Engineering of lactic acid bacteria for delivery of therapeutic proteins and peptides

Plavec, Tina Vida; Berlec, Aleš

doi:10.1007/s00253-019-09628-y

Cited by 58 publications

(39 citation statements)

References 136 publications

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“…Live LAB have been developed as biotherapeutics, especially for the treatment of gastrointestinal disorders [172][173][174]. NonGM-LAB have been readily used as probiotics, and fecal microbiota have already gained FDA acceptance for transplantation in the treatment of Clostridium difficile infection [175].…”

Section: Discussionmentioning

confidence: 99%

“…The development of engineered living biotherapeutics is expected to rise soon [176]. Several clinical trials with engineered LAB are in phase I or phase II [174], which define their necessity and their realistic therapeutic option. What is more, by 2030, microbiome therapeutics are expected to occupy close to 79% of the therapeutics segment, according to [177].…”

Section: Discussionmentioning

confidence: 99%

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Safety Aspects of Genetically Modified Lactic Acid Bacteria

Plavec

Berlec

2020

Microorganisms

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Lactic acid bacteria (LAB) have a long history of use in the food industry. Some species are part of the normal human microbiota and have beneficial properties for human health. Their long-standing use and considerable biotechnological potential have led to the development of various systems for their engineering. Together with novel approaches such as CRISPR-Cas, the established systems for engineering now allow significant improvements to LAB strains. Nevertheless, genetically modified LAB (GM-LAB) still encounter disapproval and are under extensive regulatory requirements. This review presents data on the prospects for LAB to obtain ‘generally recognized as safe’ (GRAS) status. Genetic modification of LAB is discussed, together with problems that can arise from their engineering, including their dissemination into the environment and the spread of antibiotic resistance markers. Possible solutions that would allow the use of GM-LAB are described, such as biocontainment, alternative selection markers, and use of homologous DNA. The use of GM-LAB as cell factories in closed systems that prevent their environmental release is the least problematic aspect, and this is also discussed.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Safety Aspects of Genetically Modified Lactic Acid Bacteria

Plavec

Berlec

2020

Microorganisms

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“…LAB mainly include the genera Lactobacillus , Leuconostoc , Lactococcus , Pediococcus , and Streptococcus , among others, and constitute a group of Gram-positive microorganisms, anaerobic or aerotolerant, non-spore forming, resistant to low pH, and able to produce lactic acid as the final product of the fermentation of carbohydrates ( Wang Y. et al, 2016 ; Mokoena, 2017 ; Plavec and Berlec, 2019 ). Furthermore, these bacteria have been used for a long time in several industrial processes for the production of fermented foods, such as cheese, yogurts, etc.…”

Section: Probioticsmentioning

confidence: 99%

Probiotics, Prebiotics, Synbiotics, and Paraprobiotics as a Therapeutic Alternative for Intestinal Mucositis

et al. 2020

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Intestinal mucositis, a cytotoxic side effect of the antineoplastic drug 5-fluorouracil (5-FU), is characterized by ulceration, inflammation, diarrhea, and intense abdominal pain, making it an important issue for clinical medicine. Given the seriousness of the problem, therapeutic alternatives have been sought as a means to ameliorate, prevent, and treat this condition. Among the alternatives available to address this side effect of treatment with 5-FU, the most promising has been the use of probiotics, prebiotics, synbiotics, and paraprobiotics. This review addresses the administration of these "biotics" as a therapeutic alternative for intestinal mucositis caused by 5-FU. It describes the effects and benefits related to their use as well as their potential for patient care.

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“…Vectors carrying constitutive or inducible promoters were developed and used as key tools to increase production of heterologous proteins and control their production ( Pontes et al, 2011 ). Among other factors, the level of expression of the recombinant gene is influenced by promoter properties; when comparing inducible and constitutive promoters, the former provide better control over recombinant protein expression ( Plavec and Berlec, 2019 ).…”

Section: Lactococcus Lactis: Heterologous Protein Productionmentioning

confidence: 99%

“…In recent years, various genetic tools have been developed and adapted to study and engineer LAB, including controlled gene expression systems, food-grade selection markers, advanced mutagenesis tools, and DNA vaccine vector delivery systems ( van der Els et al, 2018 ; Plavec and Berlec, 2019 ). Among these genetic tools, the CRISPR-Cas (Clustered Regularly Interspaced Short Palindromic Repeats – CRISPR associated proteins) system has been used for LAB engineering and recombination.…”

Section: Live Bacteria As Mucosal Dna Vaccine Delivery Systems: mentioning

confidence: 99%

Novel Strategies for Efficient Production and Delivery of Live Biotherapeutics and Biotechnological Uses of Lactococcus lactis: The Lactic Acid Bacterium Model

Tavares¹,

Jesus²,

Silva³

et al. 2020

Front. Bioeng. Biotechnol.

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Lactic acid bacteria (LAB) are traditionally used in fermentation and food preservation processes and are recognized as safe for consumption. Recently, they have attracted attention due to their health-promoting properties; many species are already widely used as probiotics for treatment or prevention of various medical conditions, including inflammatory bowel diseases, infections, and autoimmune disorders. Some LAB, especially Lactococcus lactis , have been engineered as live vehicles for delivery of DNA vaccines and for production of therapeutic biomolecules. Here, we summarize work on engineering of LAB, with emphasis on the model LAB, L. lactis . We review the various expression systems for the production of heterologous proteins in Lactococcus spp. and its use as a live delivery system of DNA vaccines and for expression of biotherapeutics using the eukaryotic cell machinery. We have included examples of molecules produced by these expression platforms and their application in clinical disorders. We also present the CRISPR-Cas approach as a novel methodology for the development and optimization of food-grade expression of useful substances, and detail methods to improve DNA delivery by LAB to the gastrointestinal tract. Finally, we discuss perspectives for the development of medical applications of recombinant LABs involving animal model studies and human clinical trials, and we touch on the main safety issues that need to be taken into account so that bioengineered versions of these generally recognized as safe organisms will be considered acceptable for medical use.

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Engineering of lactic acid bacteria for delivery of therapeutic proteins and peptides

Cited by 58 publications

References 136 publications

Safety Aspects of Genetically Modified Lactic Acid Bacteria

Safety Aspects of Genetically Modified Lactic Acid Bacteria

Probiotics, Prebiotics, Synbiotics, and Paraprobiotics as a Therapeutic Alternative for Intestinal Mucositis

Novel Strategies for Efficient Production and Delivery of Live Biotherapeutics and Biotechnological Uses of Lactococcus lactis: The Lactic Acid Bacterium Model

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