Clinical Neurogenetics
The group of Ludger Schöls is developing gene therapeutic approaches in monogenetic neurological diseases. Hereby, they take advantage of direct access to patients at the center of rare neurological diseases in Tübingen (Speaker: L. Schöls).
In a first in-human gene therapeutic approach the group is developing AAV-mediated replacement of the CYP7B1 gene in patients with hereditary spastic paraplegia type 5 (SPG5). Gene transfer is supposed to normalize metabolic alterations due to loss of function mutations in CYP7B1 that lead to the transfer of neurotoxic metabolites into the brain. In close collaboration with the Ott lab at the MHH, currently an AAV8-vector approach with the human CYP7B1 gene is being tested for efficacy and tolerability in a rodent cyp7b1 knockout model presenting similar metabolic changes as in SPG5 patients.
Stefan Hauser in the Schöls Lab is developing antisense oligonucleotides that help to suppress proteins with toxic gain of function like in mutant ataxin proteins with expanded polyglutamine stretches in spinocerebellar ataxia type1, type 2 and type 3 (SCAs). Following a gapmer approach, ASOs are designed to specifically address the mutant allele and screened in patient derived iPSC-derived neurons for their ability to suppress the expression of the respective protein in an allele-specific manner.
As a clinician scientist Stefanie Hayer is focussing on Adult-onset Leukoencephalpathy with axonal Spheroids and Pigmented glia (ALSP) caused by mutations in CSF1R coding for the receptor of the cytokine CSF1, which is predominantly expressed in macrophages and microglia. She developed biomarkers which now allow to closely follow presymptomatic mutation carriers and determine the optimum point of time for allogenic HSCT, the only treatment that can halt this devastating disease. For novel therapeutic approaches, she is working on CRISPR/Cas9 mediated exchange of the mutated gene by a wildtype copy in patient derived HSCs in close collaboration with Markus Mezger (Department of Pediatric Oncology).
List of GRT projects
- Allele-specific ASO development in spinocerebellar ataxia (SCA)
- Gene supplementation in hereditary spastic paraplegia type 5 (SPG5)
- CRISPR/Cas9 mediated exchange of mutated CSF1R in ALSP
GRT expertise
- iPSC-based cell models of neurogenetic diseases
- ASO screen in iPSC-derived neurons
- Mouse models of neurogenetic diseases
- AAV-based gene therapy
- CRISPR/Cas9-based modification of stem cells
Main GRT methods applied in the lab
- iPSC generation and characterization
- Neural differentiation of iPSC e.g. in neurons, astrocytes, microglia
- mRNA-based gene replacement
- AAV-based gene replacement
- CRISPR/Cas9-based gene knock-out in iPSC