ICMT Inhibition as an Approach to Treating Progeria

Progeria is a rare genetic condition in which cells throughout the body become misshapen, dysfunctional, and damaged due to the accumulation of a broken form of the structural protein lamin A, called progerin. This produces outcomes that in some ways resemble accelerated aging. Aging is, after all, the accumulation of cell and tissue damage and dysfunction - just not this particular type of damage, to any great degree. Interestingly, progerin is observed in low levels in genetically normal older individuals, so it is possible that there is some contribution from this mechanism to normal aging. The studies needed to establish whether or not this contribution is sizable enough to care about have yet to be carried out, however. Nonetheless, it is interesting to keep an eye on the development of therapies for progeria that involve suppression of progerin or its activities.

Children with Hutchinson-Gilford progeria syndrome (HGPS) age rapidly due to a rare de novo mutation which causes accumulation of a shortened form of prelamin A - called progerin - at the nuclear envelope. Progerin is toxic and causes misshapen nuclei, cell senescence, a host of aging-related disease phenotypes, and death in the teenage years from myocardial infarction or stroke. Because progerin is methylated by the enzyme ICMT, earlier studies hypothesized that targeting ICMT might be an effective anti-HGPS therapy. These studies showed that targeting ICMT with genetic strategies improves phenotypes and extends survival in mouse models of progeria and that early-stage ICMT inhibitors can overcome senescence and improve phenotypes of cells from HGPS patients.

However, further studies were not possible due to the lack of ICMT inhibitors with ample bioavailability and pharmacological properties. Scientists have now taken a big step forward by synthesizing and validating a potent ICMT inhibitor (UCM-13207, Cpd21) that can be used in vivo. Their drug improves both cellular and in vivo phenotypes of HGPS, including parts of the vascular phenotype, and extends survival of mice with progeria. The study represents an important step in the preclinical validation of this therapeutic strategy and raises hopes that clinical trials might be possible in the not-too-distant future.

Both the current and previous studies show that targeting ICMT mislocalizes progerin, alleviates senescence, and stimulates proliferation of cells from mice and children with HGPS. Both also show that targeting ICMT does not influence the characteristic nuclear blebbing phenotype of progerin-expressing cells. Moreover, the magnitude of the effects of these three approaches is comparable. Whereas the earlier studies find that blocking progerin methylation reduces its turnover and causes the protein to accumulate in the nucleoplasm, Cpd21 was found to increase progerin turnover and reduce its levels in cells and tissues. The latter result - reducing the levels of a toxic protein - is obviously more attractive from a therapeutic perspective, and it raises the questions of whether Cpd21 causes off-target effects that trigger progerin degradation or whether it influences LMNA transcription, splicing, or mRNA turnover. The current study did not distinguish between these possibilities.

Link: https://doi.org/10.1021/acscentsci.1c00828

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