シンポジウム
43 神経疾患遺伝子治療の最先端
43 Recent Advances of Gene Therapy for Neurological Disorders
座長：望月 秀樹（大阪大学大学院医学系研究科神経内科学）・Papa Stella（Emory University School of Medicine and Yerkes National Primate Research Center） |
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| 2022年7月3日 9:00～9:30 沖縄コンベンションセンター 会議場A1 第2会場
4S02m-01
Multiple targets for gene therapy in Parkinson's disease
*Stella M Papa(1)
1. Emory University
Keyword: Gene therapy, Parkinson's Disease, gene knockdown, gene transfer
Manipulating the expression of genes with high specificity and cellular or regional selectivity in the brain is a growing therapeutic strategy for neurodegenerative disorders. Gene therapies for Parkinson’s disease (PD) have explored various molecular targets with the goal not only to provide symptomatic improvement but also to offer a disease-modifying intervention. Early efforts to reduce motor impairment included gene transfer to enhance the production of dopamine from L-DOPA by targeting the amino-acid decarboxylase, or to regulate GABA levels in the subthalamic nucleus by targeting the expression of glutamic acid decarboxylase. Attempts to support dopaminergic neuron survival or regeneration were initially directed to increasing the gene expression of neurotrophic factors. More recently the suppression of genes has gained traction as a means to reduce the expression of proteins with a pathogenetic role in PD, such as α-synuclein or LRRK2. In spite of variable preclinical results, some gene therapies have made it to clinical trials while others are still in earlier stages. We will review the current status of these studies in view of their future advance to clinical use. In addition, new genes are emerging as promising candidates to target molecular mechanisms of dysfunction and neurodegeneration in PD. Therefore, we will also discuss the current work for probing gene transfer or knockdown from the perspective of future development into a gene therapy for PD. | | 2022年7月3日 9:30～10:00 沖縄コンベンションセンター 会議場A1 第2会場
4S02m-02
アデノ随伴ウイルスベクターを用いた効果的な遺伝子治療を実現するカプシドと細胞種特異的プロモーターの組み合わせ
Suitable combination of AAV capsid and cell type-specific promoter for effective gene therapy
*平井 宏和(1,2)
1. 群馬大学大学院医学系研究科、2. 群馬大学ウイルスベクター開発研究センター
*Hirokazu Hirai(1,2)
1. Gunma Univ Grad Sch Med, Gunma, Japan, 2. Gunma Univ, Viral Vector Core, Gunma, Japan
Keyword: AAV, Capsid, Promoter, Gene therapy
Recent progress of gene therapy using adeno-associated virus (AAV) vectors achieved excellent therapeutic outcome for a couple of CNS diseases, and many clinical trials for different diseases are ongoing. AAV-based gene therapy is definitely promising for intractable CNS diseases. However, since patients receive extremely high dose viruses for effective gene therapy, they often get adverse effects such as substantial liver damage and exaggerated immune reaction. Administration of high dose of AAV vectors may cause expression of a therapeutic gene in untargeted cell types/tissues. Reducing the viral dose ideally without compromising therapeutic effects has great benefits to patients. This could be attained by choosing a suitable capsid with high affinity to target cell population and employing a promoter that works selectively in the target cell type. A problem is that most experiments to characterize capsids and promoters are done using rodents (mainly mice), because properties of capsids and cell type specificities of promoters often differ among species. Here, I will show infectious properties of various natural and engineered capsids such as PHP.eB and AAV-F and cell type-specific promoters in mice and marmosets. Promoters include those specific for inhibitory neuron, excitatory neuron, cerebellar Purkinje cell, astrocyte and microglia. Based on the results, I will propose examples of effective combination of a capsid with a cell type-specific promoter for efficient transgene delivery, which help to significantly reduce a viral dose and serious adverse effects. | | 2022年7月3日 10:00～10:30 沖縄コンベンションセンター 会議場A1 第2会場
4S02m-03
小児遺伝性神経疾患に対する遺伝子治療
Gene therapy for pediatric hereditary neurological disorders
*小野寺 雅史(1)
1. 国立成育医療研究センター
*Masafumi Onodera(1)
1. National Center for Child Health and Development
Keyword: gene therapy , pediatrics, in vivo gene therapy , ex vivo gene therapy
Gene therapy for pediatric hereditary neurological diseases without any effective therapeutic options has achieved clinical results as effective as a curative treatment and some of them have been approved as pharmaceutical products based on the results. The selection of the treatment method is often determined by the cell type that causes the disease. For example, in vivo gene therapy in which a therapeutic gene is directly infused into a patient’s body is selected for a disease caused by the nerve cell itself. For diseases with neuropathy caused by accumulated metabolites representative by congenital metabolic disorders, ex vivo gene therapy is selected where dysfunctional microglia are replaced with genetically corrected ones derived from patient’s hematopoietic stem cells. Since the different kind of viral vectors and the different administration routes are sometime adopted for the same diseases, however, the proper methods have been investigated for each disease of a wide variety of pediatric neurological diseases and the clinical results regarding safety and efficacy have been published. Of very importance is to understand that gene therapy is still under development, and the therapy may affect human genes including the next generation since the mode of action of the therapeutic effect is placed on genetic manipulation. Therefore, the therapy is considered to require long-term follow-up of treated patients. In this session, I will introduce typical examples of gene therapy for pediatric hereditary neurological diseases and consider the status and future development of gene therapy for these neurological diseases. | | 2022年7月3日 10:30～11:00 沖縄コンベンションセンター 会議場A1 第2会場
4S02m-04
ALSの遺伝子治療
Gene therapy for ALS
*長野 清一(1)、佐々木 勉(1)、望月 秀樹(1)
1. 大阪大学大学院医学系研究科
*Seiichi Nagano(1), Tsutomu Sasaki(1), Hideki Mochizuki(1)
1. Grad Sch Med, Osaka Univ, Suita, Japan
Keyword: ALS, GENE THERAPY, MITOCHONDRIA, RIBOSOMES
Amyotrophic lateral sclerosis is a fatal neurodegenerative disease that affects motor neurons of the whole body to cause muscle weakness of the limbs and the trunk, dysarthria, dysphagia and respiratory failure. There is no effective treatment so far. Although the cause of the disease has not been fully understood, it is known that mislocalization and abnormal deposition of superoxide dismutase (SOD)1 or TAR-DNA binding protein (TDP)-43 occur in neurons of most ALS patients. SOD1 is an antioxidative enzyme localizing mainly in the cytoplasm, but ALS-linked mutant SOD1 mislocalizes in mitochondria and disrupts the function of the apparatus. TDP-43 is an RNA binding protein involved in the metabolism and transport of various RNAs, and it has been reported that disruption of the function may result in impaired activities of mitochondria and ribosomes in cell bodies or neurites of neurons. From this point of view, we aim to promote the function of mitochondria or ribosomes in ALS, and to develop a novel treatment strategy for ALS by increasing expression of genes related to these functions. We discuss the future of ALS gene therapy based on our data obtained so far. | |
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