Project 3: Diagnosis and Treatment of Multiple System Atrophy

ABSTRACT The focus of the Mayo site continues to be on the pathogenesis and treatment of multiple system atrophy (MSA). To achieve these goals we propose a four-pronged plan. First, we shall continue with a safety and tolerability study of intrathecal mesenchymal stem cell (MSC) in relatively early MSA. This study is based on the hypothesis that the cause and/or progression of MSA are related to a deficiency of growth factors, especially BDNF/GDNF. The study has a strong clinical scientific basis. Our research group has demonstrated a deficiency of GDNF by >50% in experimental MSA and 50% in human MSA brain. A recent double-blind placebo controlled treatment trial has found that MSC improves function in MSA. The proposed study corrects a number of deficiencies in the published study. We use the intrathecal approach to bypass the blood-brain barrier and greater safety. The intrathecal approach improves target engagement and obviates systemic target engagement and any potential systemic complications. We have built into the proposal an efficacy component by evaluation of 3 doses of MSC to determine if there is a dose-response effect. Preliminary results suggest such a dose-response effect and slowing of progression or improvement in some cases. We have therefore incorporated an extension study where subjects receive MSC every 6 months for 2 years and have received FDA approval for the extension. A positive study would position our Consortium for a formal phase III study. Second, we propose a study of MSA biomarkers. Results from clinical trials highlight the unsatisfactory nature of diagnosis based on clinical features alone, which track end-stage disease. We plan to expand our current development of autonomic biomarkers to CSF. We shall study CSF biomarkers that are specific to MSA and track activity. In CSF, DHPG and DOPAC and Flt-3 ligand will separate MSA from normal subjects and other synucleinopathies. We shall undertake detailed studies in MSA and relate findings to severity of disease. Third, we continue our goal of discovering new approaches to improve orthostatic hypotension (OH) without aggravating supine hypertension. We have preliminary work showing the 3,4 diaminopyridine (DAP) will improve standing BP without aggravating supine hypertension. We concentrate a focus specifically in MSA (pure preganglionic lesion) and compare it with PAF (pure postganglionic lesion). This drug improves the safety factor of neural transmission during baroreflex unloading (on standing). Finally, we continue our contributions to the phenotype and natural history of the synucleinopathies. The Mayo site was the largest contributor to the completed Rifampicin study. We anticipate continued, vigorous recruitment for the natural history study. The studies described in this abstract draws heavily on collaborative activity, especially with Dr. Goldstein (CSF) and Kaufmann (natural history study).