Gene therapy for restoring heart rhythm.
J Cardiovasc Pharmacol Ther
; 19(5): 426-38, 2014 Sep.
Article
em En
| MEDLINE
| ID: mdl-24742766
ABSTRACT
Efforts to use gene therapy to create a biological pacemaker as an adjunct or replacement of electronic pacemakers have been ongoing for about 15 years. For the past decade, most of these efforts have focused on the hyperpolarization-activated cyclic nucleotide gated-(HCN) gene family of channels alone or in combination with other genes. The HCN gene family is the molecular correlate of the cardiac pacemaker current, If. It is a suitable basis for a biological pacemaker because it generates a depolarizing inward current primarily during diastole and is directly regulated by cyclic adenosine monophosphate (cAMP), thereby incorporating autonomic responsiveness. However, biological pacemakers based either on native HCN channels or on mutated HCN channels designed to optimize biophysical characteristics have failed to attain the desired basal and maximal physiological heart rates in large animals. More recent work has explored dual gene therapy approaches, combining an HCN variant with another gene to reduce outward current, increase an additional inward current, or enhance cAMP synthesis. Several of these dual gene therapy approaches have demonstrated appropriate basal and maximal heart rates with little or no reliance on a backup electronic pacemaker during the period of study. Future research, besides examining the efficacy of other gene combinations, will need to consider the additional issues of safety and persistence of the viral vectors often used to deliver these genes to a specific cardiac region.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Arritmias Cardíacas
/
Fármacos Cardiovasculares
/
Terapia Genética
/
Canais Disparados por Nucleotídeos Cíclicos Ativados por Hiperpolarização
Limite:
Animals
/
Humans
Idioma:
En
Revista:
J Cardiovasc Pharmacol Ther
Assunto da revista:
ANGIOLOGIA
/
CARDIOLOGIA
/
FARMACOLOGIA
Ano de publicação:
2014
Tipo de documento:
Article
País de afiliação:
Holanda