Which of the following provides a promising therapeutic approach to treat HGPS?

Question

Which of the following provides a promising therapeutic approach to treat HGPS?

A. Activate the enzyme that farnesylates the C within the CSIM motif on Progerin.

B. Use CRISPR/Cas9 gene editing to delete the 150 bp in the Lamin A gene that encodes the 50 amino acids that immediately precede CSIM.

C. Inhibit the enzyme that farnesylates the C within the CSIM motif on Progerin.

D. Inhibit the enzyme that removes the farnesylcysteine methyl ester from Progerin.

E. Inhibit the enzyme that removes the C-terminal Ser-Ile-Met from Progerin

Explanation / Answer

C. Inhibit the enzyme that farnesylates the C within the CSIM motif on Progerin

Farnesyltransferase inhibitors (FTIs) represent a promising way to treat HGPS owing to their ability to block farnesylation of progerin and an ability to suppress development of the HGPS phenotype in mouse models. These drugs are also safe for clinical use. However, treating patients with FTIs, does not eliminate expression of progerin and prelamin A, but rather causes these proteins to accumulate in their unfarnesylated forms. Also at issue is whether the beneficial effects of FTIs are direct or secondary, because FTI treatment of HGPS-model mice results in an incomplete blockade of prelamin A maturation72. Therefore, significant levels of farnesylated progerin likely remain, and FTIs might function either through partial inhibition of progerin farnesylation or through effects on another CAAX-containing protein. Furthermore, although most cases of HGPS are associated with progerin expression, several HGPS-associated alleles have been identified that are not predicted to alter lamin A processing. The potential efficacy of FTIs in such instances remains in question, although they might be expected to interfere with the transient prenylation of mutant proteins and target them away from the nuclear periphery, which might suppress toxicity. It would therefore be useful to determine the ability of FTIs to rescue defects in nuclear organization across the spectrum of laminopathy mutations.

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