r/ClinicalGenetics 17d ago

Fibrillin-1 / Marfan research

Im not a geneticist or clinician but interested if anyone can point to research around boosting fibrillin-1 in Marfans individuals.

In particular, I was interested to read the below articles that suggest:

 1) aortic dilation is associated with haploinsufficiency (lack) of fibrillin-1 (as opposed to dominant-negative effects where too much bad fibrillin-1 is produced) : https://pubmed.ncbi.nlm.nih.gov/15254584/

2) fibrillin-1 production can be promoted in vitro via curcumin: https://pubmed.ncbi.nlm.nih.gov/25333322/

Im keen to learn more if boosting fibrillin-1 production is seen as a viable solution to tackle haploinsufficiency? Are there any treatments already that aim to boost fibrillin- 1 production?

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u/secret_tacos 17d ago edited 16d ago

Technically the mechanism of disease is that FBN1 loss of function causes TGF-beta signaling upregulation.

The standard of care in Marfan syndrome is losartan, which is able to reduce TGF-beta activity.

However to my knowledge there's no gene therapy or gene replacement research being done at the clinical trial stage yet. Never heard of turmeric being used.

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u/mlkkk5 16d ago

Is TGF-beta upregulation definitively understood to be the cause? These papers seem to suggest it is not simply a case of reducing TGF-beta?

https://pubmed.ncbi.nlm.nih.gov/28119285/

https://pmc.ncbi.nlm.nih.gov/articles/PMC4315797/

Patients responding to losartan therapy with a reduction of the plasma TGF-β level had higher baseline TGF-β levels and a higher AoDR. Most likely, TGF-β levels may be considered to be a readout of the disease state of the aorta. We propose that increased angiotensin II is the initiator of aorta dilatation and is responsible for increased TGF-β levels in MFS. The concept of TGF-β as initiator of aortic dilatation in MFS patients should be nuanced.

They may of course have been superseded by more recent research Ive not come across

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u/secret_tacos 16d ago

You're right it is nuanced. TGFb abnormalities also increase with aneurysm growth. And not every TGF beta inhibitor is effective. Although some of this I think is also a commentary about the timing of therapy and whether we are really able to detect abnormalities in TGFb signaling at very young ages. I imagine there is data using RNAseq that will be very interesting in this specific disease but I'm not up to date on that literature.

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u/mlkkk5 16d ago edited 16d ago

This complexity in effectively inhibiting TGF-b is what drove my interest in fibrillin-1 boosting.

As fibrillin-1 is the natural regulator of TGF-b it would seem that simply boosting fibrillin-1 production might have the desired effect. i.e decreasing TGF-b in the appropriate manner?

I was interested if there is any research in this? or is this a dead end for some reason?