Safety and tolerability of putaminal AADC gene therapy for Parkinson disease  

Oleh:

Christine, C. W. ; Starr, P. A. ; Larson, P. S.

Jenis: Article from Journal - ilmiah internasional
Dalam koleksi: Neurology (Official Journal of The American Academy of Neurology) vol. 73 no. 20 (Nov. 2009), page 1662-1669.
Topik: dopamine; amino acid decarboxylase; Parkinson disease

Ketersediaan

Perpustakaan FK Nomor Panggil: N11.K.2009.07 Non-tandon: 1 (dapat dipinjam: 0) Tandon: tidak ada

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Background: In Parkinson disease (PD), the benefit of levodopa therapy becomes less marked over time, perhaps because degeneration of nigrostrial neurons causes progressive loss of aromatic l-amino acid decarboxylase (AADC), the enzyme that converts levodopa into dopamine. In a primate model of PD, intrastriatal infusion of an adeno-associated viral type 2 vector containing the human AADC gene (AAV-hAADC) results in robust response to low-dose levodopa without the side effects associated with higher doses. These data prompted a clinical trial. Methods: Patients with moderately advanced PD received bilateral intraputaminal infusion of AAV-hAADC vector. Low-dose and high-dose cohorts (5 patients in each) were studied using standardized clinical rating scales at baseline and 6 months. PET scans using the AADC tracer [18F]fluoro-l-m-tyrosine (FMT) were performed as a measure of gene expression. Results: The gene therapy was well tolerated, but 1 symptomatic and 2 asymptomatic intracranial hemorrhages followed the operative procedure. Total and motor rating scales improved in both cohorts. Motor diaries also showed increased on-time and reduced off-time without increased "on" time dyskinesia. At 6 months, FMT PET showed a 30% increase of putaminal uptake in the low-dose cohort and a 75% increase in the high-dose cohort. Conclusion: This study provides class IV evidence that bilateral intrastriatal infusion of adeno-associated viral type 2 vector containing the human AADC gene improves mean scores on the Unified Parkinson’s Disease Rating Scale by approximately 30% in the on and off states, but the surgical procedure may be associated with an increased risk of intracranial hemorrhage and self-limited headache.

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