Haploinsufficiency Profiling Service for NASH Target Discovery

Through our comprehensive early discovery, nonclinical and commercialization services, Creative Biolabs is committed to developing the most promising nonalcoholic steatohepatitis (NASH) drug target for our clients. With in-depth expertise in molecular modeling, structural analysis, as well as in vivo and in vitro studies, we can provide a series of haploinsufficiency profiling services basing on a full range of state-of-art technologies. We will help our worldwide customers reduce drug development time and promote the candidate drugs to clinical trials for a wide range of disease treatment.

Introduction to Haploinsufficiency

Haploinsufficiency has been considered as a situation of loss-of-function caused by one copy of a gene in diploid organisms. In general, this loss-of-function is related to the incidence of a wide variety of diseases, such as Sotos syndrome, acute myeloid leukemia (AML) as well as NASH. More recent studies have demonstrated that haploinsufficiency may be caused by a newborn or genetically deficient mutation of a particular protein, with a 50% expression level in a cell, and thus not enough for normal functions. Meanwhile, the deletion or missense mutations in a gene copy can cause the low expression or non-functional expression of proteins, eventually leading to the haploinsufficiency. Furthermore, recent researches have shown that haploinsufficiency is one of the main causes of immunodeficiency, for instance, MonoMac syndrome is a disease caused by the one copy of a gene mutation of GATA-binding factor 2 (GATA2). GATA2 variant is associated with B cell deficiency, virus infection and the occurrence of hematopoietic malignancies. In addition, pilot studies have illustrated that the CDGSH iron-sulfur domain-containing protein 2 (CISD2) haploinsufficiency can promote the NASH progression, suggesting that the haploinsufficiency profiling will be a powerful tool for discovering the mechanism of action (MOA) and bioactivity of target candidates for NASH therapy.

Fig.1 Diagram of the HIPHOP assay. (Smith, 2010)

Our Platform for Haploinsufficiency Profiling

HaploInsufficiency profiling (HIP) is a common method for studying the sensitivity of the drug candidate at the genetic level. Creative Biolabs has developed a panel of high-throughput assays to measure the potential drug targets and identify the interaction between candidate drug and the target. In our platform, the yeast strains are widely used for carrying deletions in genes encoding known drug targets, and each yeast stain is tagged by a specific sequence of 20 base pairs as a biomarker. All the stains are cultured and grown in a particular condition, such as test compounds or candidate drugs. The abundance of these stains will be evaluated and quantified by a range of techniques, including hybridization microarray, polymerase chain reaction (PCR) and high-throughput sequencing. The surviving strains carrying specific variants will be collected in the tested condition. Currently, HIP has been regarded as a growth strategy, that is, the deleted strain is highly specific to the candidate drug and will be identified in a rapid and cost-effective manner. We have successfully accomplished a number of projects on haploInsufficiency profiling and are confident of offering a full spectrum of HIP services to discover new drug targets for disease therapy, especially for NASH treatment.

As a global contract research organization, Creative Biolabs is committed to providing a wide range of drug discovery and development services for various disease types. We utilize unrivaled, proprietary drug design, study data, product candidate, advanced project life-cycle management, as well as real-time data to ensure the ideal outcomes. For more information, please feel free to contact us or send us an inquiry.

Reference

1. Smith, A.M.; et al. A survey of yeast genomic assays for drug and target discovery. Pharmacol Ther. 2010, 127(2): 156-164.