AG Mussolino -
Junior Group Genome Engineering
The goals of the research group Genome Engineering are the further development of designer nuclease platforms to render them more specific and ready for their clinical translation to treat primary and secondary immunodeficiencies.
Patients with congenital and acquired immunodeficiencies suffer from frequent and severe infections. The therapeutic options for these patients include blood stem cell transplantation, to replace the defective immune system with a healthy one provided by the donor stem cells. However, this approach is not generally applicable. HIV patients, for instance, cannot benefit from such therapy since the virus present in their body would infect the new immune system again.
We aim at modifying blood stem cells of affected patients in such a way that the derived immune cells are resistant to HIV. Since the virus enters the target cells (T cells, macrophages) via binding to the CCR5 co-receptor, HIV-resistance can be achieved in principle by eliminating this receptor from the cell surface. This can be obtained for example by selective disruption of the gene encoding the CCR5 co-receptor using designer nucleases or, as an alternative, designer repressors or epigenetic modifiers can be used to reduce or completely abolish the expression of the CCR5 gene. The research group Genome Engineering develops novel and safer types of designer effectors as nucleases, transcriptional regulators and epigenetic modifiers, based on TALEs (transcription activator-like effectors) and CRISPR-Cas9 platforms and uses standard molecular biology as well as high-throughput techniques (e.g. next generationg sequencing and RNA-seq) to assess their activity and safety. The long-term goal is the development of long-lasting therapeutic approaches for HIV patients on the basis of targeted genome or transcriptome editing in blood stem cells and the adaptation of this methodology to other acquired and congenital disorders of the immune system.