Gene therapy has made remarkable strides in recent years, with 20 approved indications in the United States and a record number of approvals in 2023. Investigational trials are rapidly increasing across various diseases, including hemophilia B, sickle cell disease, and Duchenne muscular dystrophy. Despite the numerous advancements, the journey has been far from straightforward, particularly in the realm of rare diseases. Companies have scaled back on gene therapy endeavors due to safety concerns, efficacy issues, and the high costs associated with development and manufacturing processes.
The Challenge of Viral Vectors
Adeno-Associated Viruses (AAVs) and Their Limitations
A major challenge in gene therapy is the use of viral vectors, particularly adeno-associated viruses, commonly known as AAVs. These vectors are favored for their broad tropism, long-term expression capability, and low immunogenicity. Additionally, the wild-type AAV does not have any known associations with human diseases, making it a relatively safe option for therapeutic use. However, their ubiquity in the human population poses a significant limitation, as it is estimated that 30% to 60% of humans carry neutralizing antibodies (Nabs) against them. The presence of these antibodies can hinder the process of AAV transduction and distribution by diverting the vector away from target cells towards lymphoid tissues. This, in turn, potentially decreases the durability of transgene expression, adding another layer of complexity to the therapy.
Hepatocyte Tropism and Delivery Challenges
One significant issue with AAV-based gene therapy is their strong tropism for hepatocytes and the liver. This characteristic means that the vectors often circulate through the liver before they can reach other target tissues. Effective delivery to non-hepatic targets such as muscle or the central nervous system (CNS) has proven difficult due to poor tissue accessibility and inefficient binding to target cells. Attempts to use higher doses to achieve broader transduction also bring the risk of immune-mediated hepatotoxicity. Additionally, the non-integration of AAV into host chromosomal DNA reduces the risk of genotoxicity but also means that vector expression can be lost as the cells divide and die, especially in tissues with high turnover rates like the liver. This makes predicting the duration of therapeutic effects particularly challenging, especially in younger patients, and is further complicated by the development of antibodies that impede redosing.
Strategies to Overcome Delivery Challenges
Retargeting AAV Vectors
Addressing these challenges requires innovative and multifaceted strategies. At Regeneron, a multipronged approach is being taken to expand gene therapy’s potential. This includes retargeting AAV vectors, developing new delivery methods, and creating innovative payloads. Reducing liver tropism is essential to prevent complement activation and hepatotoxicity. This goal can be achieved through AAV capsid point mutations. Ensuring that vectors target specific tissues for efficacy remains a necessary undertaking. Regeneron’s efforts aim to enhance the delivery and expression of therapeutic genes by circumventing the natural limitations that AAVs present.
Antibody Engineering for Novel Tropism
Regeneron leverages advanced antibody engineering to confer novel tropism to AAVs, thereby improving specificity and efficacy in non-liver tissues. By using antibodies to redirect the virus to cellular targets rather than relying solely on capsid binding, the company gains greater control over the vectors’ binding properties. This approach creates a modular platform applicable to multiple AAV serotypes across various species. Two primary platforms have been developed for this retargeting effort: the first uses a protein tagging system that covalently binds antibodies to viral capsid surface loops. This method has proven successful in vitro and in vivo across different species. The second platform employs bispecific antibodies to target both the receptor of interest and the AAV itself. By bridging the capsid to the target cell, this strategy minimizes off-target binding and enhances delivery efficiency. Regeneron’s expertise with bispecific antibodies as protein therapeutics strengthens this innovative approach, highlighting its potential to improve gene therapy vectors.
Expanding the Treatable Patient Population
Suppressing Immune Responses
Beyond improving AAV gene therapy delivery, Regeneron aims to expand the treatable patient population by developing methods to suppress immune responses to AAV and facilitate redosing. Utilizing its extensive portfolio of validated antibodies, the company investigates tailored immune suppression regimens and the depletion of pre-existing Nabs before initiating gene therapy. This approach could significantly grow the number of patients eligible for gene therapy and improve the overall success rate of treatments. By finding ways to manage and mitigate immune reactions, Regeneron seeks to make gene therapy a viable option for a broader spectrum of patients, enhancing therapeutic outcomes and overcoming some of the persistent challenges faced in the field.
Gene Editing as a Promising Avenue
Gene editing presents another promising avenue, offering possibilities beyond traditional viral vector-based gene therapies. With ultracompact payloads, gene editing technologies can address viral delivery size constraints and enable targeted delivery methods like covalent and bispecific antibody platforms. Collaborative research initiatives with companies such as Mammoth Biosciences, Inc. and Intellia Therapeutics, Inc. focus on developing in vivo CRISPR-based gene editing for muscle and neurological tissues. In animal models, a targeted liver gene insertion platform co-developed by Intellia and Regeneron has demonstrated sustained expression, despite rapid liver growth. This marks an early step towards more effective gene therapies for inherited liver disorders and highlights the potential for gene editing technologies to revolutionize the approach to treating genetic conditions.
Future Prospects and Innovations
Optimizing Safety and Specificity
Despite significant barriers, the future for next-generation gene therapies looks promising. As knowledge expands and innovative technologies are harnessed, the safety and specificity of vectors can be optimized. Ensuring sustained expression and extending the benefits of gene therapy to a broader patient range are critical goals. The ongoing research and development efforts at companies like Regeneron underscore the potential for overcoming current challenges and advancing the field of genetic medicine. As scientists continue to find new methods to improve the delivery and efficacy of gene therapies, these treatments could become more accessible and effective for a wide range of conditions.
The Role of Targeted Innovations
Gene therapy has made significant advancements in recent years, boasting 20 approved indications in the United States and achieving a record number of approvals in 2023 alone. Research and investigational trials are expanding rapidly across a range of diseases, such as hemophilia B, sickle cell disease, and Duchenne muscular dystrophy. These exciting innovations signal a promising future; however, the path has been fraught with challenges, especially concerning rare diseases. Companies have notably scaled back their gene therapy efforts due to a combination of safety concerns, efficacy challenges, and the exorbitant costs tied to development and manufacturing. Despite the promising progress in gene therapy, these obstacles underscore the complexities involved in bringing such treatments to fruition. The balance between ensuring safety, proving efficacy, and managing costs continues to shape the strategies and decisions within this cutting-edge field, reflecting the intricate tapestry of scientific advancement and practical implementation.
