Gene therapy with mRNA is more cost-efficient, has a better safety profile, and is more reproducible than the viral vector, AAV, currently used for gene therapy to improve inherited retinal diseases.
Non-viral mRNA delivery for gene therapies is a more cost-efficient alternative to adeno-associated virus (AAV) gene therapies for patients with inherited retinal diseases, according to new research.1
Inherited retinal diseases lead to severe visual impairment or complete vision loss. Even though inherited retinal diseases are viewed as rare, they affect over 2 million individuals worldwide. Living with this disease impairs visual function, as well as limits daily activities and quality of life.
Many of the inherited retinal diseases occur from monogenic variations in genes, often expressed in the retinal pigment epithelium or the photoreceptors, both which support the retina and convert light into electrical signals. Researchers identified about 300 causative genes connected to inherited retinal diseases, helping gene therapy.
As of now, voretigene neparvovec (Luxteurna) is the only ocular gene therapy approved by the US Food and Drug Administration (FDA) and the European Medicines Agency designed for treating inherited retinal disease. Though, AAVs are the most common viral vector used for gene therapy—and can be used as an inherited retinal diseases treatment.2 AAVs therapeutically helps the retinal disease but are costly.1 Products and manufacturing for one gene therapy can cost anywhere from $500,000 and $1 million, excluding costs for research and development, clinical trials, and creating platforms for patient access. For instance, 2 chimeric antigen receptor cell therapies—tisagenlecleucel and axicabtagene ciloleucel—cost approximately $373,00 and $457,000 per eye, respectively
Because of the high costs, a new study, led by Pedro Antas, PhD, from NOVA Medical School at Universidade Nova de Lisboa, examined mRNA technology and non-viral delivery systems as a more affordable gene therapy option for inherited retinal diseases. The investigators implemented a parallel strategy, comparing mRNA technology with AAVs.
“The importance of addressing these conditions cannot be overstated, especially when gene therapy offers a beacon of hope,” the investigators wrote. “However, the cost of such treatments presents a significant barrier for vulnerable populations in low-to-middle income countries.”
Gene therapy with mRNA cuts production costs and resources. Also, the treatment is more straightforward and easier to reproduce than AAV gene therapies.
“In this opinion, we explore how access to gene therapy could be realized through innovative approaches, such as mRNA technology and nonviral delivery systems,” the investigators wrote. “These strategies could be the key to unlocking global access, but this necessitates a concerted effort from all stakeholders.”
The investigators pointed out the benefits of using synthetic mRNA over DNA-based methods—mRNA is fully functional in the cytoplasm, does not require nuclear translocation, achieves higher translation efficiency and rapid protein synthesis, has no risk of genomic integration and linked mutagenesis—and thus has a better safety profile—and is only transiently expressed and eventually degraded, therefore preventing long-term toxicity. Moreover, mRNA is more simple, reproducible, and a better cost.
Before recently, ocular research had primarily focused on viral vectors. Due to how costly the viral vectors are—as well as their safety concerns with serious adverse events in 35% of clinical trials testing AAV gene therapies—other gene therapies had been studied, such as nonviral nanoparticles.
“The costs of licensing patented chemical modifications into mRNA structure must be carefully considered, because they could impact affordability and widespread accessibility to innovative mRNA gene therapies,” the investigators wrote. “Hence, we believe that it is crucial to consider cooperative/collaborative approaches, such as the Access to Gene Therapies for Rare Diseases (AGORA) initiative for rare diseases.”