Gene Therapy for Parkinson's Disease Using Midbrain Developmental Genes to Regulate Dopaminergic Neuronal Maintenance

Abstract

Parkinson's disease (PD) is the second most prevalent neurodegenerative disorder. It is characterized by the progressive loss of dopaminergic (DAnergic) neurons in the substantia nigra and decreased dopamine (DA) levels, which lead to both motor and non-motor symptoms. Conventional PD treatments aim to alleviate symptoms, but do not delay disease progression. PD gene therapy offers a promising approach to improving current treatments, with the potential to alleviate significant PD symptoms and cause fewer adverse effects than conventional therapies. DA replacement approaches and DA enzyme expression do not slow disease progression. However, DA replacement gene therapies, such as adeno-associated virus (AAV)-glutamic acid decarboxylase (GAD) and L-amino acid decarboxylase (AADC) gene therapies, which increase DA transmitter levels, have been demonstrated to be safe and efficient in early-phase clinical trials. Disease-modifying strategies, which aim to slow disease progression, appear to be potent. These include therapies targeting downstream pathways, neurotrophic factors, and midbrain DAnergic neuronal factors, all of which have shown potential in preclinical and clinical trials. These approaches focus on maintaining the integrity of DAnergic neurons, not just targeting the DA transmitter level itself. In particular, critical midbrain developmental and maintenance factors, such as Nurr1 and Foxa2, can interact synergistically with neighboring glia, in a paracrine mode of action, to protect DAnergic neurons against various toxic factors. Similar outcomes could be achieved by targeting both DAnergic neurons and glial cells with other candidate gene therapies, but in-depth research is needed. Neurotrophic factors, such as neurturin, the glial-cell-line-derived neurotrophic factor (GDNF), the brain-derived neurotrophic factor (BDNF), and the vascular endothelial growth factor (VEGF), are also being investigated for their potential to support DAnergic neuron survival. Additionally, gene therapies targeting key downstream pathways, such as the autophagy-lysosome pathway, mitochondrial function, and endoplasmic reticulum (ER) stress, offer promising avenues. Gene editing and delivery techniques continue to evolve, presenting new opportunities to develop effective gene therapies for PD.

Keywords: Nurr1; Parkinson’s disease; adeno-associated virus; clinical trial; dopaminergic neuron; gene therapy; midbrain developmental genes; preclinical study.

Figure 1

Representative gene therapy clinical trials for Parkinson’s disease. Injection route and expressed viral vector for gene therapy in Parkinson’s disease.

Figure 2

Major possible genetic targets of gene therapy in Parkinson’s disease and their related pathways. Targeting the accumulation of neurotoxins, such as alpha-synuclein, by modulating autophagy, enhancing mitochondrial biogenesis, or reducing ER stress-induced apoptosis could help preserve the dopaminergic cell population.

Figure 3

Schematic figure showing midbrain factor (Nurr1 + Foxa2) combination gene therapy. The nigrostriatal pathway links the substantia nigra (SN) pars compacta in the midbrain to the dorsal striatum (comprising the caudate nucleus and putamen) in the forebrain. In healthy dopaminergic (DAnergic) neurons, Nurr1 and Foxa2 are naturally expressed and contribute to cell survival autonomously (left, normal). The degeneration of DAnergic neurons in the SN impairs this pathway, leading to Parkinson’s disease (PD). With combination treatment in glial cells (microglia, astrocytes), the environment for neuronal survival is improved (↑). Also, midbrain transcriptional factors change the expression of healthy phenotypes in DAnergic neurons, including improved dopamine synthesis and neuronal signal transmission (↑).