Glucocerebrosidase Gene Therapy Induces Alpha-Synuclein Clearance and Neuroprotection of Midbrain Dopaminergic Neurons in Mice and Macaques.
Diego SucunzaAlberto J RicoElvira RodaMaría CollantesGloria Gonzalez AseguinolazaAna Isabel Rodriguez-PerezIván PeñuelasAlfonso VázquezJosé L Labandeira-GarcíaVania BroccoliJosé Luis LanciegoPublished in: International journal of molecular sciences (2021)
Mutations in the GBA1 gene coding for glucocerebrosidase (GCase) are the main genetic risk factor for Parkinson's disease (PD). Indeed, identifying reduced GCase activity as a common feature underlying the typical neuropathological signatures of PD-even when considering idiopathic forms of PD-has recently paved the way for designing novel strategies focused on enhancing GCase activity to reduce alpha-synuclein burden and preventing dopaminergic cell death. Here we have performed bilateral injections of a viral vector coding for the mutated form of alpha-synuclein (rAAV9-SynA53T) for disease modeling purposes, both in mice as well as in nonhuman primates (NHPs), further inducing a progressive neuronal death in the substantia nigra pars compacta (SNpc). Next, another vector coding for the GBA1 gene (rAAV9-GBA1) was unilaterally delivered in the SNpc of mice and NHPs one month after the initial insult, together with the contralateral delivery of an empty/null rAAV9 for control purposes. Obtained results showed that GCase enhancement reduced alpha-synuclein burden, leading to improved survival of dopaminergic neurons. Data reported here support using GCase gene therapy as a disease-modifying treatment for PD and related synucleinopathies, including idiopathic forms of these disorders.
Keyphrases
- gene therapy
- genome wide
- cell death
- high fat diet induced
- copy number
- spinal cord
- wild type
- multiple sclerosis
- machine learning
- sars cov
- dna methylation
- risk factors
- type diabetes
- gene expression
- electronic health record
- spinal cord injury
- deep learning
- insulin resistance
- cerebral ischemia
- platelet rich plasma
- combination therapy
- skeletal muscle
- transcription factor