Gene therapy has emerged as a promising approach to treating rare genetic disorders and unmet medical needs. Adeno-associated virus (AAV)-based gene therapy is the leading platform for gene delivery; however, the natural prevalence of humoral immunity against AAV in humans limits the population of patients who can benefit from this therapy. A recent study from the University of Pennsylvania has shown that neonatal Fc receptor (FcRn)  inhibition can reduce pre-existing neutralizing antibodies (NAbs) and provide a permissive window for gene delivery via systemic AAV gene therapy in mice and nonhuman primates (NHPs). In this blog, we will discuss the utility of FcRn inhibition in transiently reducing pre-existing NAb titers to permit intravenous AAV gene therapy in patients with moderately high pre-existing NAb titers.

Natural infections of wild-type AAV in early life lead to persistent humoral immunity against AAVs, including NAbs that block AAV gene transfer to target tissues. The seroprevalence of NAbs in humans is 15–60%, depending on the AAV serotype and geographic region. This limits the success of systemic AAV-based gene therapies for diseases such as spinal muscular atrophy, Friedreich’s ataxia, hemophilia A and B, and Pompe disease. Researchers have explored several methods to overcome this limitation, including engineering AAV capsids that evade humoral immunity, methods to remove NAbs, and drugs that reduce circulating IgG levels.

FcRn plays an essential role in the long half-life of IgG, a key NAb. Inhibitors of FcRn can reduce circulating IgG levels to 20–30% of the baseline and have been developed to treat autoimmune diseases and prevent transplant rejection. M281 is a fully human IgG1 monoclonal antibody that has been shown to reduce IgG levels to <20% of the baseline level without affecting the levels of albumin or other Ig types in humans. This efficacy suggests that M281 treatment could reduce NAb titers to <1:5 in patients with a pre-existing NAb titer of 1:20, which could be amenable to AAV gene therapy.

The researchers evaluated the effect of M281-mediated IgG reduction on pre-existing NAb titers and gene transduction in the context of systemic AAV-based gene therapy in mice and NHPs. They found that M281 successfully reduced NAb titers along with total IgG levels, and it also enhanced gene delivery to the liver and other organs after intravenous administration of AAV in NAb-positive animals. These results indicate that mitigating pre-existing humoral immunity via disruption of the FcRn–IgG interaction may make AAV-based gene therapies effective in NAb-positive patients.

The data from this study demonstrates the potential of FcRn inhibitors to broaden the eligible patient population for AAV gene therapy by overcoming pre-existing NAbs. Patients with pre-existing NAbs are currently ineligible for gene therapy, so this approach could be life-saving for individuals with inherited genetic disorders or other diseases that could be treated with gene therapy.

However, the study also highlights some limitations of FcRn inhibition, particularly in terms of redosing therapeutic AAV vectors. High NAb titers follow AAV vector administration, and while FcRn inhibition can effectively reduce pre-existing NAb titers, it may not be sufficient to prevent the development of new NAbs after vector administration. Therefore, alternative or adjunctive strategies are required to overcome this obstacle, such as the induction of tolerance to AAV vectors.

One promising approach for inducing tolerance is the coadministration of rapamycin-containing nanoparticles with AAV vectors, as demonstrated in a recent study in mice and NHPs. This approach successfully induced antigen-selective tolerance to the AAV vector, allowing for redosing of intravenous AAV in naïve animals. If this approach can prevent the post-AAV NAb titer increase, even in patients with pre-existing NAbs, the combination of FcRn inhibition and rapamycin nanoparticles may represent a potential strategy to enable vector redosing in humans.

The study also highlights the importance of careful study design in evaluating the safety and efficacy of FcRn inhibitors in animal models. The researchers modified the M281 regimen used in ongoing clinical trials due to the daily dose limitation of endotoxin in their research-grade production lots. While this modification improved vector transduction in NHPs, it is important to note that such modifications may have implications for safety and efficacy in human patients. Therefore, future studies will need to carefully evaluate the optimal dosing and administration of FcRn inhibitors in humans.

In conclusion, FcRn inhibition has the potential to reduce pre-existing NAb titers and provide a permissive window for AAV gene therapy in patients with moderately high pre-existing NAb titers. This approach, in combination with other strategies such as the induction of tolerance to AAV vectors, may enable successful vector redosing in humans. These findings are promising for the field of gene therapy and could significantly broaden the eligible patient population for AAV gene therapy products.