The goal of this clinical study is to determine if a single injection of 1 or more dose levels of adeno-associated virus (AAV) gene therapy (GNSC-001) is safe and tolerated compared to placebo in participants with painful osteoarthritis (OA) of the knee.

Key Inclusion Criteria:

• OA in at least one knee (the 'target knee'), confirmed using centrally read X-ray with a Kellgren-Lawrence (KL) score of 2 or 3
• Western Ontario & McMaster University Osteoarthritis Index (WOMAC) pain score ≥ 20 (on a 50-point numerical rating scale) in the target knee during the seven days prior to Screening
• Persistent moderate to severe symptoms in the target knee, despite failure or intolerance of a 3-month trial of at least 2 conservative therapies (e.g., activity modification, weight loss, physical therapy, opioids, and anti-inflammatory medications, and injection of hyaluronic acid or steroids)
• Successful extraction of synovial fluid at Screening
• Negative pregnancy test at Screening and Baseline (subjects of childbearing potential [SOCBP])

Key Exclusion Criteria:

• Current or documented history of inflammatory arthritis (such as gout or rheumatoid arthritis), inflammation of connective tissue, or other immunological disease
• Any form of joint degeneration as part of another syndrome (e.g., Ehler's Danlos, Stickler syndrome, etc.)
• Surgery in the target knee within the 6 months prior to screening
• Previous partial or total joint replacement in target knee
• Significant and clinically evident malalignment of the target knee that would impact the subject's function, as determined by the Investigator
• Body mass index (BMI) > 38 kg/m2
• Clinically significant abnormal laboratory values at Screening in laboratory parameters that in the opinion of the Investigator, could represent a potential risk to participant safety:
• Plans to have, elective surgery of other joints or spine or intra-articular injections in the target knee, within the next 12 months