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Covid-19 CRO Service: Physiogenex Coronavirus Disease – NASH Hamster model

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Covid-19 CRO Service: Physiogenex Coronavirus Disease – NASH Hamster model

◆Summary

France CRO Physiogenex, partner of CLEA Japan, Inc. has developed Coronavirus Disease 2019 CRO service using a diet-induced obese NASH hamster model.

This obese NASH Hamster model shows greater severity of COVID-19 as observed in obese humans. Given its high similarity with the human context, this model is useful for preclinical study evaluating efficacy of drugs targeting COVID-19.

※NASH: Non-alcoholic Steatohepatitis
※This hamster is prepared only for this contract research service. We do not sell it as our animal models.


Table of contents:

COVID-19 in obese NASH Hamster

Example: Study design (w/ Free Choice Diet)

The mechanism of COVID-19 infection and lung damage

Characteristics of the Physiogenex obese NASH Hamster model 

What is Physiogenex

FAQ

Inquiry



◆COVID-19 in obese NASH Hamster

Physiogenex obese NASH Hamster model infected with SARS-CoV-2 shows greater lung damages.

・HE stain of Lung
     No infected      Infected with normal diet      Infected with Free Choice diet
HE stain of Lung

・Sirius Red stain of Lung

  Infected with normal diet       Infected with Free Choice diet        lung fibrosis quantification   
Sirius Red stain of Lung

Reference:
・The incidence of COVID-19 in patients with metabolic syndrome and non-alcoholic steatohepatitis: A population-based study
 Ghoneim et al. Metabolism 2020

・Pathogenesis and transmission of SARS-CoV-2 in golden Syrian hamsters
 Sia et al. Nature 2020 

・Spike protein recognition of mammalian ACE2 predicts the host range and an optimized ACE2 for SARS-CoV-2
 Luan et al. BBRC 2020


◆Example: Study design (w/ Free Choice Diet)

Obesity and NASH is induced by a Free Choice diet* in hamster before infection with Sars-CoV-2.
Study of design

* Free Choice Diet
The Free Choice Diet is that the subject animals can choose between normal chow diet/normal water and high fat/cholesterol diet and 10% fructose rich water, in the same housing cage. It favors hyperphagia in hamster (which cannot be induced with a high fat diet alone) and induces obesity, NASH and heart failure with preserved ejection fraction.
Free Choice Diet

Result of Free choice diet


◆The mechanism of COVID-19 infection and Lung damage



Normal : ACE2 sustains balance of the vascular structure by connecting Ang II
・Serum Ang I is converted to Ang II by ACE.
・Ang II activates the AT1R, AT2R pathway
 → Promotes vasoconstriction, inflammation, Fibrosis and ultimately lungs injury
・Ang II is converted to Ang1-7 by ACE2
 → Ang1-7 activates the Mas pathway
 → Protective against lungs injury.

Infected : SARS-Cov-2 binds ACE2
・Ang II levels increases and favors the proinflammatory/profibrotic AT1R pathway.
・SARS-Cov-2 impairs Ang II conversion to Ang1-7.
 → Cannot be protective against lungs injury.


◆Characteristic of the Physiogenex obese NASH Hamster Model

・NASH
 Hepatic fibrosis          Ballooning     Inflammation       Ballooning   Bridging fibrosis
NASH


・Decreasing lung Inf-arpha / Increasing Inflammatory IL-6 cytokine
Decreasing lung Inf-arpha / Increasing Inflammatory IL-6 cytokine

・Decreasing Serum ACE2 activity
Decreasing Serum ACE2 activity

Reference:
・Circulating ACE2 activity correlates with cardiovascular disease development
   https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5843890/

・Heart Failure with Preserved Ejection Fraction(HFpEF)
Heart Failure with Preserved Ejection Fraction(HFpEF)

Reference of the NASH Hamster model:
Elafibranor improves diet-induced nonalcoholic steatohepatitis associated with heart failure with preserved ejection fraction in Golden Syrian hamsters
 Briand et al. Metabolism 2021

More details of Physiogenex CRO service NASH Hamster model



◆What is Physiogenex:


Physiogenex provides preclinical in vivo and ex vivo CRO services and consulting in metabolic disorders such as obesity, diabetes, NASH, fibrosis, diabetic nephropathy, cardiovascular complications, dyslipidemia and atherosclerosis.

Not only the CRO service provider, Physiogenex can be a partner to develop the animal models and assess technics as needed. In addition, Physiogenex can dedicate to support your study with their various specialists of R&D, preclinical study, additional study after sales, and reevaluation of pharmacometrics. Moreover, Physiogenex can execute in vivo preclinical imaging service, too.
(From Physiogenex Homepage in 2017)
Physiogenex Service:Details of CLEA Japan support and Service Condition

◆FAQ

How is the study running?

Currently Physiogenx uses BSL3 room in Pasteur Lab. The maximum animal # is 36 per a study. The number of animal per study is expected to increase by 72 animals max in another laboratory, BSL3, from April 2022.

Do we need to have an agreement with 3 organizations, included CLEA Japan also?

Basically most of the agreements should be exchanged by 2 organizations, such as your company and Physiogenex. However, some customers wanted CLEA to support such as meeting support and had concluded nondisclosure -3 organizations-agreement.

How long does it take to do Hamster DIO?

Physiogenex regularly prepares NASH hamster with DIO treatment. Therefore, you do not need to consider its DIO term because animals are ready-to-use.

Can Physiogenex use non-NASH hamster for this service?

It is possible and even experienced. However non-NASH hamster cannot show certain symptoms by the infection so it is recommended to use NASH hamster depend on your compound nature and/or preferred measurement subjects.

Can Physiogenex do the wiping qPCR analytics without animal scarification?

Currently Pasteur Lab cannot execute wiping method. If you want to see the chronological change, you still need to sacrifice the animals.

Can Physiogenex report be good enough to use for such as IND submission?

Physiogenex has submit many customers, included mega pharmas in US/EU, and there have been no retaking request due to the inappropriateness of the official submission. It should be depended on the country officials, but there should be no problem in the major usual official submissions.

Do we need to submit a study protocol in the first place?

Physiogenex has a lot of experiences for this study and can advise the most effectiveness study design to fit of your compounds and target measurement needs. Please explain your desired wants. Then Physiogenex will consider study protocol together to make most effective and efficient way to observe.

What variant of the Covid 19 does Physiogenex use?

You can choose any variants of it if Pasteur Lab possesses, included delta variant.

When can Physiogenex start the study?

Currently Pasteur lab is very busy and should be execute 3-4 months later even it is ordered now. However, Physiogenex plans to contract another laboratory, BSL3, from April 2022. If it is successfully happened, the waiting time would be shortened after that.


◆Inquiry

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