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.
