AAV2-GDNF for Advanced Parkinson s Disease

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Objective: While medications can temporarily alleviate the symptoms of Parkinson s disease (PD), they do not influence the degenerative process. Progressive loss of nigral dopaminergic (DA) neurons (the pathological hallmark of PD) results in progressive neurologic dysfunction and death. Glial cell ...

Objective: While medications can temporarily alleviate the symptoms of Parkinson s disease (PD), they do not influence the degenerative process. Progressive loss of nigral dopaminergic (DA) neurons (the pathological hallmark of PD) results in progressive neurologic dysfunction and death. Glial cell line-derived neurotrophic factor (GDNF) was first identified based on its ability to promote the survival of embryonic DA neurons in vitro, and research has demonstrated beneficial effects of GDNF in animal models of PD. Preliminary clinical trials of GDNF infusions have yielded inconclusive results. Observed problems with tolerability and efficacy in these studies may have been related to the methods of delivery. Recent evidence indicates that gene transfer via direct delivery of viral vectors may represent a superior approach for the treatment of PD with GDNF. Study population: Twenty-four adult male and female subjects with advanced Parkinson s disease, who are candidates for surgical treatment for Parkinson s disease and who meet all Inclusion and Exclusion Criteria. Design: We propose a Phase 1 single-center, open-label, dose escalation, safety and tolerability study of adeno-associated virus, serotype 2 vector (AAV2) containing human GDNF complementary DNA. Bilateral catheters will be placed surgically through the skull and into the brain and the vector will be delivered by convection-enhanced delivery (CED) to both putamina (450 microliters per hemisphere) of 24 patients with advanced PD. An additional 76 subjects will be allowed for screening failures. Four escalating dose levels will be evaluated in the following dose cohorts (6 patients per cohort): Cohort 1 = 9 x 10(10)vg, Cohort 2 = 3 x 10(11)vg, Cohort 3 = 9 x 10(11)vg and Cohort 4 = 3 x 10(12)vg. Outcome measures: To assess the safety, tolerability, and potential clinical effects of CED of AAV2-GDNF in advanced PD patients, we will use defined clinical evaluations of PD (Unified Parkinson s Disease Rating Scale, Modified Schwab and England Activities of Daily Living scale, Hoehn and Yahr Staging, Lang and Fahn Dyskinesia Rating Scale, On-Off Patient Diary, Quality of Life, Modified Rankin Scale, Adverse Event Log and neurologic examinations), laboratory studies (hematologic, immunologic and chemistry), neuropsychological testing (Mattis Dementia Rating Scale, Beck Depression Inventory II and Parkinson Psychosis Questionnaire) and neuroimaging (magnetic resonance imaging and positron emission tomography).

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