The group focusses on translational research in monogenetic neurological diseases like cerebellar ataxias and hereditary spastic paraplegias. We aim to discover the genetic cause of the diseases using whole genome sequencing to provide a definite diagnosis for our patients and to open a window into pathogenesis and potential interventions at early stages of the disease process.

In our specialized outpatient clinics we care for large cohorts of patients with these rare diseases and include them into clinical studies that aim to establish measures for progression in the natural course of disease. Biosamples including DNA, RNA, serum, urine and CSF as well as fibroblasts and PBMC are stored in our biobank and are used for the development of biomarkers indicating disease activity.

Clinical studies are matched by basic research in the lab. Here we generate induced pluripotent stem cells (iPSC) from skin biopsies of our patients. iPSCs are re-differentiated into neurons that constitute cell culture models that are genetically identical with our patients and represent the cell type that is essentially affected by the disease. This enables us to study the earliest consequences of the respective mutations and to identify new targets for therapeutic approaches. Ultimatively, new compounds can be tested in these disease-specific neuronal cell models before they are tested in animal models and finally come back to the clinic in interventional trials.

A recent paradigmatic example of this research approach is spastic paraplegia type 5, SPG5, a rare subtype of hereditary spastic paraplegia. As the clinical progression of spastic gait disturbance is slow and frequently spans two decades or more until wheelchair dependence and because the SPG5 genotype is extremely rare (prevalence ~1:1,000,000) there is no realistic chance to prove on clinical grounds that a drug is able to slow down the disease process as hundreds of patients would be required for many years in a placebo-controlled trial. In this constellation the development of a biomarker that drives the disease process is essential to prove a compound to be effective. We found 27-hydroxy-cholesterol (27-OHC) as the substrate of 7α-hydroxylase which is mutated in SPG5 (i) to be largely increased in serum and CSF of SPG5 patients, (ii) to correlate with disease severity and (iii) to be neurotoxic in iPSC-derived human neurons and to impair axonal outgrowth and axonal branching at concentrations close to those found in SPG5 patients.

On this background we searched for interventions to lower 27-OHC levels. As 27-OHC levels correlate closely with cholesterol levels we started an investigator initiated trial (IIT) to evaluate the effects of atorvastatin on 27-OHC levels in patients with SPG5. Indeed, we proved atorvastatin (40 mg/d) to lower 27-OHC levels in SPG5 patients by 30% after only 9 weeks. This example demonstrates the power of an approach that addresses crucial steps in pathogenicity and relies on genetic stratification. This helped to lower patient numbers to 2 x 7 individuals (atorvastatin and placebo group) as every single patient responded to the drug but none to placebo (Schöls et al. Brain 2017).

Now we aim for an even more efficient lowering of 27-OHC by an AAV-mediated transfer of the mutant gene. This approach is very successful in liver and blood of knockout mice lacking 7α-hydroxylase. Whether on the long run these effects translate into the brain, needs to be tested (Wiora et al., submitted).