2008 Laennec Clinician/Educator Lecture—The Gene From Limone: Is It Golden or Not?

Abstract

Valerio Dagnoli of the lake-side town of Limone sul Garda was noted to have a very low high-density lipoprotein cholesterol (HDL-C) level (12 mg/dL) in 1975 and was referred to Cesare Sirtori at the University of Milan. Cesare Sirtori, Guido Franceschini, and collaborators from the Gladstone Laboratories in San Francisco eventually discovered that Valerio’s HDL contained a mutant form of Apo A-I with an Arginine 173 to Cysteine 173 substitution. This mutant, labeled Apo A-I milano, was present in 40 of the approximately 1000 inhabitants of Limone sul Garda. Through birth records maintained at the local church, the carriers were traced back to a common ancestral couple (Rosa Giovaneli and Giovani Pomaroli) in the 18th century. The carriers have very low HDL-C and elevated triglycerides levels, with an unexpectedly low incidence of cardiovascular disease. This led to the suggestion that this mutation may be protective, perhaps by creating a “turbo-charged” form of Apo A-I that is more athero-protective than wild-type Apo A-I. Our laboratory first demonstrated marked and rapid athero-protective, athero-regressive, and vascular anti-inflammatory effects of rApo A-I Milano in hyperlipidemic rabbits and mice, later confirmed by Sirtori and others. These promising experimental results were supported later by the small phase II clinical trial led by Dr Steve Nissen, where rapid regression of coronary atheroma was shown after 5 weekly intravenous infusions of rApo A-I milano. Difficulties in large-scale production of rApo A-Imilano at a tolerable cost and without bacterial contaminants has been an impediment in further development of this novel therapeutic approach. However, recent progress in recombinant protein expression in safflower seeds using plant biotechnology and the potential for gene transfer promise to overcome these barriers; we are currently testing these strategies in our laboratory. These new developments may allow full validation of this promising strategy in humans. Stay tuned.