TABLE 2.

Strategies of nucleic acid therapy reported for preclinical HGPS treatment

Strategy	Objective	Effects	Ref.
Prenatal genetic manipulation	To deplete methyltransferase Suv39h1	Loss of Suv39h1 in progeroid mice delayed body weight loss, increased bone mineral density, and extended lifespan	Liu et al. (2013)
	To reduce the expression and activity of isoprenylcysteine carboxyl methyltransferase (ICMT)	A hypomorphic allele of ICMT increased body weight, normalized grip strength, and extended the lifespan of progeroid mice	Ibrahim et al. (2013)
	To knockdown the phospholipase A2 receptor	Whole‐body knockout of Pla2r1 in progeroid mice ameliorated premature aging phenotypes (including rib fractures and the decline in bone content)	Griveau et al. (2018)
	To inhibit the NF‐κB pathway	The therapy increased body weight and extended the lifespan of the mouse model. In addition, after treatment, the spleen of the mouse model showed normal lymphoid follicles. The thymus of the mouse model also displayed normal tissue mass, cellularity, and architecture	Osorio et al. (2012)
	To overexpress Yamanaka factors	The therapy ameliorated organismal phenotypes associated with HGPS	Ocampo et al. (2016)
	To silence the HGPS mutation	The therapy normalized the bone morphology and mineralization in the mouse model, in which osteoblast‐ and osteocyte‐specific inducible transgenic expression of the HGPS mutation had been incorporated. It also normalized dentinogenesis, and increased the number of osteocytes in remodeled bone.	Strandgren et al. (2015)
Antisense oligonucleotide therapy	To inhibit DNA damage response	Treatment with sequence‐specific telomeric antisense oligonucleotides led to a significant reduction in the number of telomere dysfunction‐induced foci in progeroid mice. Restoration of homeostatic proliferation in the suprabasal layer of the skin of the mice was also observed	Aguado et al. (2019)
	To prevent pathogenic Lmna splicing	The therapy reduced the accumulation of progerin, ameliorated progeroid phenotypes, and extended the lifespan of progeroid mice	Osorio et al. (2011)
	To increase lamin C production at the expense of prelamin A	The therapy ameliorated the aortic pathology observed in LmnaG609G/G609G mice	Lee, Nobumori, et al. (2016)
Ex vivo treatment of cells before implantation	To reactivate the NRF2 pathway by knocking down CAND1	The therapy could not only restore the in vivo viability of MSCs obtained from the differentiation of the induced pluripotent stem cells (iPSCs) derived from HGPS fibroblasts, but could also decrease the reactive oxygen species (ROS) level and could rescue nuclear defects in those cells	Kubben et al. (2016)
CRISPR/Cas9‐based therapy	To impede lamin A/progerin production	The therapy led to a significant reduction in the number of progerin‐positive nuclei in the liver, heart and skeletal muscles of the progeroid mice	Santiago‐Fernandez et al. (2019)
	To cause lamin A/progerin‐specific transcriptional interference or RNA destabilization	The therapy suppressed epidermal thinning and dermal fat loss, ameliorated the degeneration of vascular smooth muscle cells of the aortic arch, attenuated the development of bradycardia, and increased the median survival rate of progeroid mice	Beyret et al. (2019)