The purpose of this study is to determine the safety, tolerability, and activity of ICM-203, a recombinant adeno-associated viral (AAV) vector that expresses a therapeutic gene that promotes cartilage formation, reduces joint inflammation and pain, as well as improves joint physical function, by injecting escalating doses of ICM-203 or matching placebo into the knee of subjects with mild to moderate knee osteoarthritis (OA).

Inclusion Criteria:

1. Body Mass Index (BMI) of 18.0 to 40.0 kg/m2, inclusive, at the time of screening.
2. Kellgren-Lawrence grade 2 or grade 3 OA of target knee.
3. Target knee pain between 4 and 9, inclusive, on an NRS ranging from 0 (no pain) to 10 (worst pain imaginable).
4. KOOS function in daily living score >25, a measure of knee function ranging from 0 (extreme problems) to 100 (no problems).
5. A stable treatment regimen for symptomatic relief of OA, including NSAIDs, for 4 weeks prior to screening.

Exclusion Criteria:

1. History of rheumatoid arthritis, psoriatic arthritis, gout, pseudogout, autoimmune OA, chondrocalcinosis, hemochromatosis, villonodular synovitis, and synovial chondromatosis or other disorder that in the opinion of the Investigator could cause inflammation of the knee.
2. Injection of steroid, hyaluronate or other agent, into the target knee less than 90 days prior to day 1.
3. Major injury to the target knee, such as torn ligament or severe sprain, within 12 months of screening.
4. Disability so severe that the subject cannot comply with the study requirements, including knee symptoms that result in significant difficulty or inability to walk.
5. Surgery on the target knee within 180 days prior to day 1
6. Total knee arthroplasty or other knee surgery planned in the next 12 months.
7. Active joint infection or other concurrent medical (diabetes, uncontrolled hypertension, severe osteoporosis, glaucoma) or psychiatric condition that, in the opinion of the Investigator, would make the subject unsuitable for the study.