Table 1.
Licensed pharmacotherapies used in preclinical and clinical studies as adjuvant to AAV gene therapies.
| Drug | Licensed indication(s) | Significant adverse effects in humans | Example AAV serotype trialed | Type of study |
|---|---|---|---|---|
| Corticosteroids (23, 24) |
Anti-inflammatory and immunosuppressive properties are used in most areas of medicine - Autoimmune diseases e.g. rheumatoid arthritis, systemic lupus erythematous (SLE) - Systemic and local inflammation - Acute exacerbation of asthma and inflammatory bowel disease |
Short term treatment: adrenal suppression, hyperglycemia Long term treatment: osteoporotic fracture, insulin resistance, Cushingoid features, cataracts/glaucoma, neuropsychiatric disturbances, cardiovascular risks, muscle and skin atrophy In children: growth suppression, Cushing’s syndrome, medication-induced diabetes |
AAV2 (25), scAAV9 (26) | Approved |
| AAV2 (27), AAV5 (28), AAVrh10 (29), AAV-Spark100 (30), scAAV2/8 (13), scAAV5 (31) |
Clinical | |||
| AAV1 (32) | Clinical as combination | |||
| AAVrh74 (33) | Preclinical | |||
| Rapamycin (34, 35) | Prophylaxis of organ rejection after transplantation | Thrombocytopenia, dyslipidemia, mucositis, impaired wound healing, proteinuria | AAV1 (36), AAV8 (37), AAV9 (38), AAVrh10 (29) | Clinical as combination |
| AAV8 (39) | Preclinical | |||
| AAV2 (40), (41), AAV9 (42) | Preclinical as combination | |||
| Mycophenolate mofetil (43, 44) | Prophylaxis of organ rejection after transplantation | Gastrointestinal toxicity (requiring dose reduction/discontinuation in 40-50% transplant patients), myelosuppression, infection, genotoxic | AAV8 (6), AAV2 (40) (41) | Preclinical as combination |
| Calcineurin inhibitors (45, 46) | Prophylaxis of organ rejection after transplantation | Narrow therapeutic index - nephrotoxicity, neurotoxicity, infection, gastrointestinal toxicity, malignancy | AAV1 (32) | Clinical as combination |
| AAV8, AAV9 (47) | Preclinical | |||
| AAV8 (48) | Preclinical as combination | |||
| Rituximab (49) | Rheumatoid arthritis, Non-Hodgkin’s lymphoma | Infusion reaction including cytokine release syndrome, infection, febrile neutropenia, myelosuppression, cardiotoxicity | AAV2 and 5 NAb (50) | Ex vivo human serum |
| AAV1 (36), AAV9 (38), AAVrh10 (29) | Clinical as combination | |||
| AAV8, AAV6 (51); AAV9 (42) | Preclinical as combination | |||
| Imlifidase (52) | Pre-transplant desensitization in highly sensitized, crossmatch positive renal transplant patients | Infection (pneumonia, sepsis), infusion site reaction, hepatic dysfunction, headache | AAV8, AAV-LK03 (53) | Preclinical |
| Proteasome inhibitors (54, 55) | Multiple myeloma | Peripheral neuropathy, myelosuppression (especially thrombocytopenia), cardiovascular events, herpes reactivation | AAV2 (56), AAV8 (57) | Preclinical |
| Arsenic trioxide (58) | Acute promyelocytic leukemia | Hyperleukocytosis, gastrointestinal toxicity, skin lesions, hepatic dysfunction | AAV8 (59) | Preclinical |
| Hydroxychloroquine (60) | Rheumatoid arthritis, SLE | Gastrointestinal effects, retinopathy, myopathy, QT prolongation (at high dosage) | AAV2 (61) | Preclinical |
| Rabbit anti-thymocyte globulin (62) | Prophylaxis of graft-versus-host disease or organ rejection after transplantation | Infusion reaction including cytokine release syndrome, opportunistic infection/reactivation | AAV2 (41) | Preclinical as combination |
Indications, adverse effects observed in recommended dosages, and example of AAV studies are listed below. MnTBAP and Teniposide are excluded as they are not or no longer licensed in Europe and the US.