Immunomodulatory Approaches In Preclinical Gene Therapy Studies

By Nirmala Chinnappareddy, Kelsey Brooks, Narine Lalayeva, Julie Forget, and Norbert Makori

In vivo gene therapy (GT) using Adeno-Associated Virus (AAV) vectors or Lipid Nanoparticles (LNPs) has advanced significantly in recent years; however, activation of both the innate and adaptive immune systems continues to be a major challenge, often requiring premedication with immunomodulating or suppressive agents to minimize adverse immune responses. To address these challenges, we reviewed data from 30 studies conducted over the past three years to assess the frequency of premedication use, common single-drug, and combination pretreatment regimens, and the incidence of clinical signs of immune responses in nonhuman primates.

Approximately 50% of the studies employed premedication regimens before administering AAV/LNPs, sometimes alongside additional supportive treatments. Clinical signs of innate immune responses were not observed with the following premedication protocols: (A) 2 mg/kg of dexamethasone via intravenous (IV) bolus at least 1 hour before test article administration in six studies, (B) Prednisolone at 1 or 3 mg/kg throughout the dosing period in three studies, (C) 2 mg/kg of diphenhydramine administered intramuscularly 15-30 minutes prior to dosing in one study, or (D) various combinations in individual studies, including 3 mg/kg Prednisolone and 5 mg/kg Diphenhydramine, 8 mg/kg Tocilizumab with or without 0.05 mg/kg Tacrolimus, or 750 mg/m² Rituximab with 2 mg/m²/day Sirolimus and 4 mg/kg Diphenhydramine. In conclusion, this data review provides valuable insights for designing future GT studies and selecting appropriate premedication regimens to ensure effective clinical translation.