Human Zebras and Mice

H
Zebra fish have stripes and is a model species used to understand biology


Zebrafish are a model animal species and are used as they are transparent in early life and there genes can be manipulated to express colours associated with expression of proteins such as the green and red above. You can also make fish that express fluorescent myelin

In this study, they remove a fish gene (GPR17) and replace it with the human gene variant so it expresses the human protein.

Häberlein F, Mingardo E, Merten N, Schulze Köhling NK, Reinoß P, Simon K, Japp A, Nagarajan B, Schrage R, Pegurier C, Gillard M, Monk KR, Odermatt B, Kostenis E, Gomeza J. Humanized zebrafish as a tractable tool for in vivo evaluation of pro-myelinating drugs.Cell Chem Biol. 2022 Sep 9:S2451-9456(22)00315-4. doi: 10.1016/j.chembiol.2022.08.007. 

Therapies that promote neuroprotection and axonal survival by enhancing myelin regeneration are an unmet need to prevent disability progression in multiple sclerosis. Numerous potentially beneficial compounds have originated from phenotypic screenings but failed in clinical trials. It is apparent that current cell- and animal-based disease models are poor predictors of positive treatment options, arguing for novel experimental approaches. Here we explore the experimental power of humanized zebrafish to foster the identification of pro-remyelination compounds via specific inhibition of GPR17. Using biochemical and imaging techniques, we visualize the expression of zebrafish (zf)-gpr17 during the distinct stages of oligodendrocyte development, thereby demonstrating species-conserved expression between zebrafish and mammals. We also demonstrate species-conserved function of zf-Gpr17 using genetic loss-of-function and rescue techniques. Finally, using GPR17-humanized zebrafish, we provide proof of principle for in vivo analysis of compounds acting via targeted inhibition of human GPR17. We anticipate that GPR17-humanized zebrafish will markedly improve the search for effective pro-myelinating pharmacotherapies.

I’m not sure it is helpful to blame animals as poor predictors for positive treatment options, as many failures may have human actions and inapprpriate use at the core. However, it is a preamble to justify the development of alternative models. However, without positive (repair) and negative controls (dont repair) that work in humans it is very difficult to say a new model is predictive of anything. If you have a drug that works how much do you need the models? Anyway this study looks at GPR17, This is a protein found in oligodendrocytes, which are myelin forming cells

They have removed mouse GPR17 and replaced it with human GPR17. What they report is that an agent that targets GPR17 promotes myelination. So maybe a new target for the future. So we will have to watch this space.

However the humanization study that caught my eye was the claims that you can get EAE in mice that contain human cells

BiorXiv doi: https://doi.org/10.1101/2022.02.23.481716

Infection with the human-tropic Epstein-Barr virus (EBV) is a strong risk factor for multiple sclerosis (MS), though the underlying mechanisms remain unclear. To investigate EBV infection directly, we induced experimental autoimmune encephalomyelitis (EAE) in immunocompromised mice humanized with peripheral blood mononuclear cells (PBMCs) from individuals with or without a history of EBV infection and/or diagnosis of relapsing MS. HuPBMC EAE mice generated from EBV seronegative healthy donors (HD) were less susceptible to developing severe clinical symptoms than EBV seropositive cohorts. Donor EBV seropositivity and RRMS diagnosis led to a significant incremental increase in the human Th1:Treg CD4+ T cell ratio in the brain and spinal cord, as well as increased human cytotoxic CD8+ T cell and murine macrophage infiltration and demyelination. The data indicate that a history of EBV infection, further compounded by a diagnosis of RRMS, promotes Th1-mediated disease in a novel humanized mouse model of MS. In this study they use a mouse that lacks lymphocytes (both T and B cells) and then you graft them with human white blood cells and then you induce EAE. In this study they suggest that cells from EBV infected individuals get worse EAE than from lymphocytes from people without evidence of EBV infection. This supports an important role of EBV infection.

This paper has not been peer-reviewed

Targeted depletion of the interleukin 2 receptor in NOD/scid mice (i.e. non-obese diabetic mice that have a severe combined (T & B) immune deficicency meaning that they cannot deplete transplanted cells. With a few more tweaks you can engraft humanHowever there is “window of opportunity” for performing these types of studies due to the development of lethal xenogeneic graft-versus-host disease (GVHD) within 3–4 weeks following T cell transfer. So the human cells (graft) recognise the host (Mouse) as being different and they reject and destroy the mouse. This (GVHD) is a potential side effect of allogenic (cells/transplant from someone else) HSCT and so you take immunosuppressive drugs to try and stop this , However there are ways to avoid the GVDH and rather than inject blood cells you inject stem cells and the immune system learns not to attack your own tissues. So in this paper they injected the mice with a myelin protein and they report that they get disease. I will say there may be some technical issues with this. But if replicated it means you can infect with human viruses e.g. EBV as reported here and you can test human reactive drugs.

I found this paper quite interesting as we looked at NOG mice a few years ago but it suggested to me there would be technology issues that are needed to be solved and am not sure this current work addresses these issues. I know of others who likewise had issues with the approach…So what stardust was employed here.

Now I am not going to specifically critique this paper, as it upsets people if they don’t read gushing responses and the paper will need to address some issues in my mind, I will crituque after it is published. However, I wrote to a friend for their view and it reinforced my concerns and extended them, but the issues I was thinking about have been addressed so the humanised mice are coming…So this is an exciting development as you can ask loads of questions about EBV infection.

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