Bioluminescence-optogenetics-mediated gene therapy in a sleep-disordered breathing mouse model - 21/08/24
Abstract |
Obstructive sleep apnea (OSA) incurs a huge individual, societal, and economic burden. Specific and selective targeting of hypoglossal motor neurons could be an effective means to treat OSA. Bioluminescent-optogenetics (BL-OG) is a novel genetic regulatory approach in which luminopsins, fusion proteins of light-generating luciferase and light-sensing ion channels, increase neuronal excitability when exposed to a suitable substrate. Here we develop and validate the feasibility of BL-OG for sleep-disordered breathing (SDB). Upon confirming that diet-induced obese mice represent an excellent SDB model, we employed a method of targeting the hypoglossal nucleus (12 N) by peripherally injecting retrogradely transported rAAV2/Retro. With AAV transduction, the eLMO3 protein is expressed in hypoglossal motor neurons (HMN); administration of CTZ results in production of bioluminescence that in turn activates the tethered channelrhodopsin, leading to an increase in the firing of HMN and a 2.7 ± 0.8-fold increase in phasic activity of the genioglossus muscle, a 7.6 ± 1.8-fold increase in tonic activity, and improvements in hypoventilation and apnea index without impacting sleep structure. This is therefore the first study to leverage the rAAV2/Retro vector to execute the BL-OG approach in SDB, which amplified genioglossus muscle discharge activity and increased airflow in mice after activation. This study marks the pioneering utilization of BL-OG in SDB research.
Le texte complet de cet article est disponible en PDF.Graphical Abstract |
Gene therapy has not been explored much in the field of OSA.Hu and colleagues have introduced and assessed a novel gene therapy approach, which merges bioluminescent optogenetics (BL-OG) with a highly effective retrogradely infected adeno-associated virus. The expression of eLMO3 following retrograde viral transduction enables activation of the optogenetic channel through internal light (bioluminescence) each time the luciferin (CTZ) is applied. This stimulates the genioglossus muscle, mitigates hypoventilation and decreases the apnea index (AI) in diet-induced obesity (DIO) mice.
Gene therapy has not been explored much in the field of OSA.Hu and colleagues have introduced and assessed a novel gene therapy approach, which merges bioluminescent optogenetics (BL-OG) with a highly effective retrogradely infected adeno-associated virus. The expression of eLMO3 following retrograde viral transduction enables activation of the optogenetic channel through internal light (bioluminescence) each time the luciferin (CTZ) is applied. This stimulates the genioglossus muscle, mitigates hypoventilation and decreases the apnea index (AI) in diet-induced obesity (DIO) mice.Le texte complet de cet article est disponible en PDF.
Highlights |
• | Diet-induced obese (DIO) mice represent an excellent model of SDB. |
• | Compared to rAAV2/9 and rAAV2/11, the rAAV2/Retro serotype has a higher retrograde infection efficiency. |
• | The BL-OG approach, which was used for the first time in SDB research, has demonstrated a positive safety profile. |
• | In virus-infected mice, CTZ administration increases muscle activity, improves hypoventilation and AI, without altering sleep structure. |
Keywords : Bioluminescence-optogenetics, Obstructive sleep apnea, Adeno-associated virus, Genioglossus, Coelenterazine
Plan
Vol 178
Article 117159- septembre 2024 Retour au numéroBienvenue sur EM-consulte, la référence des professionnels de santé.
L’accès au texte intégral de cet article nécessite un abonnement.
Déjà abonné à cette revue ?