Functionalgenomics.pl initiative with headquarter in Berlin, Germany operates within estabilished US-EU scientific and technological network under research collaboration agreements with following US partners: Center for Gene Therapy, Nationwide Children’s Hospital, Columbus; Mayo Clinic Jacksonville; University Of California San Diego (UCSD); Salk Institute, La Jolla; Sanford Health Sieux Falls; Nemours Children’s Hospital Wilmington. The European network includes: Helmholtz Zentrum München; University Medical Center Utrecht; Universitätsmedizin Göttingen; Universität Düsseldorf Faculty of Medicine of the Heinrich-Heine-Universität; MSH Medical School Hamburg; Københavns Universitet.

 Within the network we investigate the molecular mechanisms underlying diseases, with a particular focus on neurodevelopmental, neurological, and neuropsychiatric disorders. To gain deeper insights into the molecular pathways involved in specific diseases and to prioritize risk variants, particularly for undiagnosed disorders, we utilize stem cell-based disease modeling. By differentiating stem cells along the neuronal lineage into brain organoids, we are able to study neurodevelopmental processes in detail under the unique genetic backgrounds of individual patients. These findings are then applied to explore potential treatment strategies, including the development of deep learning-guided, patient-specific gene therapies, combined with drug repurposing, to address the observed phenotypes.

Our recent clinical and pre-clinical research focuses specifically on decoding and developing treatments for IRF2BPL-related disorders, known as NEDAMSS. You can contribute to our collaborative IRF2BPL research network by donating patient-derived cells. For more information about the IRF2BPL.DE research initiative, please visit https://irf2bpl.de/. For details on cell donation methods and procedures, please contact Dr. Pawel Lisowski directly.

Decoding of ultra rare and undiagnosed neurodevelopmental disorders

We investigate the molecular mechanisms of diseases with the special focus on neurodevelopmental, neurological and neuropsychiatric disorders starting with clinical WES suplemented with WGS and extensive functional genomics (long and short reads RNAseq, scRNAseq, spatial transcriptomics). To get insight into molecular mechanisms of particular disease and to prioritize risk variants especially for undiagnosed disorders we apply stem cell based disease modeling and differentiation of the stem cell along neuronal lineage into neurons of interest and brain organoids to study neurodevelopmental processes in details under unique patient-specific genetic background.

Genome engineering technology development

Diseases are caused by changes to the genetic code. Genome engineering technology presents prospect for decoding and treatment for diseases under investigation. We focus on genome engineering technology development of patient specific stem and neuronal cell types to perform effective and safe genome editing in patients including somatic cell genome editing of the post mitotic neuron. These research tools are based on designer nucleases technologies such as Cas nucleases, base editors, prime editors including development of homology independent sequence replacement for correction of the broader spectrum of causative mutations while affecting one gene or for targeting of large mutations. Technology is being developed to be available as a one-time somatic gene therapy.

Gene therapy delivery for neurodevelopmental disorders

Current methods, like recombinant adeno-associated viruses (rAAVs), are limited by inefficient CNS transduction, liver injury, and the risk of genotoxicity from genome integration. These issues reduce the therapeutic potential of gene editing for CNS disorders, where precision and safety are critical. For patients with severe neurodevelopmental disorders, there is an urgent need for delivery systems that enable precise, targeted, and safe gene editing in the brain. Thus our projects aim to bridge these gaps by developing neuron-specific engineered Viral-Like Particles (eVLPs) to enhance the delivery of genome editors and other gene therapy methods.

Compounds screening and drug repurposing

We develope a deep learning (DL) algorithms tailored for cell type-specific drug repurposing to identify drugs capable of promoting neuronal commitment. Drug repurposing in neurodevelopmental disorders involves identifying and application of existing drugs, originally developed for other conditions, to treat neurodevelopmental disorders. This approach leverages the known safety profiles and mechanisms of action of these drugs, enabling faster translation into clinical use compared to developing new treatments from scratch. Repurposed drugs on our 3D human brain model systems can target underlying molecular pathways, modulate neurodevelopmental processes, or alleviate specific symptoms indentified in our high content phenotypic studies. This strategy is particularly valuable in rare or poorly understood disorders, where conventional drug development may be slow or economically unfeasible (like Leigh Syndrome or IRF2BPL-related disorders).