Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

TLC-1235, a controlled-release mitochondrial protonophore (CRMP), for the reversal of insulin resistance in patients with severe lipodystrophy

Award Number: R44DK135174
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: 09/22/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2025

Group Awards By:

View Award Description

TLC-1235, a controlled-release mitochondrial protonophore (CRMP), for the reversal of insulin resistance in patients with severe lipodystrophy - TLC-1235, a controlled-release mitochondrial protonophore (CRMP), for the reversal of insulin resistance in patients with severe lipodystrophy Abstract Patients with lipodystrophies exhibit hypertriglyceridemia, severe insulin resistance, type 2 diabetes mellitus, and nonalcoholic steatohepatitis (NASH), and have limited effective treatment options. Lipodystrophy is characterized by the ectopic accumulation of lipids in liver and muscle. Increased lipids, specifically sn-1,2- diacylglycerol, within plasma membranes interfere with insulin receptor signaling and are a central mechanism for insulin resistance. Mitochondrial protonophores reduce intracellular lipids by increasing lipid oxidation in the mitochondria. Mechanistically, mitochondrial protonophores shuttle protons across the inner mitochondrial membrane via a pathway that is independent of adenosine triphosphate (ATP) synthase, thereby uncoupling nutrient oxidation from ATP production and dissipating the proton gradient as heat. The therapeutic efficacy of protonophores is linked to 1) increased oxidation of fatty acids to compensate for inefficient ATP production, 2) a decrease in the production of reactive oxygen species (ROS) from the electron transport chain, and 3) activation of the expression of AMP protein kinase (AMPK), the master regulator of cellular energy homeostasis. Thus, small molecule mitochondrial protonophores represent a novel strategy to reduce ectopic lipid accumulation by increasing cellular energy expenditure. Indeed, multiple groups have validated this mechanism of action by demonstrating large improvements in insulin sensitivity and dyslipidemia, with concomitant reductions in hepatic triglycerides and markers of inflammation in relevant nonclinical models. TLC-1235 is a functionally liver-targeted, controlled-release mitochondrial protonophore (CRMP) that will promote selective mitochondrial uncoupling in the liver while minimizing high systemic exposures (Cmax) that have been associated with adverse effects of systemic uncoupling including hyperthermia, excessive weight loss, and muscle injury. During this Direct-to-Phase-2 project, we will initiate Investigational New Drug (IND)-enabling activities for TLC- 1235, including Good Laboratory Practice (GLP) manufacturing, drug metabolism and pharmacokinetics (DMPK), and toxicology and safety pharmacology studies. Additional work to support the filing of an IND will be funded by the Company.


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 = $0 )
2026	2024	ORSOBIO, INC.	101 JEFFERSON DR	MENLO PARK	CA	94025	SAN MATEO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	11/19/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2022	ORSOBIO, INC.	101 JEFFERSON DR	MENLO PARK	CA	94025	SAN MATEO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	2/12/2025	NEW	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $999,999 )
2024	2024	ORSOBIO, INC.	101 JEFFERSON DR	MENLO PARK	CA	94025	SAN MATEO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	8/16/2024	NON-COMPETING CONTINUATION	$999,999
														Subtotal = $999,999

Issue Date FY: 2023 ( Subtotal = $999,999 )
2023	2023	ORSOBIO, INC.	101 JEFFERSON DR	MENLO PARK	CA	94025	SAN MATEO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	2	9/8/2023	EXTENSION WITH OR WITHOUT FUNDS	$999,999
2023	2022	LIVER COMPANY INC., THE	2671 MARSHALL DR	PALO ALTO	CA	94303	SANTA CLARA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	10/24/2022	NEW	$0
2023	2022	ORSOBIO, INC.	101 JEFFERSON DR	MENLO PARK	CA	94025	SAN MATEO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	1	8/18/2023	NEW	$0
														Subtotal = $999,999

Issue Date FY: 2022 ( Subtotal = $299,999 )
2022	2022	LIVER COMPANY INC., THE	2671 MARSHALL DR	PALO ALTO	CA	94303	SANTA CLARA	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	9/22/2022	NEW	$299,999
														Subtotal = $299,999

Grand Total All Awards = $2,299,997

Top

All Categories

About

Search

Reports

Data Submission

Award Information

TLC-1235, a controlled-release mitochondrial protonophore (CRMP), for the reversal of insulin resistance in patients with severe lipodystrophy

Award Number: R44DK135174

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: 09/22/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2025

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer