Table 1.

Summary of discussed nucleic acid therapies

Molecule	Mode of action	Benefits/adverse effects	Developmental stage
Antithrombotic therapy for primary and secondary stroke prevention
ARC1779 (aptamer)	Blocks platelet activation through vWF-GPIb interaction	Dose- and concentration-dependent inhibition of vWF activity and platelet function / No major bleeding events or side effects reported	Phase I
		Decreased rate of CEA-related embolic events and radiographic defined stroke / Increased bleeding events	Phase II
Ch-9.14-T10 (aptamer)	vWF-targeting aptamer (similar to ARC1779)	Attenuated ferric chloride induced carotid artery thrombosis in the mouse	Preclinical (in vivo)
REG1 (aptamer–antidote system)	Blocked conversion of factor X to Xa	Controllable anticoagulation in healthy volunteers / No major bleeding events or side effects reported	Phase I
		Trend towards fewer ischemic complications among patients undergoing cardiac catheterization / Serious allergic reactions observed	Phase IIb
		Decreased in-stent thrombosis after PCI. / Increased bleeding risk and severe allergic reactions to the PEG moiety	Phase III
Atherogenic stroke prevention
Mipomersen (ASO)	Decreased hepatic protein synthesis of apoB-100	Decreased major cardiac events / Hepatotoxicity	Phase III ( available under a REMS)
IONIS-APO(a)Rx (ASO)	Decreased hepatic protein synthesis of apoB-100	Dose-dependent Lp(a)-reduction / No serious adverse events reported	Phase I
Prevention in inherited stroke syndromes
NOTCH3-targeting ASO	Altered pre-mRNA splicing to correct the number of cystein molecules	NOTCH-3 protein was functional and did not form pathologic aggregates	Preclinical (in vitro)
Acute ischemic stroke therapy: thrombolysis
tPA binding RNA aptamer	Inhibited tPA-LRP-1 complex formation	Attenuated BBB disruption and neuronal excitotoxicity without affecting tPA’s fibrinolytic activity	Preclinical (in vitro)
Acute ischemic stroke therapy: neuroprotection
miR-215	Overexpression of miR215 thought to attenuate upregulation of Act-1 and Il-17	Inhibited apoptosis and autophagy as well as attenuated infarct volume and functional deficits	Preclinical (in vitro, in vivo)
Acute ischemic stroke therapy: inflammation
miR-1906	Suppressed TLR-4	Decreased the inflammatory response	Preclinical (in vivo)
miR-21 mimic	Inhibited MAPK-signaling through MAP2K3	Attenuated BBB disruption, infarct extent, and functional deficit severity	Preclinical (in vivo)
anti-miR-613	Putative molecular target not reported	Decreased lipid peroxidation and ROS formation	Preclinical (in vitro)
Spatholobus suberectus	Decreased miR494, lead to upregulating of sox8 mTOR/MAPK	Improved functional outcomes after stroke	Preclinical (in vitro)
AQP-4 targeting siRNA	AQP-4 knockdown lead to c-fos and NGFI-B upregulation	Proof of principle that inhibiting AQP-4 affects astrocyte viability	Preclinical (in vitro)
Acute ischemic stroke therapy: recovery
miR-17-92	Inhibited phosphatase and tensin homolog target genes with resultant phosphorylation of downstream proteins	Increased neuronal differentiation, plasticity, and enhanced neurological recovery	Preclinical (in vivo)
anti-miR-155	Increased expression of SMAD 5, Rictor, eNOS, and Rheb	Increased microvascular and BBB integrity, attenuated neuronal injury, and increased functional recovery	Preclinical (in vivo)
Ischemic stroke biomarkers
circRNA-284-to-miR-221 ratio		Increased ratio identified patients with symptomatic carotid disease	Observational

Act-1 = nuclear factor (NF)-κB activator; apoB-100 = apolipoprotein B; AQP-4 = aquaporin-4; ASO = antisense oligonucleotide; BBB = blood brain barrier; CEA = carotid endarterectomy; eNOS = endothelial nitric oxide synthase; IONIS-APO_(a)Rx = antisense apolipoprotein A inhibitor, Il-17 = interleukin 17, LRP-1 = low-density lipoprotein receptor-related protein-1, Lp(a) = lipoprotein(a), mTOR = mechanistic target of rapamycin, MAPK = mitogen-activated protein kinases, MAP2K3 = mitogen-activated protein kinase kinase 3, NGFI-B = nerve growth factor inducible protein-B, NOTCH3 = neurogenic locus notch homolog protein 3, REG1 = pegnivacogin + anivamersen, REMS = risk evaluation and mitigation strategy, Rheb = ras homolog enriched in brain, Rictor = rapamycin-insensitive companion of mammalian target of rapamycin, ROS = reactive oxygen species, SMAD 5 = mothers against decapentaplegic homolog 5, sox8 = sex determining region Y-box 8, TLR-4 = toll like receptor-4, tPA = tissue-type plasminogen activator, vWF-GPIb = von Willebrand factor–glycoprotein Ib interaction