Gene Therapy in Parkinson's Disease Rationale and Current Status
Gene Therapy in Parkinson's Disease Rationale and Current Status
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DOI：
10.2165/11533740-000000000-00000
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发表时间：
2010-01-01
期刊：
影响因子：
6
通讯作者：
Maguire-Zeiss, Kathleen A.
中科院分区：
文献类型：
--
作者：
Feng, Li Rebekah;Maguire-Zeiss, Kathleen A.
帕金森氏病是第二种最常见的年龄相关性神经退行性疾病，其典型特征是黑质多巴胺神经元的进行性损失和神经递质多巴胺的随之减少。患者表现出一系列临床症状，最常见的影响运动功能，包括静止性震颤、僵硬、运动不能、运动迟缓和姿势不稳定。目前的药物干预是姑息性的，主要目的是通过增加多巴胺的产生和/或抑制这种关键神经递质的代谢来增加多巴胺水平。治疗家族性和散发性帕金森病的金标准是外周给予多巴胺前体左旋多巴。然而，许多患者逐渐发展为左旋多巴引起的运动障碍和运动波动。此外，当黑质纹状体通路的一部分完整时，多巴胺增强疗法是最有用的。因此，随着黑质多巴胺神经元和纹状体投射的数量减少，这些治疗变得不那么effective.Current translational research is focused on the development of novel disease-modifying therapies，包括那些利用基因治疗方法。在此，我们提出了一个概述目前基因治疗帕金森氏病的临床试验。采用重组腺相关病毒2型（rAAV 2）或慢病毒载体，这些临床试验主要集中在三个方面：通过增加神经递质的产生来增加多巴胺水平;调节神经元表型;和神经保护。本文中讨论的前两种疗法主要是通过直接传递参与神经递质合成的基因（氨基酸脱羧酶、酪氨酸羟化酶和GTP [三磷酸鸟苷]环化水解酶1）来增加多巴胺的产生。为了绕过退化的黑质纹状体通路，第三项临床试验利用rAAV 2将谷氨酸脱羧酶递送到丘脑底核，将兴奋性神经元的子集转化为GABA产生细胞。相反，最终的临床试验旨在通过纹状体递送携带神经保护基因neurturin的rAAV 2来保护退化的黑质纹状体。基于临床前研究，这种基因治疗方法被认为可以通过增强神经元存活来减缓疾病进展。此外，我们还讨论了每项临床试验的结果，并讨论了迄今为止帕金森病基因治疗所实现的边际但增量临床进展的潜在理由。
Parkinson's disease is the second most common age-related neurodegenerative disorder, typified by the progressive loss of substantia nigra pars compacta dopamine neurons and the consequent decrease in the neurotransmitter dopamine. Patients exhibit a range of clinical symptoms, with the most common affecting motor function and including resting tremor, rigidity, akinesia, bradykinesia and postural instability. Current pharmacological interventions are palliative and largely aimed at increasing dopamine levels through increased production and/or inhibition of metabolism of this key neurotransmitter. The gold standard for treatment of both familial and sporadic Parkinson's disease is the peripheral administration of the dopamine precursor, levodopa. However, many patients gradually develop levodopa-induced dyskinesias and motor fluctuations. In addition, dopamine enhancement therapies are most useful when a portion of the nigrostriatal pathway is intact. Consequently, as the number of substantia nigra dopamine neurons and striatal projections decrease, these treatments become less efficacious.Current translational research is focused on the development of novel disease-modifying therapies, including those utilizing gene therapeutic approaches. Herein we present an overview of current gene therapy clinical trials for Parkinson's disease. Employing either recombinant adeno-associated virus type 2 (rAAV2) or lentivirus vectors, these clinical trials are focused on three overarching approaches: augmentation of dopamine levels via increased neurotransmitter production; modulation of the neuronal phenotype; and neuroprotection. The first two therapies discussed in this article focus on increasing dopamine production via direct delivery of genes involved in neurotransmitter synthesis (amino acid decarboxylase, tyrosine hydroxylase and GTP [guanosine triphosphate] cyclohydrolase 1). In an attempt to bypass the degenerating nigrostriatal pathway, a third clinical trial utilizes rAAV2 to deliver glutamic acid decarboxylase to the subthalamic nucleus, converting a subset of excitatory neurons to GABA-producing cells. In contrast, the final clinical trial is aimed at protecting the degenerating nigrostriatum by striatal delivery of rAAV2 harbouring the neuroprotective gene, neurturin. Based on preclinical studies, this gene therapeutic approach is posited to slow disease progression by enhancing neuronal survival. In addition, we discuss the outcome of each clinical trial and discuss the potential rationale for the marginal yet incremental clinical advancements that have thus far been realized for Parkinson's disease gene therapy.