Enzymes><Evolution><Factor VIII Deficiency><Feline Species><Felis catus><Felis domestica><Felis domesticus><Felis sylvestris catus><G(A(2)) Ganglioside><G(M1) Ganglioside><G(M1) Gangliosidosis><G(M2) Ganglioside><G(M2) Gangliosidoses><GA(2) Ganglioside><GAL gene><GAL-GMAP><GALN><GLB1><GLB1 gene><GLNN><GMAP><GUSB deficiency><Galactopyranose><Galactopyranoside><Galactosamine><Galactose><Galanin><Ganglioside GM1><Ganglioside GM2><Gangliosidoses GM2><Gangliosidosis GM1><Gene Expression><Gene Transfer><Gene Transfer Clinical><Generalized Glycogenosis><Genes><Genetic Alteration><Genetic Change><Genetic Intervention><Genetic defect><Genotype><Glucuronidase><Glycogen storage disease type II><Glycogenosis 2><Glycogenosis Type II><Hemophilia><Hemophilia A><Histologic><Histologically><Human><Hurler variant><Hurler-like syndrome><Hydrogen Oxide><Incidence><Infant><Injections><Intravenous><Investigational Drugs><Investigational New Drugs><Investigators><Ionizing Electromagnetic Radiation><Ionizing radiation><Ions><Landing syndrome><Libraries><Lipids><Liver><Lysosomal Enzyme Disorders><Lysosomal Storage Diseases><Lysosomal alpha-1,4-Glucosidase Deficiency Disease><MPS VII><MPSVII><MR Imaging><MR Tomography><MRI><MRIs><Magnetic Resonance Imaging><Magnetism><Maltase-Glucoamylase><Maltases><Measures><Mediating><Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance><Medicine><Methods><Mice><Mice Mammals><Modality><Modern Man><Modification><Monosialosyl Tetraglycosyl Ceramide><Mucopolysaccharidosis 7><Mucopolysaccharidosis VII><Murine><Mus><Mutation><NMR Imaging><NMR Tomography><Nervous System Diseases><Nervous System Disorder><Neuraxis><Neurologic Disorders><Neurological Disorders><Norman-Landing syndrome><Nuclear Magnetic Resonance Imaging><Organ><Oxidation-Reduction><Patients><Peripheral Nervous System><Phenotype><Pompe Disease><Preclinical Testing><Prevalence><Procedures><Production><Prognosis><Property><Protein Deficiency><Proteins><Radiation-Ionizing Total><Radiopaque Media><Rat><Rats Mammals><Rattus><Recycling><Redox><Research Personnel><Researchers><Safety><Sandhoff Disease><Sandhoff Jatzkewitz disease><Series><Slice><Sly Disease><Sly Syndrome><Spinal Muscular Atrophy><Structure><Survival Rate><Tay-Sachs Disease Ganglioside><Tay-Sachs disease with visceral involvement><Techniques><Technology><Testing><Thalamic structure><Thalamus><Three-Dimensional Imaging><Time><Tissues><Toxic effect><Toxicities><Translating><Translations><Treatment Efficacy><Type II GM2 Gangliosidosis><Waste Products><Water><Zeugmatography><acid maltase deficiency><adeno associated virus group><alpha 1,4 glucosidase deficiency><alpha-D-Glucoside glucohydrolases><beta galactosidase deficiency><beta-D-Glucuronoside glucuronosohydrolase><beta-Hexosaminidase><beta-N-Acetyl-D-hexosaminidase><beta-N-Acetyl-D-hexosaminide N-acetylhexosaminohydrolase><beta-N-Acetyl-hexosaminidase><beta-galactosidase-1 (GLB1) deficiency><beta-galactosidase-1 deficiency><beta-glucuronidase deficiency><beta-glucuronidase deficiency mucopolysaccharidosis><beta-n-acetylhexosaminidase><bio-markers><biologic marker><biomarker><cerebral GM1 gangliosidosis><chemical synthesis><clinical development><contrast enhanced><deficiency of protein><design><designing><developmental><experiment><experimental research><experimental study><experiments><familial neurovisceral lipidosis><full scale manufacturing><galanin prepropeptide><galanin-message-associated peptide><galanin/GMAP prepropeptide><gene repair therapy><gene therapy><gene therapy clinical trial><gene-based therapy><gene-based treatment><gene-directed therapy><gene-targeted therapy><gene-targeted treatment><generalized infantile gangliosidosis><generalized infantile gangliosidosis with bony involvement><genetic therapy><genome mutation><genomic therapy><glucoinvertase><glucosidosucrase><hepatic body system><hepatic organ system><hexosaminidase><hexosaminidase a and b deficiency><imaging agent><in vivo><inborn lysosomal enzyme disorder><intervention efficacy><ionizing output><large scale manufacturing><large scale production><lysosomal disease><lysosomal disorder><lysosome storage diseases><magnetic><manufacture><mass production><model of animal><mouse model><mucopolysaccharide storage disease VII><mucopolysaccharidosis (MPS) VII><mucopolysaccharidosis type VII><murine model><native protein drug><neurological disease><neuronal Gm(1) gangliosidosis><neurovisceral lipidosis><oxidation reduction reaction><pediatric><pharmaceutical protein><post treatment><pre-clinical testing><prevent><preventing><protein drug agent><protein-based drug><pseudo-Hurler disease><scale up><sugar><technology implementation><technology validation><thalamic><therapeutic efficacy><therapeutic enzyme><therapeutic protein><therapy efficacy><translation><translation to humans><translational applications><type I gagliosidosis GM1><type I generalized gangliosidosis GM1><α-glucosidase><β-D-Glucuronoside glucuronosohydrolase><β-Hexosaminidase><β-glucuronidase><β-glucuronidase deficiency>