A Phase 1/2a Study to Assess the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of Single and Multiple Doses of IONIS-ENaCRx in Healthy Volunteers and Patients With Cystic Fibrosis

Inclusion Criteria (Healthy Volunteers) 1. Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal. 2. Males must be surgically sterile or, abstinent or, if engaged in sexual relations with a woman of child-bearing potential, the subject or the subject's non-pregnant female partner must be using a highly effective contraceptive method 3. Willing to refrain from strenuous exercise/activity for at least 72 hours prior to study visits 4. Body mass index (BMI) \< 35 kg/m2 with a minimum weight of 45 kg 5. Normal diffusing capacity in the lung (≥ 80% predicted) at Screening Exclusion Criteria (Healthy Volunteers) 1. Clinically-significant (CS) abnormalities in medical history, screening laboratory results, physical or physical examination that would render a subject unsuitable for inclusion, including but not limited to: 1. Urine protein/creatinine (P/C) ratio ≥ 0.2 mg/mg 2. Positive test (including trace) for blood on urinalysis 3. Alanine aminotransferase (ALT), aspartate aminotransferase (AST), bilirubin, alkaline phosphatase (ALP), serum creatinine, blood urea nitrogen (BUN), fasting blood glucose, potassium \> upper limit of normal (ULN) 4. Platelet count \< LLN 2. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1 3. Respiratory infection within 4 weeks of Study Day 1 4. Presence or past history of CS chronic respiratory disease, including any current history (or within 2 years) of asthma. History of allergic rhinitis is acceptable 5. Forced expiratory volume in 1 second (FEV1) \< 80% of predicted at Screening or an FEV1/FVC ratio of \< 0.7 6. Smoking of a tobacco or nicotine-containing product within the previous 6 months (use of a nicotine patch is permitted) or a smoking history of ≥ 10 pack years 7. Any CS finding on chest radiograph 8. Uncontrolled hypertension (blood pressure \[BP\] \> 160/100 mm Hg) at Screening 9. Treatment with another investigational drug, biological agent, or device within one month of screening, or 5 half-lives of investigational agent, whichever is longer 10. Any history of previous treatment with an oligonucleotide 11. Regular use of alcohol within 6 months prior to screening or hard drugs within 1 year prior to screening, or positive urine drug screen at Screening 12. Blood donation of 50 to 499 mL within 30 days of screening or of \> 499 mL within 60 days of screening Inclusion Criteria (Cystic Fibrosis Participants) 1. Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal. 2. Males must be surgically sterile or, abstinent or, if engaged in sexual relations with a woman of child-bearing potential, the subject or the subject's non-pregnant female partner must be using a highly effective contraceptive method 3. Confirmed diagnosis of CF by seat chloride and/or genetics by referring clinician 4. FEV1 \>/= 50% of predicted 5. Stable CF disease as judged by the Investigator 6. Weight \> 40 kg Exclusion Criteria (Cystic Fibrosis Participants) 1. Clinically-significant (CS) abnormalities in medical history, screening laboratory results, physical or physical examination that would render a subject unsuitable for inclusion, including but not limited to: 1. Abnormal liver function defined as \> 2 times upper limit of normal (ULN) for bilirubin, or 3 time ULN for ALT, AST, or alkaline phosphatase 2. Platelet count \< LLN 2. Active infection requiring systemic antiviral or antimicrobial therapy that will not be completed prior to Study Day 1 3. Respiratory infection within 4 weeks of Study Day 1 4. Colonization with Burkholderia cepacia or M. abscessus