Development of synthetic biotics as treatment for human diseases

Abstract

Advances in synthetic biology have allowed the generation of strains of bacteria that are genetically altered to have specific therapeutic benefit. These synthetic biotics, also widely referred to as engineered living therapeutics have tremendous potential as a new therapeutic modality and several have advanced into the clinic and human testing. This review outlines some of the unique attributes of synthetic biotics as well as some of the challenges in their development as prescription products. Regulatory considerations are discussed and a case study of a program that has advanced into Phase 2 testing is provided: SYNB1618 for the treatment of PKU.

Microbiome engineering: engineered live biotherapeutic products for treating human disease

“…As discussed by the authors, the successful completion of this clinical trial provided proof of the potential to use eLBPs in the treatment of rare metabolic conditions (Puurunen et al, 2021). In addition, data from this study has been used to develop in vitro gut-onchip (Nelson et al, 2021) and predictive pharmacology models (Charbonneau et al, 2021); showing that results from clinical trials can feed back into the preceding laboratory design process, in order to help address some of the limitations present in animal models (Brennan, 2022). Following the successful trial of SYNB1618, Synlogic developed the SYNB1934 strain (Adolfsen et al, 2021).…”

“…We expect clinical trials evaluating these more complex systems to arise; although it will be essential to ensure these systems behave in a predictable and robust manner. Furthermore, it should be noted that an integral feature of eLBPs is that a single strain can be engineered to target more than one condition simultaneously (Brennan, 2022). As stated by Puurunen et al (2021) this is particularly promising for the treatment of metabolic diseases and differentiates eLBPs from traditional methods, such as enzyme replacement therapy (Puurunen et al, 2021).…”

“…Furthermore, additional genetic elements (e.g. auxotrophies and inducible promoters) allow for greater control and flexibility of eLBPs in the host and environment (Brennan, 2022). For example, Harimoto et al (2022) developed a programmable surface capsular polysaccharide (CAP) system Frontiers in Bioengineering and Biotechnology frontiersin.org in Escherichia coli Nissle 1917; through inducible expression the CAP system controlled bacterial encapsulation and subsequently, showed a ten-fold increase in the maximum tolerated dose and anti-tumour efficacy of the strain in a mouse model of cancer (Harimoto et al, 2022).…”

“…To date, the microbiota has been linked to neurological diseases (via the gut-brain axis) (Morais et al, 2021;Liu et al, 2022), inflammatory diseases (such as ulcerative colitis) (Caruso et al, 2020), and cancer (Helmink et al, 2019), amongst others (Pascal et al, 2018;Gurung et al, 2020;Hao et al, 2021). It is this profound effect that the microbiota is thought to impart on the human host that has driven interest in microbiome engineering methods, which aim to modify the human host-microbiota system for a therapeutic purpose; particularly for diseases where current treatment is inadequate or non-existent (Brennan, 2022).…”

Targeted Antimicrobial Agents as Potential Tools for Modulating the Gut Microbiome

“…Effects of probiotics on the gut microbiome have been extensively reviewed ( George Kerry et al, 2018 ; Fuenzalida et al, 2021 ) and engineered bacteria is a complicated topic. When designing such engineered bacteria, multiple factors need to be considered including the selection of chassis bacteria, control circuits, secretion strategies, and payload proteins (see review: Mays and Nair, 2018 ; Aggarwal et al, 2020 ; Brennan, 2021 ; Lynch et al, 2022 ; Shen et al, 2022 ).…”