OECD 488 transgenic rodent mutation assay (TGRA) using the Big Blue(r) rat

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        "title": "OECD 488 transgenic rodent mutation assay (TGRA) using the Big Blue(r) rat",
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        "description": "The conduct of an OECD 488 transgenic rodent mutation assay (TGRA) using the Big Blue(r) rat using cII mutant selection for the University of Sheffield. Studies will be conducted to GLP, and are based on the following preliminary study design: 1. Breeding of target cohort of 46 Big Blue male rats, with delivery of a target of 44 rats to Charles River Laboratories (CRL) facility, Ashland Ohio, USA. 2. Transfer of HPLC analytical method for dose formulation analysis (DFA) and method transfer summary performed by CRL. 3. Method validation, homogeneity, solubility and stability work to enable GLP dose formulation analysis during Big Blue(r) TGRA main study, performed by CRL. 4. 7-day dose-range finding study (DRF), wild type Fischer F344 male and female rats, to determine limit dose of 1000 mg / kg body weight /day or MTD, performed by CRL. 5. Big Blue(r) TGRA rat main study, male only, using vehicle, 3 dose groups and concurrent positive control conducted at CRL. Each group will contain at least 6 male rats, conducted in accordance with OECD 488; daily test item administration by oral gavage for 28 days (positive control will be dosed days 1, 3, 10, 17 & 24 only); termination and schedule necropsy on day 31 with duodenum, liver and bone marrow removed from all animals, flash frozen and stored prior to shipment to Gentronix. 6. Pig-A in vivo mutation analysis will be integrated into the Big Blue(r) TGRA study, with all study animals screened for elevated Pig-A locus mutation in the pre-study acclimatisation phase, and then a blood sample taken from all animals on study on day 31 as a terminal bleed to minimise animal handling procedures and impact onto the Big Blue(r) TGRA study. Pig-A analysis will be performed by CRL, unless Sheffield advises of an alternative third party analysis partner, consistent with GLP study principles. 7. Dose formulation analysis during conduct of the main study, performed by CRL. 8. Analysis of liver and duodenum (bone marrow will not be analysed initially) from 5 animals per dose group in the in vitro phase of the Big Blue(r) TGRA study as per OECD 488 will be conducted at and performed by Gentronix. DNA will be extracted, packaged into lambda bacteriophage used to infect E. coli strain G1250 to determine phage packaging efficiency and cII mutation detection after plating on agar. Phage packaging titres of at least 125,000 per animal will be determined, to facilitate estimation of mutation frequency. 9. GLP reporting of results.",
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                "description": "In August 2021 the University of Sheffield entered into a contract with WuXi AppTec (Hong Kong) Ltd (Find A Tender Service Contract Award Notice Publication Reference: 2021/S 000-021618) for the provision of IND enabling toxicology study services for M102 (small-molecule drug candidate; oral route, once daily), including 2 animal studies. It is now the intention of the University of Sheffield to contract the third animal study (Big Blue) to Gentronix Limited. Studies will be conducted to GLP, and are based on the following preliminary study design: The conduct of an OECD 488 transgenic rodent mutation assay (TGRA) using the Big Blue(r) rat using cII mutant selection for the University of Sheffield. Studies will be conducted to GLP, and are based on the following preliminary study design: 1. Breeding of target cohort of 46 Big Blue male rats, with delivery of a target of 44 rats to Charles River Laboratories (CRL) facility, Ashland Ohio, USA. 2. Transfer of HPLC analytical method for dose formulation analysis (DFA) and method transfer summary performed by CRL. 3. Method validation, homogeneity, solubility and stability work to enable GLP dose formulation analysis during Big Blue(r) TGRA main study, performed by CRL. 4. 7-day dose-range finding study (DRF), wild type Fischer F344 male and female rats, to determine limit dose of 1000 mg / kg body weight /day or MTD, performed by CRL. 5. Big Blue(r) TGRA rat main study, male only, using vehicle, 3 dose groups and concurrent positive control conducted at CRL. Each group will contain at least 6 male rats, conducted in accordance with OECD 488; daily test item administration by oral gavage for 28 days (positive control will be dosed days 1, 3, 10, 17 & 24 only); termination and schedule necropsy on day 31 with duodenum, liver and bone marrow removed from all animals, flash frozen and stored prior to shipment to Gentronix. 6. Pig-A in vivo mutation analysis will be integrated into the Big Blue(r) TGRA study, with all study animals screened for elevated Pig-A locus mutation in the pre-study acclimatisation phase, and then a blood sample taken from all animals on study on day 31 as a terminal bleed to minimise animal handling procedures and impact onto the Big Blue(r) TGRA study. Pig-A analysis will be performed by CRL, unless Sheffield advises of an alternative third party analysis partner, consistent with GLP study principles. 7. Dose formulation analysis during conduct of the main study, performed by CRL. 8. Analysis of liver and duodenum (bone marrow will not be analysed initially) from 5 animals per dose group in the in vitro phase of the Big Blue(r) TGRA study as per OECD 488 will be conducted at and performed by Gentronix. DNA will be extracted, packaged into lambda bacteriophage used to infect E. coli strain G1250 to determine phage packaging efficiency and cII mutation detection after plating on agar. Phage packaging titres of at least 125,000 per animal will be determined, to facilitate estimation of mutation frequency. 9. GLP reporting of results. Schedule - subject to CRL timelines and Study Plan * In-life study phases commence at CRL in either December 2022 (if dose range finding study required) or January 2023 (if main phase OECD 488 study only) * In-life study phases complete at CRL in February 2023 * Post-life in vitro phases commence at Gentronix Limited in February 2023 * Post-life in vitro phases complete at Gentronix Limited in April 2023 * Draft report - by end May 2023 Gentronix's Limited's choice of partnership with CRL was based on 4 main factors: 1. They are a significant contract research organisation, high animal welfare standards and with capabilities at their Ashland facilities to conduct all necessary aspects of the in-life Big Blue studies. These include supporting toxicological and analytical endpoints and in particular they have coverage for all expected routes of exposure/administration including via inhalation; 2. The laboratory team at Ashland has previous experience of acting as GLP main test site and Study Director for Big Blue(r) studies, commissioned by the previous asset owner being BioReliance Corporation. This substantially de-risks the GLP compliance elements of these studies, and was viewed favourably in our discussions with the UK MHRA prior to commencing work on this project; 3. The USA location and relative close proximity to our animal facility breeding location in NY. This enables ground transportation of animals within a timeframe that provides no compromise on animal welfare and shipments are routine from our contract breeder to these facilities; 4. In many circumstances they were and are an established service provider to the same clients Gentronix Limited receives enquiries from for Big Blue(r) studies. This de-risks commercial, contractual and legal discussions. At present the CRL Ashland facility is the only site capable of conducting GLP compliant in-life subcontract work for Big Blue studies on behalf of Gentronix.",
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        "procurementMethodRationale": "Negotiated procedure without prior publication 32. (2) (b) (ii) - The works, supplies of services can be provided only by a particular economic operator for the following reason: o Competition is absent for technical reasons Explanation BigBlue test and MutaMouse test are both qualified genotoxicity studies using transgenic rodent models to enable the US FDA investigational new drug (IND) filing and the initiation of first-in-human studies. BigBlue assay uses transgenic rats, while MutaMouse assay uses transgenic mice. To identify the rodent and non-rodent species relevant to human, the research teams at UoS and its partners (including Aclipse) have conducted a metabolite identification study. Potential metabolites of M102 were identified and possible metabolic pathways were predicted in liver microsomes from various species (mouse, rat, dog, monkey, human). It was observed that the metabolites in human liver microsomes were relevant to those of rats and monkey. As a result, rat and monkey were selected as appropriate rodent and non-rodent species for toxicological evaluations for M102. In fact, the non-GLP M102 general toxicological study in rats has already been performed which makes the BigBlue assay the next scientifically logical step. The use of BigBlue assay (i.e., transgenic rat model) to evaluate the in vivo genotoxicity of M102 can be well justified. Gentronix Limited have proprietary ownership of the Big Blue genetically specific breeding colony and methodology, meaning that there are no other CLP compliant providers who can provide this assay. A single source is therefore proposed to formalise the solution provided by Gentronix Limited for the following reasonss that it has proprietary ownership of the Big Blue(r) Transgenic Rodent (TGR) Gene Mutation Assay which is stipulated in order to obtain FDA approval. The Services to be delivered will commence around December 2022, are due to take 6 months and complete by May 2023"
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