Abstract
Antisense oligonucleotide (AON)-based therapies hold promise for a range of neurodegenerative and neuromuscular diseases and have shown benefit in animal models and patients. Success in the clinic is nevertheless still limited, due to unfavourable biodistribution and poor cellular uptake of AONs. Extensive research is currently being conducted into the formulation of AONs to improve delivery, but thus far there is no consensus on which of those strategies will be the most effective. This systematic review was designed to answer in an unbiased manner which delivery strategies most strongly enhance the efficacy of AONs in animal models of heritable neurodegenerative and neuromuscular diseases. In total, 95 primary studies met the predefined inclusion criteria. Study characteristics and data on biodistribution and toxicity were extracted and reporting quality and risk of bias were assessed. Twenty studies were eligible for meta-analysis. We found that even though the use of delivery systems provides an advantage over naked AONs, it is not yet possible to select the most promising strategies. Importantly, standardisation of experimental procedures is warranted in order to reach conclusions about the most efficient delivery strategies. Our best practice guidelines for future experiments serve as a step in that direction.
Highlights
A number of neurodegenerative and neuromuscular disorders are due to known genetic defects
The development of antisense-based therapeutics has seen an increase in research efforts in a variety of neuromuscular and neurodegenerative disorders, such as Duchenne muscular dystrophy[46], myotonic dystrophy type 110, spinal muscular atrophy[47], spinocerebellar ataxia type 248 and type 349,50, Huntington’s disease[51,52], spinal and bulbar muscular atrophy[53,54] and amyotrophic lateral sclerosis (ALS) and frontotemporal dementia[55,56]
Multiple antisense drugs are in advanced clinical trials and antisense therapies for Duchenne muscular dystrophy and spinal muscular atrophy have been approved by the FDA
Summary
A number of neurodegenerative and neuromuscular disorders are due to known genetic defects. SiRNAs, on the other hand, are excluded from our analysis, as these are double-stranded and have a markedly different mechanism of action Depending on their chemistry, AONs can either sterically block (e.g. to modulate splicing) or cause degradation of the target mRNA through RNase H activity. Intrathecal injection increases the delivery efficiency of therapeutic compounds to the central nervous system This strategy has been employed successfully for SMA using the antisense drug Nusinersen, which was recently approved by the FDA11–14 reviewed by[15,16]. Another intrathecally administered antisense drug, which targets SOD1 (IONIS-SOD1Rx) for the treatment of ALS17, is in phase 1/2a clinical trial There is a pressing need for better delivery strategies, as has been stressed recently by a group of researchers in the field[18]
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