MRI‐guided Phase 1 Trial of Putaminal AADC Gene Therapy for Parkinson’s Disease

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ABSTRACT

Objective

To understand the safety, putaminal coverage, and enzyme expression of adeno‐associated viral vector serotype‐2 encoding the cDNA for the enzyme aromatic L‐amino acid decarboxylase (VY‐AADC01) delivered using novel intraoperative monitoring to optimize delivery.

Methods

Fifteen subjects (3 cohorts of 5) with moderately‐advanced Parkinson’s disease and medically‐refractory motor fluctuations received VY‐AADC01 bilaterally co‐administered with gadoteridol to the putamen using intra‐operative MRI‐guidance to visualize the anatomic spread of the infusate and calculate coverage. Cohort 1 received 8.3×1011 vg/mL and ≤450 μL per putamen (total dose ≤7.5×1011 vg); cohort 2 received the same concentration (8.3×1011 vg/mL) and ≤900 μL per putamen (total dose ≤1.5×1012 vg); cohort 3 received 2.6×1012 vg/mL and ≤900 μL per putamen (total dose ≤4.7×1012 vg). (18)F‐fluoro‐L‐dihydroxyphenylalanine positron emission tomography at baseline and 6 months post‐procedure assessed enzyme activity; standard assessments measured clinical outcomes.

Results

MRI‐guided administration of ascending VY‐AADC01 doses resulted in putaminal coverage of 21% (cohort 1), 34% (cohort 2) and 42% (cohort 3). Cohorts 1, 2 and 3 showed corresponding increases in enzyme activity assessed by positron emission tomography of 13%, 56%, and 79%, and reductions in anti‐parkinsonian medication of ‐15%, ‐33%, and ‐42%, respectively at 6 months. At 12 months, there were dose‐related improvements in clinical outcomes including increases in patient‐reported ON‐time without troublesome dyskinesia (1.6, 3.3, and 1.5 hours, respectively), and quality of life.

Interpretation

Novel intraoperative monitoring of administration facilitated targeted delivery of VY‐AADC01 in this phase 1 study, which was well tolerated. Increases in enzyme expression and clinical improvements were dose dependent.

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