Stanley T. Crooke
Sunday, October 28, 2012
2:30 PM-3:30 PM
Antisense Technology: Past, Present, Future
Stanley T. Crooke
Progress in antisense technology has identified multiple post hybridization mechanisms that have been successfully exploited to produce pharmacological effects in cells, animals and humans. Advances in understanding the pharmacokinetics and toxicological properties of various types of oligonucleotides have also been reported. Together these data support optimism that RNA based therapeutics may bring value.
Session 10: Oligonucleotide Safety, PK, and Toxicity
Wednesday, October 31, 2012
2:00 PM-2:30 PM
Renal Tolerability of 2'-MOE Antisense Oligonucleotides (ASOs) and The Role of Drug Accumulation
Husam Younis, Scott P. Henry
Antisense oligonucleotides (ASO) distribute well to several tissues, and drug concentrations are typically greatest in the liver and kidney following systemic delivery. The relatively long tissue residence of ASO therapeutics is due to their long half-life (e.g. 2 to 4 weeks in liver or kidney), and affords infrequent dose administration (i.e. weekly to monthly). At relatively high doses drug accumulation of ASO therapeutics in the liver and kidney has been observed in animals. The objective of this presentation will review the safety profile of ASO therapeutics as it relates to drug accumulation in the kidney. The renal safety of the 2'-methoxy-ethyl (2'-MOE) class of ASOs will be described in rodents and non-human primates. The translation of findings observed in the kidney in animals to human safety will also be discussed.
Session 3: Chemical Modifications & Structural Biology II
Monday, October 29, 2012
12:00 PM-12:30 PM
Structure-Activity Relationships of RNase H Antisense Oligonucleotides
Multiple classes of nucleic acid analogs which increase affinity for complementary RNA were profiled for their ability to increase the potency of second generation antisense oligonucleotides in animals. As part of this effort, the biophysical, structural and biological properties of oligonucleotides modified with 2′,4′-bridged nucleic acids (BNA or LNA), alpha-L-locked nucleic acids (alpha-L-LNA), hexitol nucleic acids (HNA), tricyclo DNA (tcDNA) and 2′-modified furanose analogs were characterized. Details from these profiling efforts which resulted in the selection of a new chemistry for use in human trials will be reported.
Session 6: RNAi/ASO Preclinical Studies
Tuesday, October 30, 2012
10:30 AM-11:00 AM
Targeting alpha1-antitrypsin for the Treatment of A1AT Liver Disease
Shuling Guo1, Sheri L. Booten1, Gene Hung1, Andrew Watt1, Keith Blomenkamp2, Jeffery H. Teckman2, Susan M. Freier1, Michael L. McCaleb1, Brett P. Monia1
2St. Louis University School of Medicine
Alpha-1 antitrypsin deficiency (AATD) is a rare genetic disease due to mutations of the alpha-1 antitrypsin (A1AT) gene. Emphysema associated with AATD is caused by the deficiency of systemic A1AT protein (loss-of-function phenotype) and can be treated with augmentation therapy. In contrast, AATD Liver Disease, which is caused by aggregation and retention of mutant A1AT protein in the liver, can only be treated by liver transplantation. The hepatic pathology is the result of a toxic gain-of-function of the mutant Z protein, which affects both children and adults. We have developed optimized 2’-O-methoxyethyl (“2nd Generation”) phosphorothioate antisense oligonucleotide (ASO) drugs targeted against A1AT to determine if reducing the expression of A1AT production in liver would improve AATD-related liver disease. ASOs were designed to utilize an RNaseH-dependent mechanism of action, which promotes cleavage of A1AT mRNA. Administration of A1AT ASOs to PIZ transgenic mice expressing the mutant human gene resulted in significant reductions in hepatic A1AT mRNA and circulating A1AT levels that were dose dependent. Importantly, ASO treatment of PIZ mice produced significant reductions in A1AT protein aggregates in liver, reduced markers of fibrosis (e.g., TIMP1), and slowed fibrosis progression. Futhermore, administration of A1AT ASOs in non-human primates (50 mg/kg x 12 wk) resulted in marked reductions in hepatic and circulating A1AT mRNA and protein levels. Our data demonstrate that antisense oligonucleotide treatment can potently reduce mutant A1AT protein production and represents a potential treatment for AATD liver disease.