The group focusses on translational research in neurogenetic diseases like cerebellar ataxias and hereditary spastic paraplegias. We aim to discover the genetic cause of the diseases using whole exome and genome sequencing approaches as this offers a definite diagnosis for our patients and opens a window into pathogenesis and potential interventions in early stages of the disease process.
We see many patients with these rare diseases in our specialized outpatient clinics and include them into studies establishing 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 generating induced pluripotent stem cells (iPSC) from skin biopsies of our patients. iPS cells are re-differentiated into neurons that constitute cell culture models that are genetically identical with our patients and represent the cell type that is more or less exclusively affected by the disease. This helps us studying very early consequences of the respective mutations and identifying new targets for therapeutic approaches. Finally, 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 frequently spanning several decades before the loss of ambulation and because this specific genotype is extremely rare with a prevalence of about 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 established 27-hydroxy-cholesterol (27-OHC) as a biomarker of SPG5 as (i) it is largely increased in serum and CSF of SPG5 patients. (ii) 27-OHC levels were shown to correlate with disease severity. (iii) 27-OHC impaired axonal outgrowth and axonal branching in iPSC-derived human neurons in concentrations close to those found in SPG5 patients.
On this background we searched for interventions to lower 27-OHC levels in patients. As 27-OHC levels are known to correlate with cholesterol levels we started an investigator initiated trial to prove 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 approached that addresses crucial steps in pathogenicity. Strict genetic stratification of the HSP cohort 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).