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Clinically Translatable MRI Reporter Genes and Imaging Methods with Ultra-High Specificity and Sensitivity

Award Number: R01EB031008
ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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Clinically Translatable MRI Reporter Genes and Imaging Methods with Ultra-High Specificity and Sensitivity - PROJECT SUMMARY Magnetic resonance (MR) reporter genes have the potential to monitor transgene expression non- invasively in real time at high resolution. These genes can be applied to interrogate the efficacy of gene therapy, monitor oncolytic virotherapy, and assess cellular differentiation, cell trafficking, and specific metabolic activity. Despite initial efforts toward developing MRI reporter genes, there are numerous complications, caused by the low sensitivity and specificity of detection, the requirement for substrates with undesirable pharmacokinetics, and the difficult interpretation of often delayed signal changes. We have previously demonstrated that many of these challenges can be overcome with the use of a lysine rich protein (LRP) reporter gene, that is detectable by chemical exchange saturation transfer (CEST) MRI, in which a frequency-selective radio-frequency pulse is used to saturate the amide exchangeable proton signal of the protein reporter. Our previous research efforts (supported by R01-EB031008) were focused on optimizing the amide proton-based reporter gene stability, maximizing the reporter protein expression, and optimizing the detection sensitivity by maximizing the amide proton exchange rate (kex). While we succeeded on all three counts, we found that the small chemical shift dispersion (Dw) of amide protons ultimately limits the sensitivity and specificity, while the very high RF powers required to efficiently saturate these fast-exchanging amide protons limits the clinical translation potential. Taking the reporter gene technology to the next level will require both (1) designing reporter proteins with exchangeable protons with significantly increased Dw, allowing for much higher specificity and sensitivity; and (2) developing MRI methods for detecting fast exchanging protons that do not require high saturation powers and can be implemented on clinical MRI scanners. In our previous research efforts to optimize amide-based reporter proteins, we discovered peptides and proteins containing tyrosine (Tyr) and tryptophan (Trp) residues that demonstrated CEST contrast from highly shifted (4-10 ppm) phenol OH and indole NH protons, with optimal kex of 2000-6000 s-1. In addition, we discovered that a water resonant chemical exchange-sensitive spin-lock (CESL) magnetic resonance fingerprinting (MRF) method can provide high detection sensitivity for fast exchanging protons without requiring high RF powers, making it suitable for clinical translation. We hypothesize that chemical exchange sensitive reporter proteins can be detected with ultra-high sensitivity and specificity under clinically relevant conditions. To test this hypothesis, and establish the clinical potential of MRI reporter genes, we will capitalize on two transformative technologies developed in our labs; (Aim 1) the discovery of Tyr- and Trp-based reporters with large Dw and fast kex; (Aim 2) the development of a CESL-MRF method for quantification of the reporter protein concentration and kex. Finally, the new reporter genes and CESL-MRF will be tested for imaging oncolytic virotherapy in mouse tumor models (Aim 3).


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: 2026 ( Subtotal = $511,947 )
2026	2026	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	6	1/9/2026	NON-COMPETING CONTINUATION	$511,947
														Subtotal = $511,947

Issue Date FY: 2025 ( Subtotal = $667,932 )
2025	2025	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	001	5	4/9/2025	COMPETING CONTINUATION	$667,932
2025	2024	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	002	4	8/28/2025	NON-COMPETING CONTINUATION	$0
2025	2024	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	4	4/1/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $667,932

Issue Date FY: 2024 ( Subtotal = $620,343 )
2024	2024	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	001	4	6/7/2024	NON-COMPETING CONTINUATION	$50,639
2024	2024	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	4	12/14/2023	NON-COMPETING CONTINUATION	$569,704
														Subtotal = $620,343

Issue Date FY: 2023 ( Subtotal = $681,396 )
2023	2023	THE GENERAL HOSPITAL CORPORATION	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	001	3	1/24/2023	NON-COMPETING CONTINUATION	$68,139
2023	2023	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	3	12/9/2022	NON-COMPETING CONTINUATION	$613,257
														Subtotal = $681,396

Issue Date FY: 2022 ( Subtotal = $682,727 )
2022	2022	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	2	12/2/2021	NON-COMPETING CONTINUATION	$614,455
2022	2022	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	001	2	7/22/2022	NON-COMPETING CONTINUATION	$68,272
														Subtotal = $682,727

Issue Date FY: 2021 ( Subtotal = $680,476 )
2021	2021	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	001	1	5/26/2021	NEW	$0
2021	2021	MASSACHUSETTS GENERAL HOSPITAL, THE	55 FRUIT ST	BOSTON	MA	02114	SUFFOLK	USA	Discovery and Applied Research for Technological Innovations to Improve Human Health	000	1	3/29/2021	NEW	$680,476
														Subtotal = $680,476

Grand Total All Awards = $3,844,821

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Clinically Translatable MRI Reporter Genes and Imaging Methods with Ultra-High Specificity and Sensitivity

Award Number: R01EB031008

ORGANIZATION: NATIONAL INSTITUTE Of BIOMEDICAL IMAGING & BIOENGINEERING

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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