G-CSF prevents the progression of structural disintegration of white matter tracts in amyotrophic lateral sclerosis: a pilot trial

Background

The hematopoietic protein Granulocyte-colony stimulating factor (G-CSF) hasneuroprotective and -regenerative properties. The G-CSF receptor isexpressed by motoneurons, and G-CSF protects cultured motoneuronal cellsfrom apoptosis. It therefore appears as an attractive and feasible drugcandidate for the treatment of amyotrophic lateral sclerosis (ALS). Thecurrent pilot study was performed to determine whether treatment with G-CSFin ALS patients is feasible.

Methods

Ten patients with definite ALS were entered into a double-blind,placebo-controlled, randomized trial. Patients received either 10µg/kg BW G-CSF or placebo subcutaneously for the first 10 days andfrom day 20 to 25 of the study. Clinical outcome was assessed by changes inthe ALS functional rating scale (ALSFRS), a comprehensive neuropsychologicaltest battery, and by examining hand activities of daily living over thecourse of the study (100 days). The total number of adverse events (AE) andtreatment-related AEs, discontinuation due to treatment-related AEs,laboratory parameters including leukocyte, erythrocyte, and platelet count,as well as vital signs were examined as safety endpoints.Furthermore, we explored potential effects of G-CSF on structural cerebralabnormalities on the basis of voxel-wise statistics of Diffusion TensorImaging (DTI), brain volumetry, and voxel-based morphometry.

Results

Treatment was well-tolerated. No significant differences were found betweengroups in clinical tests and brain volumetry from baseline to day 100.However, DTI analysis revealed significant reductions of fractionalanisotropy (FA) encompassing diffuse areas of the brain when patients werecompared to controls. On longitudinal analysis, the placebo group showedsignificant greater and more widespread decline in FA than the ALS patientstreated with G-CSF.

Conclusions

Subcutaneous G-CSF treatment in ALS patients appears as feasible approach.Although exploratory analysis of clinical data showed no significant effect,DTI measurements suggest that the widespread and progressive microstructuralneural damage in ALS can be modulated by G-CSF treatment. These findings maycarry significant implications for further clinical trials on ALS usinggrowth factors.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00298597","term_id":"NCT00298597"}}NCT00298597