Systemic DNA/RNA heteroduplex oligonucleotide administration for regulating the gene expression of dorsal root ganglion and sciatic nerve.

Neuropathic pain, a heterogeneous condition, affects 7%-10% of the general population. To date, efficacious and safe therapeutic approaches remain limited. Antisense oligonucleotide (ASO) therapy has opened the door to treat spinal muscular atrophy, with many ongoing clinical studies determining its therapeutic utility. ASO therapy for neuropathic pain and peripheral nerve disease requires efficient gene delivery and knockdown in both the dorsal root ganglion (DRG) and sciatic nerve, key tissues for pain signaling. We previously developed a new DNA/RNA heteroduplex oligonucleotide (HDO) technology that achieves highly efficient gene knockdown in the liver. Here, we demonstrated that intravenous injection of HDO, comprising an ASO and its complementary RNA conjugated to α-tocopherol, silences endogenous gene expression more than 2-fold in the DRG, and sciatic nerve with higher potency, efficacy, and broader distribution than ASO alone. Of note, we observed drastic target suppression in all sizes of neuronal DRG populations by in situ hybridization. Our findings establish HDO delivery as an investigative and potentially therapeutic platform for neuropathic pain and peripheral nerve disease.

DNA/RNA heteroduplex oligonucleotide technology for regulating lymphocytes in vivo.

Manipulating lymphocyte functions with gene silencing approaches is promising for treating autoimmunity, inflammation, and cancer. Although oligonucleotide therapy has been proven to be successful in treating several conditions, efficient in vivo delivery of oligonucleotide to lymphocyte populations remains a challenge. Here, we demonstrate that intravenous injection of a heteroduplex oligonucleotide (HDO), comprised of an antisense oligonucleotide (ASO) and its complementary RNA conjugated to α-tocopherol, silences lymphocyte endogenous gene expression with higher potency, efficacy, and longer retention time than ASOs. Importantly, reduction of Itga4 by HDO ameliorates symptoms in both adoptive transfer and active experimental autoimmune encephalomyelitis models. Our findings reveal the advantages of HDO with enhanced gene knockdown effect and different delivery mechanisms compared with ASO. Thus, regulation of lymphocyte functions by HDO is a potential therapeutic option for immune-mediated diseases.

Association of intramural fat deposition in the interatrial septum with focal atrial tachyarrhythmias originating near the atrioventricular node.

We describe a case with three focal atrial tachycardias (ATs) and focal atrial fibrillation (AF) originating from the interatrial septum (IAS) near the atrioventricular node (AVN). Contrast-enhanced computed tomography demonstrated the association of fat deposition within the anterior IAS near the AVN with successful ablation sites of these ATs and AF. This is the first report that the intramural fat deposition in the IAS could be associated with the formation of AT and AF re-entry circuits originating near the AVN.

Coexistence of left-sided atrioventricular accessory pathways with a common inferior pulmonary vein ostium.

BACKGROUND: As the technique for radiofrequency catheter ablation for atrial fibrillation (AF) has progressed, so has our knowledge of both normal and abnormal anatomy of the left atrium and pulmonary veins (PV). We treated several AF patients with accessory conduction pathways (ACP) who were also found to have a common ostium of inferior PVs (CIPV), a relatively rare PV anomaly. No relation between ACP and PV anomalies has ever been reported, and the aim of our study was to study this association. METHODS AND RESULTS: This study included 137 consecutive patients (104 men; mean age, 60±9 years) who underwent AF ablation for paroxysmal and persistent AF at our institution from March 2009 to August 2010. We analyzed coexisting supraventricular tachycardias and left atrium and PV morphology by multidetector row CT. Thirty-eight of 137 patients (27.7%) were found to have some PV anomaly, consisting of 13 with a common trunk of left PV, 19 with right additional PV, 3 with a common trunk of right PV, and 3 with CIPV. Thirty-one patients (22.6%) had supraventricular tachycardias. They were 26 cases of atrial flutter, 4 of Wolff-Parkinson-White syndrome, and 3 of atrioventricular nodal reentrant tachycardia. The prevalence of a coexisting ACP was significantly higher in patients with CIPV than in those without CIPV (3 of 3 [100%] versus 1 in 134 [0.7%]; P<0.0001). All ACPs with CIPV were located in the left side. The other supraventricular tachycardias were not associated with any PV anomalies. CONCLUSIONS: There is a possible association between CIPV and left-sided ACP in AF patients. This suggests that there is a likelihood of developmental association between them.