Engineering of Genome Editing Tools
Modifying the genome is an extremely powerful technology. It enables researchers to study gene functions in model systems and to develop therapies for patients with genetic disorders. While programmable CRISPR-Cas nucleases are ideal for generating gene deletions, they rely on homology-directed repair for introducing precise changes – a process that occurs only in dividing cells. More recently developed CRISPR-based tools do not suffer from these shortcomings, as they employ nuclease-impaired Cas proteins that edit the genome by bringing DNA-modifying enzymes into direct proximity to the target locus. So far, three different classes of such 2nd generation CRISPR-based genome editing tools have been developed: Base editors, prime editors, and transposase editors. In our lab, we have a strong interest in further developing these systems to generate variants with increased efficiency and fidelity. To achieve these goals, we perform structure-guided rational protein engineering and directed protein evolution.
Establishment of in vivo Genome Editing Approaches
In vivo genome editing is a powerful strategy for treating genetic diseases. Several preclinical studies have recently demonstrated proof-of-concept for the cure of monogenetic disorders via CRISPR-based methods. In our lab we tackle metabolic diseases that require gene correction in the liver, and neurological disorders where genome editing is required in the brain. Since both organs have a slow cellular turnover rate, we focus exclusively on 2nd generation CRISPR-based tools that do not require homology-directed repair and enable precise editing in non-dividing cells. In our projects we primarily assess safety and efficacy of in vivo genome editing approaches in different animal models. Through collaborations with other groups, we moreover anticipate to establish novel clinically viable delivery vehicles. Our long-term goal is to bring genome editing into the clinic and to facilitate the treatment of patients suffering from severe genetic diseases.
Identification of drug targets using high-throughput CRISPR screening
For many complex diseases the genetic components causing disease formation and progression are not fully understood. Identifying these genes, however, would be extremely valuable, as they represent potential drug targets that could be exploited to establish pharmacological treatments. In our lab, we perform CRISPR-Cas screening in vivo in animal models and ex vivo in human organoids to identify genes involved in the progression of colorectal and pancreatic cancer. Considering that both cancer types are associated with a hypoxic microenvironment and immune evasion, we have a particular focus on investigating the genetics of these two cancer hallmarks. Overall, we hope that our functional genomics approaches will support the development of targeted and personalized anti-cancer therapies.