Doubts About Therapy for Neurological Diseases With Antisense Oligonucleotides.


Doubts About Therapy for Neurological Diseases With AntisenseOligonucleotides To the EditorThe review by Corey1 and the accompanying editorial paint a very positive picture about the potential of antisense oligonucleotides (ASOs) to treat neurological diseases such as Friedrich ataxia,2 spinal muscular atrophy,3 and Duchenne muscular dystrophy. Although the principle on whichASO-based treatment is based is promising, a reviewof the literature, however, reveals critical lacunae in thedata that have been used to claim efficacy. Antisense oligonucleotides can be used in different therapeuticstrategies. Inoneapproach,ASOshybridize tospecific sequences inpre-mRNA,whichare important insplicingof thetargeted exon. This approach has been used tomodulate splicing to achieve exon skipping or exon inclusion to treat Duchenne muscular dystrophy or spinal muscular atrophy.3 Treatment wouldbe expected to restorenear-normal levels of dystrophin or survivalmotor neuronmRNA. In Friedrich ataxia, the treatingASOtargets theexpandedrepeatwithin intron1ofFXNpremRNA, thus preventingmutant RNA frombinding to genomic DNA and allowing the restoration of frataxin transcription.1,2 However, there are formidable biological barriers to successful ASO treatment. These include difficulty crossing the vascularendotheliumandthedenseextracellularmatrix; rapid oligonucleotide clearance by the reticuloendothelial system; cell membrane barrier to intracellular entry and the need for efficient release from endosomes to achieve adequate oligonucleotide concentrations in the cytoplasm; andminimizing off-target hybridization. Recent advanced imaging studies tracking delivered oligonucleotides, such as siRNAwith fluorescent imaging andelectronmicroscopy, have shown that escape of siRNA from endosome to cytosol, both in vitro and in vivo, occurs transiently and very inefficiently (1%-2%) even when using effective lipid nanocarrier systems.4 Taking such studiesofoligonucleotidedelivery into consideration, thepreponderance of evidence suggests that the ASOs are unlikely to even reach their intracellular pre-mRNA/RNA targets. Because thetargetofASOtreatment isat theRNAlevelwith the aim of restoration of near-normal RNA levels of survival motorneuronandFrataxinordystrophinRNA, it is crucial that this be demonstrated using non–polymerase chain reaction (PCR) methods such as RNase protection assays or northern blot assays.This is important asPCRamplificationof rare transcripts after spontaneous exon skipping, for example, is of no clinical significance. If, as reported afterASO treatment, nearnormal levels of protein have been restored,2,3 then demonstration of restoredRNA levels using these non-PCRmethods would be expected to be straightforward. In conclusion, it is emphasized that consistent with this critique,5 similar claims of efficient restoration of dystrophin inDuchennemusculardystrophyusingtheexon-skippingASOs etiplirsen (Sarepta Therapeutics) and drisapersen (BioMarin) have been rejected by US Food and Drug Administration Scientific Advisory Committees in 2016. This underlines the critical need for rigorous preclinical validationwith evidence of non-PCR–based data for RNA restoration after ASO treatment, in cell cultures and animal models, before conducting clinical trials for spinalmuscular atrophy, Friedrich ataxia, or other diseases.

DOI: 10.1001/jamaneurol.2016.4332

Cite this paper

@article{Bhagavati2016DoubtsAT, title={Doubts About Therapy for Neurological Diseases With Antisense Oligonucleotides.}, author={Satyakam Bhagavati}, journal={JAMA neurology}, year={2016}, volume={73 12}, pages={1502} }