Gene therapy for neurological disorders: progress and prospects

Abstract

Adeno-associated viral (AAV) vectors are a rapidly emerging gene therapy platform for the treatment of neurological diseases. In preclinical studies, transgenes encoding therapeutic proteins, microRNAs, antibodies or gene-editing machinery have been successfully delivered to the central nervous system with natural or engineered viral capsids via various routes of administration. Importantly, initial clinical studies have demonstrated encouraging safety and efficacy in diseases such as Parkinson disease and spinal muscular atrophy, as well as durability of transgene expression. Here, we discuss key considerations and challenges in the future design and development of therapeutic AAV vectors, highlighting the most promising targets and recent clinical advances.

Focused ultrasound opening of the blood–brain barrier for treatment of Parkinson's disease

“…Implanting engineered genes has already entered into the experimental therapeutics of PD, both for improving symptomatic control and for the goal of disease modification . Several studies have been carried out.…”

“…Implanting engineered genes has already entered into the experimental therapeutics of PD, both for improving symptomatic control and for the goal of disease modification. 15,16 Several studies have been carried out. In one of them, the surgical insertion was carried out with the same stereotaxic procedure used for placing deep brain stimulation electrodes.…”

Parkinson's disease gene therapy: Will focused ultrasound and nanovectors be the next frontier?

“…In a similar vein, a recent clinical trial combined a multicatheter convection enhanced delivery system with T1‐weighted MR imaging of gadolinium‐labeled artificial cerebrospinal fluid to verify the putamen‐wide coverage of GDNF . In addition, new vectors that can be delivered systemically or into the CSF‐filled spaces may provide widespread transfection . However, this approach lacks the regional specificity often required for trophic factor therapy, with widespread delivery being potentially dangerous …”

“…8 In addition, new vectors that can be delivered systemically or into the CSF-filled spaces may provide widespread transfection. 9 However, this approach lacks the regional specificity often required for trophic factor therapy, with widespread delivery being potentially dangerous. 10 Yet another approach that we believe has promise for addressing these key issues combines (1) MR image-guided focused ultrasound (FUS) for noninvasive, regionally specific, targeting, and transient opening of the blood-brain barrier (BBB) with (2) systemically injected nanovectors that are specifically engineered to penetrate through brain tissue.…”

Pathogenesis‐targeted therapeutic strategies in Parkinson's disease

“…Although the prion-like caudal-rostral spread of pathology 2 (Braak's hypothesis) has been challenged by some, 3,4 several clinical trials are now exploring anti-α-synuclein strategies as potential disease-modifying therapies in PD. [5][6][7] A number of antibodies targeting multiple epitopes of α-synuclein have been tested in several animal models of synucleinopathy. 8 Using a mThy1-α-synuclein transgenic mouse model of PD, monoclonal antibodies directed against the C-terminus of α-synuclein were found to reduce levels of C-terminus-truncated fragments of the protein and ameliorate PD-like pathology and motor function.…”