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Extended preservation of human livers: a nature inspired, high subzero controlled, limited freezing approach

Award Number: R44DK124053
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/13/2019
PERIOD OF PERFORMANCE END DATE: 08/31/2025

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Extended preservation of human livers: a nature inspired, high subzero controlled, limited freezing approach - ABSTRACT 1 in 5 liver waitlist patients do not receive a new liver in time, while many more patients are never listed but could benefit from liver replacement. While “bridge-to-transplant” technologies (ventricular assist devices and dialysis) have transformed the outlook for heart failure and kidney failure, no such treatment exists for patients with liver failure. Current liver sharing limits (approx. 500 miles) are based on limited preservation durations (6-10 hours). By extending preservation to just a few days we can enable nationwide (theoretically global) donor-recipient matching, allowing many livers that go untransplanted today (e.g. subsets of extended criteria donor livers that have been shown to offer substantial survival benefits) to be offered to the patients who most need them. Transplant surgeons have expressed excitement about this possibility, and it is thought that this achievement would have a profound impact on liver waitlist mortality. Among other benefits, this can also increase graft lifespan and reduce immunological rejection, eliminate the need for costly jet and helicopter transport, transform the practice of liver transplantation from emergency surgery to a flexibly scheduled procedure, and mitigate the severe disparities in liver transplantation. It will also allow immune tolerance induction protocols that have now achieved success in living donation to be adapted to the deceased donor context. To meet these needs, we will develop a comprehensive system for banking human livers for transplantation for periods of 5-7 days with a stretch goal of 10+ days or longer. We have created an integrated two-pronged approach to develop new stasis cocktails optimized for the critical phases of liver preservation: preconditioning and protection (prior to storage), preservation (during storage) and revival- resuscitation-repair (after storage). In parallel, we are creating devices for advanced perfusion, storage, and organ assessment before transplant decision. Our approach adapts the best strategies of freeze-tolerant and hibernating species, augmenting them with recent scientific and bioengineering advances. Importantly, we do not seek to solve all the problems of classical cryopreservation, but rather to be the first to develop preservation in thermodynamic equilibrium at high subzero (HSZ) temperatures (-10°C to -30°C), combined with programmed metabolic depression and enhanced stress tolerance. Feasibility of this approach has already been demonstrated; we have banked rat livers for 5 days at HSZ temperatures, and successfully preserved the first whole human liver lobe at -15°C. For this fast-track proposal, the Phase 1 goal will be to further refine our protocols and validate our initial unprecedented storage duration by banking rat livers for 5-7 days and using comprehensive post-preservation normothermic machine perfusion with functional assessment. We will also scale to whole human liver lobes, with subsequent hepatocyte isolation. Phase 2 will focus on optimizing key parameters that affect preservation outcomes in rat and human livers. Our goal is 6-10+ days of storage via (i) optimal modulation of ice growth, (ii) nature-inspired de-toxify/reenergize perfusion phase and (iii) precise control of thermodynamics using a prototype Bio-Thermodulator device.


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: 2024 ( Subtotal = $361,067 )
2024	2024	SYLVATICA BIOTECH INC	4401 LEEDS AVE	NORTH CHARLESTON	SC	29405	CHARLESTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	8/8/2024	NON-COMPETING CONTINUATION	$361,067
														Subtotal = $361,067

Issue Date FY: 2023 ( Subtotal = $926,465 )
2023	2023	SYLVATICA BIOTECH INC	3973 RIVERS AVE	NORTH CHARLESTON	SC	29405	CHARLESTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	8/30/2023	NON-COMPETING CONTINUATION	$926,465
2023	2019	SYLVATICA BIOTECH INC	3973 RIVERS AVE	NORTH CHARLESTON	SC	29405	CHARLESTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/28/2023	NEW	$0
														Subtotal = $926,465

Issue Date FY: 2022 ( Subtotal = $705,323 )
2022	2022	SYLVATICA BIOTECH, INC.	3973 RIVERS AVE STE 101	NORTH CHARLESTON	SC	29405	CHARLESTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	9/14/2022	EXTENSION WITH OR WITHOUT FUNDS	$705,323
														Subtotal = $705,323

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2019	SYLVATICA BIOTECH, INC.	3973 RIVERS AVE STE 101	NORTH CHARLESTON	SC	29405	CHARLESTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/16/2021	NEW	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $21,089 )
2020	2019	SYLVATICA BIOTECH, INC.	2231 TECHNICAL PKWY STE D	NORTH CHARLESTON	SC	29406	CHARLESTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	11/7/2019	NEW	$0
2020	2019	SYLVATICA BIOTECH, INC.	2231 TECHNICAL PKWY STE D	NORTH CHARLESTON	SC	29406	CHARLESTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	12/3/2019	NEW	$21,089
														Subtotal = $21,089

Issue Date FY: 2019 ( Subtotal = $278,617 )
2019	2019	SYLVATICA BIOTECH, INC.	2231 TECHNICAL PKWY STE D	NORTH CHARLESTON	SC	29406	CHARLESTON	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/13/2019	NEW	$278,617
														Subtotal = $278,617

Grand Total All Awards = $2,292,561

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Extended preservation of human livers: a nature inspired, high subzero controlled, limited freezing approach

Award Number: R44DK124053

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/13/2019

PERIOD OF PERFORMANCE END DATE: 08/31/2025

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