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Real-Time Tracking of Gene Therapy by Bioactivated MR contrast Probes

Award Number: R01NS115571
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Real-Time Tracking of Gene Therapy by Bioactivated MR contrast Probes - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	4/14/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $548,624 )
2024	2024	NORTHWESTERN UNIVERSITY	633 CLARK ST	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	5	6/6/2024	NON-COMPETING CONTINUATION	$548,624
														Subtotal = $548,624

Issue Date FY: 2023 ( Subtotal = $659,071 )
2023	2023	NORTHWESTERN UNIVERSITY	633 CLARK STREET	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	4	5/26/2023	NON-COMPETING CONTINUATION	$659,071
														Subtotal = $659,071

Issue Date FY: 2022 ( Subtotal = $655,861 )
2022	2022	NORTHWESTERN UNIVERSITY	633 CLARK	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	3	5/24/2022	NON-COMPETING CONTINUATION	$655,861
														Subtotal = $655,861

Issue Date FY: 2021 ( Subtotal = $645,047 )
2021	2021	NORTHWESTERN UNIVERSITY	633 CLARK	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	5/27/2021	NON-COMPETING CONTINUATION	$645,047
														Subtotal = $645,047

Issue Date FY: 2020 ( Subtotal = $629,733 )
2020	2020	NORTHWESTERN UNIVERSITY	633 CLARK	EVANSTON	IL	60208	COOK	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	8/27/2020	NEW	$629,733
														Subtotal = $629,733

Grand Total All Awards = $3,138,336

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Real-Time Tracking of Gene Therapy by Bioactivated MR contrast Probes

Award Number: R01NS115571

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 09/01/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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