Systematic screening identifies therapeutic antisense oligonucleotides for Hutchinson–Gilford progeria syndrome

Small-Molecule Therapeutic Perspectives for the Treatment of Progeria

“…To enhance cellular uptake and stability, B143 was conjugated with a palmitoyl acid chain. In vivo administration of this lipid modified ASO, named L-B143, induced a robust reduction in progerin mRNA levels in all tissues, but the extent of progerin protein reduction differed between organs, a result that suggests a long half-life and tissue-specific turnover of progerin in vivo [37]. Nonetheless, L-B143 produced a significant extension of lifespan in the transgenic mouse model of HGPS that expresses the human LMNA gene with the classic G608G mutation when administered subcutaneously at doses of 17 mg/kg or 50 mg/kg, although some toxicity concerns were reported at the highest dose.…”

“…Nonetheless, L-B143 produced a significant extension of lifespan in the transgenic mouse model of HGPS that expresses the human LMNA gene with the classic G608G mutation when administered subcutaneously at doses of 17 mg/kg or 50 mg/kg, although some toxicity concerns were reported at the highest dose. In this case, the improvement in survival and overall increase in body weight in treated animals run parallel to a reduction in incidence and severity of progeria-induced hypertrophy of the media in interstitial arteries of the heart, but it did not significantly correct aortic morphology [37]. At the same time, an independent study carried out by Collin's group analyzed a series of phosphorodiamidate morpholino oligomers (PMOs) directed against the exon 11 cryptic splice site in five nucleotide intervals.…”

Molecular and Cellular Mechanisms Driving Cardiovascular Disease in Hutchinson-Gilford Progeria Syndrome: Lessons Learned from Animal Models

“…G608G BAC mice therefore constitute a very valuable tool for studying several features of the HGPS-associated vascular phenotype and testing new therapeutic approaches. Indeed, work in homozygous G608G BAC mice recently demonstrated that treatment with LMNA -targeted antisense oligonucleotides reduces progerin levels and increases longevity [ 44 , 64 ], and this was accompanied by amelioration of VSMC depletion and adventitial thickening in one of the studies [ 44 ]. In another study, partial correction of the HGPS-associated mutation LMNA c.1824C>T by in vivo systemic base editing in homozygous G608G BAC mice led to the total prevention of VSMC loss and adventitial thickening and a striking 2.4-fold increase in lifespan [ 43 ].…”

“…Research with mouse models has significantly advanced knowledge about HGPS-associated pathology, including CVD, and has paved the way to the development of therapies with the potential to ameliorate or even cure HGPS [ 43 , 44 , 64 , 68 , 69 , 70 ]. However, therapies that are effective in HGPS-like mouse models have yielded only modest benefit in HGPS patients [ 31 , 32 , 33 ].…”

Adenine base editing to treat progeria syndrome and extend the lifespan

“…Various strategies to mitigate the effects of the LMNA c.C1824T mutation have been explored. Inhibitors of protein farnesylation have demonstrated efficacy in clinical trials with HGPS patients, with improvement of some aspects of the disease and even a modest increase in length of survival [1] . Despite being a promising approach that has received approval from the United States Food and Drug Administration for the treatment of HGPS, inhibition of farnesylation is limited in its efficacy and therefore insufficient on its own; furthermore, it produces substantial gastrointestinal side effects.…”