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Less Is More: Novel Hepatocyte-Targeted siRNA Conjugates for Treatment of Liver-Related Disorders.

ABSTRACT: N-acetyl-galactosamine (GalNAc) conjugation enhances liver specificity for therapeutic oligonucleotides. Here we report on a novel design with improved activity and stability compared with a triantennary design. We applied a versatile monovalent serinol-GalNAc conjugation strategy. First, 1-4 serial serinol-linked GalNAc units were conjugated to terminal positions of small interfering RNA (siRNA) molecules. In primary hepatocytes, 5' antisense GalNAc conjugates were inactive, whereas 3' antisense and 3' or 5' sense conjugates displayed low activity for single GalNAc units, while 2-4 serial GalNAc conjugates were all equally potent. In mice, 5' sense conjugates with 2-4 serial GalNAc units were all as potent as a triantennary GalNAc control (1 mg/kg). Second, increased spacing between two serial 5' sense-conjugated GalNAc units did not affect in vitro activity. Finally, two single GalNAc units were positioned at opposite ends of the sense strand. A single dose (0.3 mg/kg) of this novel conjugate in mice showed a 3-fold reduction of serum target protein level at day 7 and 4-fold lower serum level at day 27, relative to an equimolar dose of a triantennary GalNAc conjugate of the same siRNA. Improved tritosome stability (by liquid chromatography-mass spectrometry [LC-MS] analysis) can at least partially explain the increased activity and duration of action for the novel GalNAc conjugate.

SUBMITTER: Weingartner A

PROVIDER: S-EPMC7321783 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:The range of outcomes for young adults with Autism Spectrum Disorders (ASD) and the early childhood factors associated with this diversity have implications for clinicians and scientists.This prospective study provided a unique opportunity to predict outcome 17 years later for a relatively large sample of children diagnosed with ASD at 2 years old. Diagnostic and psychometric instruments were administered between 2 and 19 with data from 2, 3, and 19 included in this study. Clinicians administered tests without knowledge of previous assessments whenever possible. Caregivers provided additional information through questionnaires.Significant intellectual disabilities at 19 were predicted by age 2 about 85% of the time from VIQ and NVIQ scores together, though prediction of young adult outcome for youths with average or higher intelligence was more complex. By 19, 9% of participants had largely overcome core difficulties associated with ASD and no longer retained a diagnosis. These youths with Very Positive Outcomes were more likely to have participated in treatment and had a greater reduction in repetitive behaviors between age 2 and 3 compared to other Cognitively Able youths (VIQ ?70) with ASD. Very Positive Outcome youths did not differ phenotypically from Cognitively Able ASD individuals at 2 but both groups differed from Cognitively Less Able individuals (VIQ <70).Those most at risk for intellectual disabilities and ASD can be reliably identified at an early age to receive comprehensive treatment. Findings also suggest that some cognitively able children with ASD who participate in early intervention have very positive outcomes, although replication with randomized, larger samples is needed. In order to improve understanding of very positive outcomes in ASD, future research will need to identify how variations in child characteristics and environmental factors contribute to the nature and timing of growth across individuals and areas of development.

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Less Is More: Novel Hepatocyte-Targeted siRNA Conjugates for Treatment of Liver-Related Disorders.

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