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Essential Topics for the Regulatory Consideration of Phages as Clinically Valuable Therapeutic Agents: A Perspective from Spain.

ABSTRACT: Antibiotic resistance is one of the major challenges that humankind shall face in the short term. (Bacterio)phage therapy is a valuable therapeutic alternative to antibiotics and, although the concept is almost as old as the discovery of phages, its wide application was hindered in the West by the discovery and development of antibiotics in the mid-twentieth century. However, research on phage therapy is currently experiencing a renaissance due to the antimicrobial resistance problem. Some countries are already adopting new ad hoc regulations to favor the short-term implantation of phage therapy in clinical practice. In this regard, the Phage Therapy Work Group from FAGOMA (Spanish Network of Bacteriophages and Transducing Elements) recently contacted the Spanish Drugs and Medical Devices Agency (AEMPS) to promote the regulation of phage therapy in Spain. As a result, FAGOMA was asked to provide a general view on key issues regarding phage therapy legislation. This review comes as the culmination of the FAGOMA initiative and aims at appropriately informing the regulatory debate on phage therapy.

SUBMITTER: Vazquez R

PROVIDER: S-EPMC9025261 | biostudies-literature | 2022 Mar

REPOSITORIES: biostudies-literature

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Essential Topics for the Regulatory Consideration of Phages as Clinically Valuable Therapeutic Agents: A Perspective from Spain.

Vázquez Roberto R Díez-Martínez Roberto R Domingo-Calap Pilar P García Pedro P Gutiérrez Diana D Muniesa Maite M Ruiz-Ruigómez María M Sanjuán Rafael R Tomás María M Tormo-Mas María Ángeles MÁ García Pilar P

Microorganisms 20220326 4

Antibiotic resistance is one of the major challenges that humankind shall face in the short term. (Bacterio)phage therapy is a valuable therapeutic alternative to antibiotics and, although the concept is almost as old as the discovery of phages, its wide application was hindered in the West by the discovery and development of antibiotics in the mid-twentieth century. However, research on phage therapy is currently experiencing a renaissance due to the antimicrobial resistance problem. Some count ...[more]

PMID: 35456768

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Project description:Background Testosterone (T) is the main androgen playing a crucial role in regulating the function of both reproductive and non-reproductive organs. Current methods for assessing T levels in humans do not reflect the biological androgenic activity (BAA), which may be important for example in the diagnosis of hypogonadism and clarifying pathogenetic mechanisms linking androgen deficiency to various comorbidities. In this study, we aimed to identify new protein markers of BAA in humans and test their predictive value in relation to some androgen deficiency linked pathologies. Methods and Findings Plasma samples (n=90) from 30 healthy chemically castrated young volunteer males (19-32 years) were collected at three different time points: baseline – prior to treatment with GnRH antagonist), three weeks after GnRH antagonist treatment, and at the end of the study, two weeks thereafter. Following the second blood sampling, all men were supplemented with 1000 mg T undecanoate. The samples were analysed by mass spectrometry-based proteomics. A total of 676 proteins were identified among which expression of 46 was statistically significantly associated with T concentration (p<0.05, ANOVA paired). Based on ROC-analysis, 3 candidate proteins were selected, 4-hydroxyphenylpyruvate dioxygenase (4HPPD), insulin-like growth factor-binding protein 6 (IGFBP6) and fructose-bisphosphate aldolase (ALDOB). Together with a mathematically calculated variable (MMA: Multi-Marker Algorithm), based on the combination of 4HPPD and IGFBP6 values, their predictive value in relation to low T levels and cardio-metabolic risk factors was tested in 75 males suffering from infertility, 32-43 years of age. Of these males, four were diagnosed with type 2-diabetes and 14 with the metabolic syndrome. Clinical chemistry data regarding cardio-metabolic parameters, bone mineral density and androgen receptor CAG repeat lengths were assessed. The three proteins significantly distinguished between low (< 8 nmol/L) and normal (> 12 nmol/L) morning fasting T (AUC: 0.70-0.77). The MMA had an even higher accuracy (AUC=0.80) in identifying subjects with low T. 4HPPD, ALDOB and MMA showed higher accuracy than T (AUC=0.85-0.92 vs. AUC=0.55; p<.001) in identifying infertile patients with type 2 diabetes mellitus and metabolic syndrome (AUC=0.74-0.78 vs. AUC=0.56; p<0.05). These markers also showed higher AUC than T in predicting adverse cardiovascular risk lipid profile and insulin resistance patients but the differences were not statistically significant. 4HPPD and MMA distinguished patients with low bone density (z-score in DEXA scan < -1), but no difference was observed when comparing with AUC for T,. The androgenic dependence of 4HPPD and ALDOB were confirmed by finding statistically significant lower levels of these markers in men with androgen CAG repeat lengths < 21 (p=0.002) and >22 (p=0.038) as compared to those with CAG of 21-22. No statistical significances were found for IGFBP6. Conclusions 4HPPD and ALDOB were identified as potential biomarkers for diagnosis of male hypogonadism and in identifying subjects at high risk of some of its clinical sequelae. More extensive testing should be carried out in order to elucidate their usefulness in clinical assessment of androgenic activity, not only in adult males but also in women and in pre-pubertal boys.

Project description:BACKGROUND: Interest in phage therapy has grown over the past decade due to the rapid emergence of antibiotic resistance in bacterial pathogens. However, the use of bacteriophages for therapeutic purposes has raised concerns over the potential for immune response, rapid toxin release by the lytic action of phages, and difficulty in dose determination in clinical situations. A phage that kills the target cell but is incapable of host cell lysis would alleviate these concerns without compromising efficacy. RESULTS: We developed a recombinant lysis-deficient Staphylococcus aureus phage P954, in which the endolysin gene was rendered nonfunctional by insertional inactivation. P954, a temperate phage, was lysogenized in S. aureus strain RN4220. The native endolysin gene on the prophage was replaced with an endolysin gene disrupted by the chloramphenicol acetyl transferase (cat) gene through homologous recombination using a plasmid construct. Lysogens carrying the recombinant phage were detected by growth in presence of chloramphenicol. Induction of the recombinant prophage did not result in host cell lysis, and the phage progeny were released by cell lysis with glass beads. The recombinant phage retained the endolysin-deficient genotype and formed plaques only when endolysin was supplemented. The host range of the recombinant phage was the same as that of the parent phage. To test the in vivo efficacy of the recombinant endolysin-deficient phage, immunocompromised mice were challenged with pathogenic S. aureus at a dose that results in 80% mortality (LD80). Treatment with the endolysin-deficient phage rescued mice from the fatal S. aureus infection. CONCLUSIONS: A recombinant endolysin-deficient staphylococcal phage has been developed that is lethal to methicillin-resistant S. aureus without causing bacterial cell lysis. The phage was able to multiply in lytic mode utilizing a heterologous endolysin expressed from a plasmid in the propagation host. The recombinant phage effectively rescued mice from fatal S. aureus infection. To our knowledge this is the first report of a lysis-deficient staphylococcal phage.

Dataset Information

Essential Topics for the Regulatory Consideration of Phages as Clinically Valuable Therapeutic Agents: A Perspective from Spain.

Publications

Essential Topics for the Regulatory Consideration of Phages as Clinically Valuable Therapeutic Agents: A Perspective from Spain.

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