Gene therapy for Parkinson’s disease: contemporary practice and emerging concepts

ABSTRACT

Introduction

Gene therapy is a rapidly evolving technology that has predominantly utilized viral vectors to effectively deliver genetic material inside neurons to modulate the expression of one or more particular genes. Several gene therapy clinical trials have been conducted in Parkinson’s disease (PD) by exploring strategies to either restore dopamine synthesis, enhance the production of trophic factors, enhance lysosomal function, or modify the interaction between different functional nodes of the basal ganglia.

Areas covered

In this review, the authors sought to discuss contemporary practice, emerging concepts, and unmet needs for the future of gene therapy in PD.

Expert opinion

While safety has been demonstrated, clinical trials on gene therapy for PD highlight the need for higher than anticipated volumes of infusion in order to optimize dose and vector coverage. Neurosurgical delivery techniques for gene therapy have rapidly evolved from the use of multiple trans-frontal trajectories to a single parietooccipital shape-conforming infusion. The employment of convection-enhanced delivery with reflux-resistant cannulas has further improved the vector diffusion into the target structures. Future technological developments will reduce the invasiveness and duration of surgery, improve specificity and transduction capacity with novel capsid designs, and implement strategies to control transgene expression.

KEYWORDS:

• Parkinson’s
• gene therapy
• vector
• adeno-associated virus
• lentivirus
• GDNF
• trial
• neurosurgery

Article highlights

• Gene therapy for central nervous system neurodegenerative disorders involves the use of a vector, usually an adeno-associated virus or a lentivirus, to carry complementary DNA sequences into specific brain areas to modulate the expression of one or more particular genes.

• Multiple gene therapy clinical trials have been conducted in Parkinson’s disease to restore the synthesis of dopamine, to enhance the production of trophic factors, or to modify the interaction between different functional nodes of the basal ganglia.

• Gene therapy clinical outcomes improved by optimizing the putaminal coverage through the use of larger infusion volumes (increased from 40 µL in early studies up to 1800 µL in recent studies) and higher vector titers as supported by evidence from the phase-I clinical studies.

• Surgical techniques for gene therapy have rapidly evolved over the last few years with the employment of reflux-resistant cannulas, convection-enhanced delivery, and improved ability to target desired brain structures with shape-conforming infusion strategies.

• Safety has been demonstrated with gene therapy intraparenchymal administration in patients with PD, with minimal incidence of intracranial hemorrhages and other surgical complications, and no adverse events related to immunogenicity or off-target effects of transgene expression.

• Innovative techniques to minimize surgical invasiveness or duration, implementation of molecular strategies to modulate gene expression and target specificity, and increasing attention to specific genetic mutations associated with PD are anticipated to represent the major innovations in the field of gene therapy over the next 5 years.

Declaration of interest

K Bankiewicz is the founder of and equity holder of Brain Neurotherapy Bio, Inc. and Voyager Therapeutics, gene therapy companies. AD Van Laar previously received research support from Voyager Therapeutics and is an employee of Brain Neurotherapy Bio, Inc. R Lonser received consulting fees from Voyager Therapeutics and holds equity in it. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or conflict with the subject matter or materials discussed in this manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.