Ionis Pharmaceuticals Presents New Preclinical Data at the North American Cystic Fibrosis Conference

Ionis presented four posters on preclinical findings at the 30th Annual North American Cystic Fibrosis Conference (NACFC) on October 27-29, 2016 in Orlando Florida. These posters highlight the substantial progress Ionis has made in its cystic fibrosis (CF) drug discovery program. The following posters were presented at the NACFC Conference:

Poster #18 – 16-0104
Antisense Oligonucleotide-Mediated Upregulation of CFTR via Steric Block of Post-Transcriptional Control Elements: A Novel Approach for Cystic Fibrosis Therapeutics
Shruti Sasaki; Chenguang Zhao; Jeff R. Crosby; Brett P. Monia and Shuling Guo
Poster #22 – 16-0105
Upregulation of CFTR with Nonsense Mutations by Promoting PTC Read-through or Modulating the Nonsense Mediated Decay Pathway with Antisense Oligonucleotides
Melissa M. Keenan; Lulu Huang; Ming Du; David Bedwell; Shuling Guo; Brett P. Monia
Poster #154 – 16-0103
Targeted Knockdown of Nedd4L in Airway Epithelial Cells with Antisense Oligonucleotides Establishes Adult-onset Cystic Fibrosis Mouse
Chenguang Zhao; Jeff Crosby; Michael McCaleb; Shuling Guo; Brett P. Monia
Poster #213 – 16-0102
Treatment Opportunities for Cystic Fibrosis Using Aerosolized ENaC Antisense Oligonucleotides
Jeff R. Crosby; Chenguang Zhao; Dong Bai; Chong Jiang; Hiroshi Kawabe; Michael L. McCaleb; Daniela Rotin; Shuling Guo; Brett P. Monia


Cystic fibrosis is a life-threatening genetic disease that affects approximately 30,000 people within the US and 70,000 people worldwide. CF is an autosomal recessive disorder caused by mutations in the gene that encodes CFTR, a chloride channel expressed in epithelial cells, including those in the lung. Over 1,700 mutations have been identified in CFTR that lead to CF. Despite recent progress in treatment approaches, including FDA approval for two breakthrough treatments for people with certain CF mutations, the expected life span for people with CF remains, on average, about 39 years, demonstrating a continued unmet medical need for effective treatment options.

The epithelial sodium channel, ENaC, is overactive in CF patients, resulting in airway dehydration and difficulty clearing infections. Small-molecule inhibitors of ENaC, such as amiloride, have limited therapeutic efficacy due primarily to the short half-lives of these drugs. New ENaC inhibitors with prolonged duration of action are being developed, but recent reports indicate that these drugs also inhibit ENaC activity in the kidney resulting in high blood potassium levels (hyperkalemia), a condition that can lead to sudden death from cardiac arrhythmias(1).

Researchers at Ionis Pharmaceuticals have previously demonstrated that aerosolized antisense compounds containing advanced oligonucleotide chemistries distribute broadly in the lung with a long half-life, negligible systemic exposure and excellent tolerability (2-6). Recently, Ionis researchers developed potent aerosolized antisense inhibitors against mouse ENaC and tested them in multiple CF mouse models to better understand their therapeutic potential. They found that treatment with Generation 2.5 ENaC antisense oligonucleotides (ASOs) specifically suppresses ENaC expression, resulting in the reduction of markers of CF mucus pathology. ENaC ASO treatment prevented CF phenotypes from occurring and reversed existing CF phenotypes in multiple preclinical models (Crosby et al. manuscript under review with the American Journal of Respiratory and Critical Care Medicine). Because aerosol delivery of ASOs produces low plasma drug levels, potent target reduction in the lungs was achieved with no effects on kidney ENaC and plasma potassium levels. This preclinical data demonstrates that targeting ENaC with aerosolized antisense drugs represents a potential new therapy for CF patients that can avoid the potentially dangerous side effect observed with small molecules drugs and bring benefit regardless of a CF patient’s CFTR mutation status.

In September 2016, Cystic Fibrosis Foundation Therapeutics, Inc. (CFFT) issued Ionis Pharmaceuticals an award of $3,000,000 to support development of Ionis’ cystic fibrosis (CF) drug discovery program, including the identification of an antisense drug candidate targeting the human epithelial sodium channel (ENaC) and the preclinical development of this compound. CFFT also granted awards earlier this year supporting two postdoctoral positions at Ionis to study up-regulation of the cystic fibrosis transmembrane conductance regulator (CFTR) expression using novel antisense mechanisms.


  1. O’Riordan, T.G., Donn, K.H., Hodsman, P., Ansede, J.H., Newcomb, T., Lewis, S.A., Flitter, W.D., White, V.S., Johnson, M.R., Montgomery, A.B., et al. 2014. Acute hyperkalemia associated with inhalation of a potent ENaC antagonist: Phase 1 trial of GS-9411. J Aerosol Med Pulm Drug Deliv 27:200-208.
  2. Crosby, J.R., Guha, M., Tung, D., Miller, D.A., Bender, B., Condon, T.P., York-DeFalco, C., Geary, R.S., Monia, B.P., Karras, J.G., et al. 2007. Inhaled CD86 antisense oligonucleotide suppresses pulmonary inflammation and airway hyper-responsiveness in allergic mice. J Pharmacol Exp Ther 321:938-946.
  3. Duan, W., Chan, J.H., McKay, K., Crosby, J.R., Choo, H.H., Leung, B.P., Karras, J.G., and Wong, W.S. 2005. Inhaled p38alpha mitogen-activated protein kinase antisense oligonucleotide attenuates asthma in mice. Am J Respir Crit Care Med 171:571-578.
  4. Fey, R.A., Templin, M.V., McDonald, J.D., Yu, R.Z., Hutt, J.A., Gigliotti, A.P., Henry, S.P., and Reed, M.D. 2014. Local and systemic tolerability of a 2’O-methoxyethyl antisense oligonucleotide targeting interleukin-4 receptor-alpha delivery by inhalation in mouse and monkey. Inhal Toxicol 26:452-463.
  5. Karras, J.G., Crosby, J.R., Guha, M., Tung, D., Miller, D.A., Gaarde, W.A., Geary, R.S., Monia, B.P., and Gregory, S.A. 2007. Anti-inflammatory activity of inhaled IL-4 receptor-alpha antisense oligonucleotide in mice. Am J Respir Cell Mol Biol 36:276-285.
  6. Karras, J.G., McGraw, K., McKay, R.A., Cooper, S.R., Lerner, D., Lu, T., Walker, C., Dean, N.M., and Monia, B.P. 2000. Inhibition of antigen-induced eosinophilia and late phase airway hyperresponsiveness by an IL-5 antisense oligonucleotide in mouse models of asthma. J Immunol 164:5409-5415.