Translational medicine

Translational medicine is an interdisciplinary branch poised to become the major contributor of modern medicine in improvising human health. The goal of Translational medicine research at Asian Institute of Gastroenterology is to coalesce various disciplines of gastroenterology, resources, technological expertise and intellectual functions of clinicians and researchers to promote enhancements in prevention, diagnosis, and therapies of the digestive system.

AIG Hospitals has developed state of the art Translational medicine labs to translate research findings to societal benefit. The institute has a strong translational research team comprising of molecular biologists, geneticists, stem cell experts and clinician scientists. Prevalence of gastrointestinal diseases (GI) is increasing worldwide. Recognizing the need for identifying the genetic basis of GI diseases in India, whole genome sequencing is being conducted in different GI diseases aiding in better understanding the molecular basis.GMP facility is developed for cutting-edge research to conduct studies on cell-based therapies for patients with liver pancreatic and luminal diseases.

TRANSLATION IN MOLECULAR DIAGNOSIS: VIRAL HEPATITIS

Molecular detection of nucleic acid by PCR is pivotal for diagnosis and treatment of Hepatitis B (HBV) and Hepatitis C virus (HCV) that infect the human liver. At present, we are involved in such procedures for detection /quantification of HBV and HCV nucleic acid (viral load), virus genotyping, drug-resistant mutants etc using the state of the art technique and equipment. In doing so, we tried to look into a translational research question regarding the existence of virus sub-population in HBV chronicity. In this process, we developed a method which is able to detect such populations of virus which are not being detected by the commercial diagnostic system. This system developed by us is currently being tested and can be a value addition upon customization, as a diagnostic add-on to the routine test for better-personalized patient management and help to prevent transmission of the disease by identifying apparently negative but carriers of undetectable HBV sub-populations in the society.

MOLECULAR GENETICS: CHRONIC PANCREATITIS

Chronic Pancreatitis in the Indian context is different as compared to the West. Furthermore, the prevalence of CP in India is comparatively higher, idiopathic in nature afflicting the younger generations. Genetic susceptibility is considered to play a predominant role in the causation of pancreatitis irrespective of the etiology (Idiopathic, alcoholic). Individuals carrying variants in genes namely SPINK1, PRSS1, CTRC, CTSB, CFTR, CASR, CLDN2, CPA1 have a higher risk of developing the disease. We developed a genetic panel that assesses the risk of predisposition to pancreatitis in an individual that aids in imparting counselling to affected individuals and their families.

NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD)

Non-alcoholic liver disease (NAFLD) describes a range of liver conditions beginning with accumulation of fat in the liver(fatty infiltration) that progresses to non-alcoholic steatohepatitis (NASH; fat accumulation along with inflammation and scarring), cirrhosis (scar tissue replaces hepatic cells), that may finally lead to hepatocellular carcinoma (HCC). While conditions up to NASH are reversible, progression beyond NASH to cirrhosis is irreversible. Therefore it is very important to identify individuals with genetic susceptibility for fat accumulation at an early stage so that appropriate interventions that include weight reduction, lifestyle modifications, can be planned to curtail/avoid progression to higher stages. Currently, genetic variants in PNPLA3 and TM6SF2 genes are being tested to assess the risk of an individual to develop NAFLD translating to advocate dietary changes to minimize the risk and its complications

TARGETED THERAPY FOR COLORECTAL CANCER

Personalized medicine is an evolving approach to cancer, where treatment is tailored based on tumour characteristics including the mutations they harbour. Epidermal growth factor receptor (EGFR) plays an important role in the activation of pathways involved in colorectal cancer (CRC) pathogenesis. It is commonly over-expressed in metastatic CRC. Therefore it is an attractive target for anti-cancer therapies. Two drugs (cetuximab and panitumumab) are monoclonal antibodies that block EGFR action. These EGFR therapies are rendered ineffective when there are mutations in genes that activate downstream signalling pathways. Mutations in KRAS, BRAF, or NRAS genes can all activate the RAS-RAF-MAPK pathway, which is downstream from EGFR. Therefore detecting mutations in these important downstream genes is essential before initiating treatment as they predict resistance to EGFR immunotherapy.

NUDT15, AZATHIOPRINE AND IBD

Azathioprine (AZA) is a cost-effective drug that is widely used for the maintenance of remission in patients with steroid-resistant or dependent Inflammatory bowel disease. Leucopenia (decrease in the number of White blood cells) is a common complication in a subset of patients treated with AZA. Therefore it is very important to identify patients who are at a higher risk of leucopenia to avoid unnecessary complications. A variant in NUDT15 gene is known to have a strong association with thiopurine induced leucopenia in Asian ethnicity. Our research identified that patients with variants in NUDT15gene are at a higher risk of developing leucopenia. This is now translated and is being used to determine the dosage of the drug to be used in IBD patients and hence is important to know the genotype before the drug is administered.

GILBERT’S SYNDROME AND UGT1A1 GENE

Gilbert’s syndrome (GS), a common genetic condition that is harmless, and is caused because of a defective liver enzyme that is essential to the disposal of bilirubin. The abnormality in this liver enzyme results in mild elevations of bilirubin in the blood. It is usually caused by a repeat polymorphism in the promoter region of UGT1A1 gene (UGT1A1*28) apart from a missense mutation (G71R). People with GS occasionally show symptoms of jaundice, which does not need treatment. Therefore it is important to diagnose GS by genotyping for variants in UGT1A1 gene so that patients do not opt for treatment; branded/unbranded that may be detrimental.

CELL BASED THERAPIES

• Islet cell transplantation: Autologus islet cell transplantation is initiated for the first time in the country for patients with uncontrolled diabetes in chronic pancreatitis and patients undergoing pancreatic surgery for pain relief in chronic pancreatitis. Pancreatic tissue removed after surgery is subjected to clinical grade islet isolation in the GMP facility by skilled personnel and infused back into patients liver by a team of interventional radiologists and surgeons. This procedure which is a standard of care in western countries effectively prolongs/prevents surgical diabetes and improves patients quality of life.Allogenic islet transplantation for patients with Type1 diabetes is under process.
• Stem cell transplantation for pancreatogenic diabetes: Mesenchymal stem cell transplantation: This procedure is conducted as a clinical study protocol for chronic pancreatitis patients with poorly controlled diabetes. Mesenchymal stem cells are harvested from the bone marrow of patients and infused into their pancreas to insulin-secreting islet functions and control diabetes. Subcutaneous adipose tissue-derived mesenchymal stem cell study is conducted in chronic pancreatitis patients undergoing surgery for improving islet functions in patients with recently diagnosed pancreatogenic diabetes.
• Stem cell transplantation for chronic liver disease: Hematopoietic stem cells are harvested form mobilized bone marrow in chronic liver disease patients and infused back into the liver. This procedure is demonstrated to benefit the patients as a bridge to liver transplantation ie., till the time the patient gets a donor’s liver.

Mesenchymal stem cell transplantation: Stem cells are harvested from bone marrow in chronic liver disease patients and infused back into patient’s liver. This is conducted as a study protocol.