Synthetic Biology Design as a Paradigm Shift toward Manufacturing Affordable Adeno-Associated Virus Gene Therapies

Abstract

Gene therapy has demonstrated enormous potential for changing how we combat disease. By directly engineering the genetic composition of cells, it provides a broad range of options for improving human health. Adeno-associated viruses (AAVs) represent a leading gene therapy vector and are expected to address a wide range of conditions in the coming decade. Three AAV therapies have already been approved by the FDA to treat Leber’s congenital amaurosis, spinal muscular atrophy, and hemophilia B. Yet these therapies cost around $850,000, $2,100,000, and $3,500,000, respectively. Such prices limit the broad applicability of AAV gene therapy and make it inaccessible to most patients. Much of this problem arises from the high manufacturing costs of AAVs. At the same time, the field of synthetic biology has grown rapidly and has displayed a special aptitude for addressing biomanufacturing problems. Here, we discuss emerging efforts to apply synthetic biology design to decrease the price of AAV production, and we propose that such efforts could play a major role in making gene therapy much more widely accessible.

The CASwitch: a synthetic biology solution for high-performance inducible gene expression systems in biotechnology

“…However, producing AAV vectors is challenging and costly, requiring specialized facilities and equipment 24,25 . Therefore, developing methods to improve AAV vector production is vital for advancing gene therapy and gene editing technologies [26][27][28][29][30] .…”

“…However, current large-scale industrial bioproduction face challenges in terms of efficiency and scalability, as it mainly relies on transient transfection of HEK293 cell lines 24,25 . Attempts to develop more scalable systems, such as AAV producer cell lines with inducible expression of viral genes, have been hampered by the toxicity associated with leaky expression of viral genes [26][27][28][29][30] . In this context, the CASwitch v.2 expression system may offer a reliable solution having the ability to significantly reduce leakiness while maintaining high levels of maximal achievable expression.…”

WiTNNess: An international natural history study of infantile‐onset TNNT1 myopathy

“…24,35,36 Most gene-based therapies target a small clinical population. 37 This is juxtaposed to substantial development and manufacturing costs, 38 as well as an implicit expectation that such agents will be administered in highly resourced urban settings (https://patienteducation.asgct.org/gene-therapy-101/genetherapy-centers). Consequently, people who are poor, uninsured, or otherwise disadvantaged often have difficulty securing access to life-saving therapies.…”

Encapsulated Bacteria with a Light-Repressed Deadman Switch for Liver Gene Delivery

“…Also, the cost of producing sufficiently high titers of AAV vectors and other viral vectors for therapeutic purposes is very steep [9][10][11].…”