Targeting repair of oxidative damage to battle disease
Description: Established and emerging data demonstrate that oxidative damage is critical in the etiology of many diseases (e.g., cancer, cardiovascular disease, atherosclerosis, hypertension, ischemia/reperfusion injury, diabetes mellitus, neurodegenerative disorders, rheumatoid arthritis, and ageing). Extensive biochemical insights into oxidative DNA lesions, associated repair proteins and their link to disease have been made to date. Yet, a thorough understanding of the underlying pathogenic mechanisms is largely missing, and targeted therapies exploiting oxidative DNA damage have so far been unexplored. Here, we will increase our knowledge into oxidative DNA damage and repair, and selectively target DNA repair proteins involved in oxidative damage, such as Nudix hydrolases (MTH1) and glycosylases (OGG1), for proof-of-concept clinical trials for diseases involving oxidative damage.
Specifically we aim to:
A) Understand oxygen-induced DNA lesions and gain mechanistic insights into oxidative DNA repair
B) Establish and explore the MTH1 protein as a target for treatment of cancer and inflammation
C) Identify and explore inhibitors of the OGG1 enzyme as anti-viral agents (e.g., for Ebola) and as therapy for inflammatory, autoimmune and neurodegenerative diseases.
In aim A) we will determine which polymerases are important for incorporation of oxidized nucleotides in DNA using a large set of mutant cells of both essential and non-essential polymerases, and measuring levels of oxidized bases in DNA directly. Furthermore, we will explore which oxidized bases (apart from those already known) are targeted by the MTH1 enzyme as well as elucidate the precise mechanistic action of MTH1 using both live cell imaging and proteomic assays. Our long-term goal is to develop inhibitors for a wide range of Nudix hydrolases and DNA glycosylases, creating indispensable tools for further exploring their biological role in oxidative DNA damage repair and disease.
In aim B), we will leverage on our drug discovery platform which is entirely established within an academic laboratory, in order to develop our newly found MTH1 inhibitors into effective anticancer therapies. To this aim, we will progress our candidate drug(s) towards clinical trials by rigorously following regulatory requirements and filing for mandatory approval. Simultaneously, we will validate our preliminary finding that MTH1 inhibitors can kill activated T lymphocytes in vitro and in vivo. We will explore the underlying mechanism, perform validation in pre-clinical disease models in vivo, and eventually perform proof-of-concept clinical trials.
In aim C) we will evaluate the role of OGG1 in inflammation using redox-sensitive fluorescent dyes and live cell microscopy. OGG1 inhibitors will be developed and used as tools to unravel the mechanisms of OGG1 activity and explore their therapeutic potential. Additionally, preliminary data indicate a role for OGG1 inhibitors in preventing RNA virus production. Here, we will test the mechanism of action involved and explore the role of OGG1 in RNA metabolism.
Altogether, this ambitious and comprehensive research programme on oxidative DNA damage will increase our understanding of the fundamental mechanisms of oxidative metabolism and repair, provide novel mechanistic insights and shed light on the role of oxidative damage in disease. Importantly, we will generate inhibitors targeting a wide range of oxidative repair proteins, which will be absolutely central for making advances in this field. By making inhibitors in an academic framework, we can freely share them in an open innovation approach thereby facilitating scientific breakthroughs. By working closely with clinicians we can explore the therapeutic potential of our newly developed molecules and initiate ad hoc clinical trials. Given the widespread involvement of oxidative damage in disease, these treatments may potentially change clinical practice in the management of many different disease typ
Funder: Vetenskapsrådet
Amount: SEK 44,210,000
Funding type: research
Funder scheme: Research environment
Start date: 2016-01-01
End date: 2025-12-31
Investigator: Thomas Helleday
Institution: Karolinska Institutet
Funded outputs count: 46
Funder award ID: 2015-00162
OpenAlex ID: G5267358864