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.
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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.