Struggles at Sarepta Cast Doubt on the robustness of the AAV Treatment Technique
In the realm of gene therapies, adeno-associated viruses (AAVs) have been the go-to standard for delivering functional genes to patients with genetic diseases since the 1980s. However, recent years have seen a surge in efforts to improve the safety of AAV-based therapies, particularly in addressing liver injuries.
The current strategies revolve around capsid engineering to evade immune responses, detargeting the liver to reduce toxicity, and exploring alternative delivery platforms.
One key approach is capsid redesign to evade preexisting neutralizing antibodies and reduce immune activation. For instance, Voyager Therapeutics has developed third-generation AAV capsids with mutated antibody epitopes, improving immune evasion while maintaining efficient gene transfer. Machine learning aids in optimizing such capsid mutations to balance tropism and safety.
Another strategy is detargeting the liver to minimize vector-related liver toxicity. Companies like Regeneron are focusing on developing capsids that avoid liver transduction to prevent liver-associated toxicities commonly seen with AAV gene delivery.
Regulatable transgene expression systems are another avenue of research, aiming to reduce continuous hepatic expression burden by allowing pharmacological control to switch gene expression on and off. This could potentially decrease liver toxicity during inactive disease phases, as demonstrated in AAV gene therapy approaches for liver-related diseases.
Alternative non-viral delivery methods are also gaining attention, with lipid nanoparticles (LNPs) being a promising alternative due to their lower immunogenicity and reduced liver injury compared to viral vectors. Though challenging to target organs beyond the liver, LNPs avoid many virus-related complications.
These advancements aim to lower the incidence of liver injury associated with AAV gene therapies. However, the future of AAVs is not entirely bleak. Despite Sarepta Therapeutics' AAV gene therapies Elevidys and SRP-9004 being linked to patient deaths from liver injury, experts like Kakkis see Sarepta's drug as a first-generation drug, opening the door to other improvements in AAV technology.
In other news, Ultragenyx received a Complete Response Letter from the FDA for its Sanfillippo candidate UX111, citing manufacturing concerns. On a positive note, Novartis' Luxturna, the first FDA-approved gene therapy, uses an AAV vector. It's worth noting that AAVs can deliver DNA directly to the nucleus of non-dividing cells, separating them from retroviruses and lentiviruses.
As the field of gene therapies continues to evolve, it's clear that the focus on safety and improving delivery methods will be key to unlocking the full potential of AAVs.
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