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Ubiquitin D as a potential therapeutic target for NASH, HCC and chronic kidney diseases

Award Number: R01DK133930
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: 08/01/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Ubiquitin D as a potential therapeutic target for NASH, HCC and chronic kidney diseases - Abstract: Non-alcoholic steatohepatitis (NASH), an advanced form of non-alcoholic fatty liver disease (NAFLD), is one of the major causes of cirrhosis and hepatocellular carcinoma (HCC). There is currently no approved treatment for NASH and patients with advanced fibrosis are at highest risk of mortality due to cardiovascular diseases (CVD). Furthermore, presence of NAFLD increases the risk of chronic kidney disease (CKD) by about 80%. It is not known how NASH and CKD influence each other, but together they can influence CVD and patient mortality. Therefore, a therapeutic target that can improve NASH and its associated co-morbidities such as CKD and CVD will be of great benefit in clinics. We found that Ubiquitin D (UBD) is highly upregulated in NASH livers (primarily in the hepatocytes), HCC tumors and kidneys of CKD mice. Interestingly, UBD was recently found to be one of the six progression-related genes that play a vital role in the progression of NAFLD and positively correlates with steatosis, ballooning, inflammation, fibrosis and NAS score. Similarly, multiple reports link renal UBD to proteinuria and kidney disease. UBD is known to participate in alternative ubiquitination pathway and interact with key cellular proteins such as p53, p62 and MAD2 but the precise mechanism of its role in NASH/HCC and CKD remains unclear. Absence of UBD (in Ubd-/- mice) improved overall metabolic health and extended the mouse lifespan. Despite all the compelling evidences, UBD has not been tested as a therapeutic target for NASH and CKD. Here, we propose to suppress UBD using anti-sense oligos (ASOs) as a therapeutic approach to treat NASH and CKD. We have already developed a “GalNAc” conjugated ASO that is potent in suppressing UBD gene expression in the hepatocytes. Our preliminary data indicates that anti-UBD GalNAc-ASO significantly improved NASH and fibrosis. According to our knowledge, UBD pathway has not been investigated for its therapeutic potential before and also is not a current focus of any industry or academia. Therefore, UBD is a novel target and anti-UBD ASOs provide novel therapeutic leads with a potential to improve both NASH and CKD. We will take advantage of a unique pre-clinical mouse model of diet-induced NASH that also develop CKD and CVD with mortality at later stages (established in our lab). We will address whether anti-UBD ASOs could improve all three disease outcome along with survival benefit. We will supplement this model with additional preclinical models of NASH, HCC and CKD. The following 2 Specific Aims will be addressed in this proposal: Aim 1 will Identify whether UBD suppression prevents NASH and its progression to Cirrhosis and HCC. Additionally, we will translate our findings to human using human primary cell derived 3-D spheroid cell cultures. Aim 2 will investigate the effect of UBD suppression on CKD, CVD and survival benefit either in the context of NASH and/or CKD. Successful completion of the proposed aims will establish UBD as a novel therapeutic target for NASH and CKD.


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 = $500,000 )
2026	2026	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	6/18/2026	NON-COMPETING CONTINUATION	$500,000
														Subtotal = $500,000

Issue Date FY: 2025 ( Subtotal = $500,000 )
2025	2025	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	3	7/2/2025	NON-COMPETING CONTINUATION	$500,000
2025	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/18/2025	NEW	$0
														Subtotal = $500,000

Issue Date FY: 2024 ( Subtotal = $480,000 )
2024	2024	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	8/23/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$480,000
2024	2024	SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE	10901 N TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	002	2	8/27/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
2024	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	8/22/2024	NEW	$0
														Subtotal = $480,000

Issue Date FY: 2023 ( Subtotal = $500,000 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/27/2023	NEW	$500,000
														Subtotal = $500,000

Grand Total All Awards = $1,980,000

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Ubiquitin D as a potential therapeutic target for NASH, HCC and chronic kidney diseases

Award Number: R01DK133930

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: 08/01/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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