521. Platelets Transfusion New Role as Brain Therapeutics for Acute Neuronopathic Gaucher Disease

There has no effective treatment for neuronopathic Gaucher Disease (nGD) due to the difficulty of therapeutics to cross the blood-brain-barrier. Platelets are blood elements that contain cytoplasmic secretory vesicles containing proteins involved in hemostasis, inflammation and angiogenesis. We have recently shown that platelets/megakaryocytes could serve as efficient and protective depots for lysosomal enzyme generation and distribution. In this study the potential therapeutic benefits of platelet transfusion in treating neuronopathic GD (nGD) was evaluated using a murine model of acute nGD (4L;C), which resembles types 2 and 3 Gaucher disease. Platelets containing significant amounts of wild type acid s-glucosidase enzyme (GCase) were isolated from GFP mice and transfused weekly into 4L;C mice for four times beginning at 21 days of age, resulting in an average 10-13% of donor-derived GFP+ platelets in circulation with half-life of 52 hr. Importantly, moderate platelet transfusion led to significantly increase of life-span in 4L;C mice from 47 days to 55 days with reduction of splenomegaly. The accumulation of glycosylsphingosin was significantly reduced in spleen, liver and brain. Moreover, the abnormal walk patterns with splaying of hindlimbs exhibited in 4L;C mice were improved significantly in platelet-treated mice, indicating amelioration of motor neuron dysfunction and hindlimb paresis. The improvement of short-term memory deficit in treated 4L;C mice was evidenced in repeated open-field test. Immunohistochemistry analysis showed that the elevated brain CD68+ signals, a marker for activated microglia cells, were normalized in cerebellum folium and middle brain regions, and partially corrected in the cortex, cerebellum DCN, brainstem, thalamus and spinal cord of treated 4L;C mice, indicating the reduction of pro-inflammation by platelet transfusion. Notably, RIPK3-positive signals within Purkinje neurons in cerebellum of nGD mice were significantly reduced, suggesting therapeutic benefit of platelet transfusion on neuronal necroptosis. This study reveals an under-appreciated, unexpected role for platelets in treating CNS diseases. These results provide proof of concept that platelet transfusion can achieve CNS benefits with brain substrate reduction and improvement in neurological function, as well as reducing pro-inflammation and neuronal necroptosis. The findings will open a door for new clinical approaches with platelet transfusion in treating nGD and potentially other brain diseases.