Chemogenetic activation of hypoglossal motoneurons in a mouse model of Pompe disease

Singer, Michele L.; Rana, Sabhya; Benevides, Ethan S.; Barral, Brian E.; Byrne, Barry; Fuller, David D.

doi:10.1152/jn.00026.2022

Cited by 5 publications

(3 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A small but growing body of work has employed DREADDs to activate hypoglossal (XII) motoneurons in the brainstem 8 . Collectively, these studies show that once hM3D(Gq) is expressed in XII motoneurons, DREADD ligands will rapidly produce an increase in the EMG activation of tongue muscles 14, 15 . This increase in tongue muscle output tends to manifest as an increase in the inspiratory related activation, and tonic discharge across the respiratory cycle.…”

Section: Discussionmentioning

confidence: 82%

Chemogenetic stimulation of phrenic motor output and diaphragm activity

Benevides,

Thakre,

Rana

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

Impaired diaphragm activation contributes to morbidity and mortality in many neurodegenerative diseases and neurologic injuries. We conducted experiments to determine if expression of an excitatory DREADD (designer receptors exclusively activation by designer drugs) in the mid-cervical spinal cord would enable respiratory-related activation of phrenic motoneurons to increase diaphragm activation. Wild type (C57/bl6) and ChAT-Cre mice received bilateral intraspinal (C4) injections of an adeno-associated virus (AAV) encoding the hM3D(Gq) excitatory DREADD. In wild type mice, this produced non-specific DREADD expression throughout the mid-cervical ventral horn. In ChAT-Cre mice, a Cre-dependent viral construct was used to drive DREADD expression in C4 ventral horn motoneurons, targeting the phrenic motoneuron pool. Diaphragm EMG was recorded during spontaneous breathing at 6-8 weeks post-AAV delivery. The selective DREADD ligand JHU37160 (J60) caused a bilateral, sustained (>1 hr) increase in inspiratory EMG bursting in both groups; the relative increase was greater in ChAT-Cre mice. Additional experiments in a ChAT-Cre rat model were conducted to determine if spinal DREADD activation could increase inspiratory tidal volume (VT) during spontaneous breathing without anesthesia. Three to four months after intraspinal (C4) injection of AAV driving Cre-dependent hM3D(Gq) expression, intravenous J60 resulted in a sustained (>30 min) increase in VT assessed using whole-body plethysmography. Subsequently, direct nerve recordings confirmed that J60 evoked a >50% increase in inspiratory phrenic output. The data show that mid-cervical spinal DREADD expression targeting the phrenic motoneuron pool enables ligand-induced, sustained increases in the neural drive to the diaphragm. Further development of this technology may enable application to clinical conditions associated with impaired diaphragm activation and hypoventilation.

show abstract

Section: Discussionmentioning

confidence: 82%

Chemogenetic stimulation of phrenic motor output and diaphragm activity

Benevides,

Thakre,

Rana

et al. 2024

Preprint

Self Cite

View full text Add to dashboard Cite

show abstract

“…mCherry expression was confirmed in hypoglossal motoneurons in all mice, confirming retrograde movement of AAV9. This approach could address dysphagia, dysarthria and sleep disordered breathing in patients with Pompe disease [69 ▪ ].…”

Section: Gene Therapy For Pompe Diseasementioning

confidence: 99%

Current avenues of gene therapy in Pompe disease

Leon-Astudillo,

Trivedi,

Sun

et al. 2023

Current Opinion in Neurology

Self Cite

View full text Add to dashboard Cite

Purpose of review Pompe disease is a rare, inherited, devastating condition that causes progressive weakness, cardiomyopathy and neuromotor disease due to the accumulation of glycogen in striated and smooth muscle, as well as neurons. While enzyme replacement therapy has dramatically changed the outcome of patients with the disease, this strategy has several limitations. Gene therapy in Pompe disease constitutes an attractive approach due to the multisystem aspects of the disease and need to address the central nervous system manifestations. This review highlights the recent work in this field, including methods, progress, shortcomings, and future directions. Recent findings Recombinant adeno-associated virus (rAAV) and lentiviral vectors (LV) are well studied platforms for gene therapy in Pompe disease. These products can be further adapted for safe and efficient administration with concomitant immunosuppression, with the modification of specific receptors or codon optimization. rAAV has been studied in multiple clinical trials demonstrating safety and tolerability. Summary Gene therapy for the treatment of patients with Pompe disease is feasible and offers an opportunity to fully correct the principal pathology leading to cellular glycogen accumulation. Further work is needed to overcome the limitations related to vector production, immunologic reactions and redosing.

show abstract

“…Interestingly, this last technique could also allow the use of visible light for therapeutic purposes in pathologies related to neuronal hyper-excitability. On the other hand, chemogenetics (Sternson and Roth, 2014 ; Eisdorfer et al, 2022 ; Parusel et al, 2022 ; Singer et al, 2022 ) is a forefront technique that frequently uses the in vivo injection of a viral vector to induce the expression of genetically modified G-protein coupled receptors (GPCR), which are inert for endogenous ligands but specifically activated by “designer drugs.” These expressed receptors are termed DREADDs (Receptors Exclusively Activated by Designer Drugs) (Urban and Roth, 2015 ; Burnett and Krashes, 2016 ; Roth, 2016 ; Smith et al, 2021 ; Mueller et al, 2022 ). We can compare it with optogenetics, which employs viral vectors to induce, in excitable cells, the expression of light-activated proteins sensitive to specific types of light (“designer light” at particular wavelengths).…”

mentioning

confidence: 99%