Nature Medicine | Spoonful of Medicine

Top models

Speaking of mammals (see the end of my previous entry), not even rats and mice always cut it when it comes to providing good models of human disease. Take, for example, cystic fibrosis. There are a couple of mouse models of the disease (we have published at least one of them), but the community does not seem to be satisfied with them. It is therefore great to see a pair of papers in the JCI reporting on two new attempts at generating the ideal model of cystic fibrosis.

The two of studies are very similar. In the first one, Xingshen Sun and colleagues report the first description of genetically engineered ferrets. They started by targetting the CFTR gene (the gene affected in the disease) in fibroblasts using an adeno-associated viral (AAV) construct, and then used a nuclear transfer protocol to obtain cloned ferrets heterozygous for the CFTR mutation. In the second one, Christopher Rogers and colleagues employed a similar strategy in pigs to obtain heterozygous piglets carrying the CFTR mutation.

The next steps will be to establish how much these models truly recapitulate human disease, and then use them to learn new biology about the disease and/or for preclinical drug-discovery work.

The figures, taken from the papers, show the cloned CFTR ferrets and a non-cloned albino at different ages, and the first CFTR heterozygous pig at one day of age.



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    Chri Muller said:

    Some of us were discussing this after attending a conference where some pharma companies presented their in vitro and in vivo data. Even for antimicrobials, anticancer, antidiabetic agents and probably many others, it looks like even if you have a preclinical candidate which does wonders in your animal model, it still has a very good chance of bombing when it enters clinical trials or even when it goes for ADMET testing. Considering this fact and the fact that pet care and even animal husbandry are such important fields for human life, are these molecules (the ones which are ineffective in humans but seem promising in animal models?) taken up for veterinary care? At least, all this money industry is sinking into drug discovery need not be completely wasted.

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    JCL said:

    good question. i don’t think they go into animal care, because many of the human diseases that people model in mice or rats do not occur in these species. and even if they did, from the point of view of veterinary care, you care about cattle, or about cats and dogs, which in turn have a different set of diseases.

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    Chris Muller said:

    But when disease is induced in animal models to begin testing, surely the means of inducing that disease and the manifestations must be meaningful and common to similar disease caused in humans? If that is the case, except for mice which seem to get cancer no matter what you give them, why not consider at least some areas of research (for example, obesity {I see many fat dogs and cats around these days]?

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    JCL said:

    models are supposed to be meaningful and accurate surrogates of human disease, but the reality is that they often aren’t good. we carry on using them because that’s what we have and because we continue learning interesting biology from them. but very few of them have ultimately translated into therapies.

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    RSL said:

    The last post asked if promising therapies that come out of preclinical trials (that is mice and other mammals) but bomb in human trials could still be used in the veterinary setting. The answer according to my vet, a leading cat specialist in NYC, is yes. But only if studies were specifically done in the species of interest (cats in his case) and showed a true benefit. He is reluctant to use it otherwise for moral and legal reasons. For example, ACE inhibitors, which are used clinically to treat progressive chronic kidney disease in humans, was only adapted in cats after studies in cats showed it was effective. Whereas spironolactone, a mineralcorticoid receptor inhibitor, that has shown promise for treating proteinuria in humans has not been tested specifically in cats and thus my vet won’t consider it.

    So potentially “failed” therapies for humans could be adopted for veterinary care, but only after appropriate trials have been performed. The good news, I suppose, is that unlike human trials getting enough “subjects” to enroll in a veterinary trial in a cost-effective manner probably shouldn’t be a problem.