Bringing next-generation therapeutics to the clinic through synthetic biology
Highlights
► Synthetic biology tools are being applied towards the clinical development of enhanced therapeutics. ► Engineered genetic circuits can create ‘smart’ drugs with sensing and actuating capabilities. ► Therapeutic devices may be delivered through viral vectors, encapsulated cells, or bacteria. ► With initial clinical trials underway, safety will be the first priority.
Introduction
Advances in synthetic biology have enabled the genetic engineering of microbes into an expanding array of living sensors, actuators, and chemical factories. The development of such tools for mammalian systems has been comparatively slower, in large part due to the increased complexity of mammalian cells compared to protozoans. However, efforts to address these challenges and implement synthetic biological approaches in mammalian cells and toward clinical applications offer the potential for a new generation of therapeutics that complement or even address shortcomings of traditional small molecule and protein biologics. As one example, small molecule drugs are typically administered orally or intravenously and enter the systemic circulation, which in contrast to localized delivery could yield untoward side effects. However, synthetic biology could ultimately create living ‘smart drugs’ that can sense a pathological signal or state in a complex, noisy environment and actuate an appropriately tuned, localized therapeutic response in situ.
Synthetic biology has been applied to healthcare in numerous ways, from yeast engineered for the cost-effective production of the anti-malarial artemisinin [1] to mosquitoes designed to propagate dominant-lethal genetic circuitry throughout Dengue-transmitting mosquito populations [2]. These and other examples have been detailed in several elegant reviews [3, 4, 5]. Here, we focus on clinical applications in which synthetic genetic systems are being engineered for direct administration to patients, including strategies to directly modify host cells, to implant encapsulated genetically modified cells, and to administer genetic devices contained in a bacterial vector (Figure 1).
Section snippets
Devices for direct host cell modification
Genetic modification of a patient's cells offers a direct means to treat chronic cell and tissue dysfunction, and efforts in viral gene therapy have enjoyed increasing success in establishing the feasibility and efficacy of this approach [6, 7, 8, 9, 10, 11, 12, 13, 14]. Synthetic biology can potentially augment traditional gene therapy strategies by enhancing control of the therapeutic gene to be expressed, for example through circuit architecture involving environmental sensing or feedback,
Devices for implanted encapsulated cells
Early cell implantation therapies involved pancreatic islet cell administration into diabetic patients to sense blood glucose levels and secrete insulin [25]. To prevent immune clearance, the cells were microencapsulated in a material (originally porous alginate-poly-l-lysine, though many others have since been investigated) that allowed diffusion of small molecules and proteins yet prevented macromolecule transport necessary for immune reactivity. Encapsulation technologies for therapeutic
Devices for delivery via bacterial vectors
In some instances, genetically engineered bacteria themselves may be delivered as therapy. It has been well documented that several bacterial genera including Escherichia, Clostridium, and Salmonella naturally target and accumulate within tumors when injected intravenously [32•]. Though the homing mechanisms remain incompletely understood, bacterial tumor targeting relies on increased blood flow at the inflamed tumor site, bacterial entrapment in the turbulent tumor vasculature, and chemotaxis
Conclusion and perspectives
The past decade has witnessed an impressive rise in the capabilities of the synthetic biology field, spurred by rapid advances in DNA sequencing and synthesis. Though most work to date has focused on microbial engineering for industrial processes, developing and applying synthetic biological tools for biomedical application holds substantial promise. Novel treatments may provide prophylactics, therapeutics, and diagnostics not possible with current technologies, and tangible successes would
References and recommended reading
Papers of particular interest, published within the period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
The authors would like to thank Albert Keung and Ivel Morales, M.D., for their critical reading of this manuscript. This work was funded by the Department of Energy Award DE-SC0001216
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2016, Advanced Drug Delivery ReviewsCitation Excerpt :Early efforts to use cells as therapeutic devices included their encapsulation into various biomaterials to bypass complications of the immune response when using allogeneic and/or xenogeneic cell sources [184,185]. Many biomaterials provide an optimal environment for cell survival because small molecules and nutrients move freely between the native tissue and the encapsulated cells [186–190]. For this reason, the implantation of genetically modified cells encapsulated within biomaterials presents an exciting alternative for therapeutic gene circuit delivery.
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