A6 Reprogramming platform and induced pluripotent disease models for the development of novel therapeutics for PID


PRINCIPAL INVESTIGATOR
OF THE SUBPROJECT

Bild von Dr. med. PhD Axel Schambach

Axel Schambach

Axel Schambach, Dr. med. PhD
Hannover Medical School
Dept. of Experimental Hematology
Carl-Neuberg-Str. 1
30625 Hannover
Phone: +49 511 532-6069
Fax: +49 511 532-6068
E-Mail: schambach.axel@mh-hannover.de


TITLE OF SUBPROJECT

Reprogramming platform and induced pluripotent disease models for the development of novel therapeutics for PID


CONDITION/TOPIC

Primary Immunodeficiencies (PID)


OBJECTIVE(S)

  1. Create patient-specific induced pluripotent stem cell (iPSC) systems for modeling of disease pathophysiology
  2. Develop new iPSC knockout models in related pathways using CRISPR/Cas9 designer nucleases
  3. Identify and validate therapeutic approaches by:
    a) small molecule drugs involved in signaling pathways
    b) gene therapy using improved retroviral vector technologies or site-directed repair of causative mutations by CRISPR/Cas9 and homologous recombination

SUMMARY

Novel primary cell-based platforms for disease modelling and developing corresponding therapeutic options are of crucial importance for rare diseases like PID, where patient material is very limited. Induced pluripotent stem cells (iPSC) provide an expandable source of patient- and disease-specific autologous cells for drug screening and validation of novel therapeutics. In the ongoing PID-NET project, we have established a versatile and highly efficient reprogramming platform for generation of iPSC and developed a protocol for differentiation into hematopoietic cells. Based on these achievements, we aim to create new experimental systems for PID based on iPSC for modelling disease pathophysiology. As next steps, we will create new iPSC knock-out models using the CRISPR/Cas9 RNA-guided designer nuclease to introduce new PID-related mutations and to examine the effects of additional upstream and downstream mutations in the same signaling cascade. In an attempt to discover potential new treatment options, we will test small molecule compounds, which modulate these signaling pathways. Finally, we will utilize gene therapy approaches based on improved, silencing-resistant lentiviral vectors and site-directed genetic repair using CRISPR/Cas9 to experimentally validate modern therapeutic concepts for PID. This project will serve as a rich resource for a better understanding of PID and for the development of potential new therapeutic options for PID.