Stereotaxic-assisted gene therapy in Alzheimer’s and Parkinson’s diseases: therapeutic potentials and clinical frontiers

ABSTRACT

Introduction

Alzheimer’s disease (AD) and Parkinson’s disease (PD) are neurodegenerative disorders causing cognitive deficits and motor difficulties in the elderly. Conventional treatments are mainly symptomatic with little ability to halt disease progression. Gene therapies to correct or silence genetic mutations predisposing to AD or PD are currently being developed in preclinical studies and clinical trials, relying mostly on systemic delivery, which reduces their effectiveness. Imaging-guided stereotaxic procedures are used to locally deliver therapeutic cargos to well-defined brain sites, hence raising the question whether stereotaxic-assisted gene therapy has therapeutic potentials.

Areas covered

The authors summarize the studies that investigated the use of gene therapy in PD and AD in animal and clinical studies over the past five years, with a special emphasis on the combinatorial potential with stereotaxic delivery. The advantages, limitations and futuristic challenges of this technique are discussed.

Expert opinion

Robotic stereotaxis combined with intraoperative imaging has revolutionized brain surgeries. While gene therapies are bringing huge innovations to the medical field and new hope to AD and PD patients and medical professionals, the efficient and targeted delivery of such therapies is a bottleneck. We propose that careful application of stereotaxic delivery of gene therapies can improve PD and AD management.

KEYWORDS:

• Neurodegeneration
• siRNA
• CRISPR
• stereotaxis
• nanocarriers

Abbreviations in text

6-OHDA6-hydroxydopamine

AADC l-amino acid decarboxylase

AAVs adeno-associated viruses

AD Alzheimer’s disease

AEP asparagine endopeptidase

APOE apolipoprotein E

APP Amyloid precursor protein

ASOsantisense oligonucleotides

Aβbeta-amyloid

BACE1β-site APP cleaving enzyme-1

BBBblood-brain barrier

CRISPRclustered regularly-interspaced short palindromic repeats

CTcomputed tomography

LncRNAlong noncoding RNAs

MAO-Bmonoamine oxidase-B

miRNAmicroRNA

MPTP1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine

MRImagnetic resonance imaging

NFTsneurofibrillary tangles

NGFnerve growth factor

Nrr1nuclear receptor-related factor1

PDParkinson’s disease

PEGpoly(ethylene glycol)

Pitx3pituitary homeobox 3

PLGApolylactic-co-glycolic acid

PSENpresenilin

ROSreactive oxygen species

shRNAshort hairpin RNA

siRNAsmall interfering RNA

TALENstranscription activator-like effector nucleases

α-synα-synuclein

Article highlights

• Alzheimer’s and Parkinson’s diseases are the two major ageing-correlated neurodegenerative diseases.

• Gene-based biotherapeutics may help correcting or silencing genetic mutations predisposing or contributing to disease progression.

• Gene-based biotherapeutics administered systemically, packaged into viral or non-viral vectors, face many challenges hindering their efficient brain delivery.

• Stereotaxic neurosurgeries are a relatively less invasive alternative to deliver therapeutics directly to the brain.

• Clinical studies implementing stereotaxis to deliver gene biotherapeutics are hugely lagging.

• Imaging-guided stereotaxic interventions with miniaturization and optimal cost-effectiveness are the current future directions for better delivery of gene therapeutics in Alzheimer’s and Parkinson’s diseases.

Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer on this manuscript has received grant funding and consulting fees from numerous companies in the gene therapy field, including Brain Neurotherapy Bio, Biogen, Corlieve, Neurocrine, Sanofi, Sio, uniQure and Voyager. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.