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Melanocortin 4 receptor agonists to treat sleep disordered breathing in obesity

Award Number: R01HL174409
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/22/2024
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Melanocortin 4 receptor agonists to treat sleep disordered breathing in obesity - Obesity hypoventilation syndrome (OHS) is a severe form of sleep disordered breathing (SDB) characterized by daytime hypercapnia and hypoventilation during sleep. OHS is driven by chronically decreased CO2 sensitivity and depressed ventilatory responses to CO2 (hypercapnic ventilatory response, HCVR). Non-invasive ventilation restores CO2 sensitivity and treats OHS. However, adherence to this treatment is poor. There is no effective pharmacotherapy for OHS. Leptin increases HCVR and treats hypoventilation in leptin deficient ob/ob mice. Diet-induced obese (DIO) mice emulate all features of human OHS, including awake hypercapnia, upper airway obstruction during sleep and sleep hypoventilation. However human and mouse DIO become resistant to leptin limiting leptin as a pharmacotherapy. This proposal is focused on identifying pharmacological targets downstream of the leptin network to treat OHS. Leptin upregulates pro-opiomelanocortin, which is a pre- hormone post-transcriptionally processed into several peptides, including α melanocyte stimulating hormone, a ligand for the melanocortin 4 receptor (MC4R) promoting energy expenditure. The MC4R agonist setmelanotide has been approved for treatment of genetic forms of obesity linked to mutations in the POMC/MC4R/leptin pathways. The role of MC4R in control of breathing remains unknown. Our exciting preliminary data shows that setmelanotide augments the HCVR and treats SDB in DIO mice, that chemogenetic activation of MC4R (+) neurons in the parafacial region containing the chemosensitive retrotrapezoid nucleus (RTN) increases baseline ventilation and HCVR without any effect on metabolism; and that MC4R (+) parafacial neurons project to brainstem respiratory premotor neurons, that, in turn, project to the phrenic motor nucleus. Our overarching hypothesis is that MC4R agonists treat OHS by augmenting hypercapnic sensitivity in MC4R+ neurons in the parafacial region, which is a major center of CO2 sensitivity. In Specific Aim 1, we will determine the therapeutic benefits of the MC4R agonist setmelanotide in OHS in DIO mice. We hypothesize that (A) a single dose will acutely; and (B) a three-month course of setmelanotide will chronically augment HCVR and abolish SDB in randomized placebo-controlled trials; and that (C) the effect of setmelanotide on ventilation will be prevented by the MC4R blocker SHU9119. In Specific Aim 2, we will use DIO Mc4r-Cre mice to examine if the respiratory effects of MC4R activation by setmelanotide can be mimicked by chemogenetic activation and attenuated by chemogenetic inhibition of MC4R+ parafacial neurons. In in vitro Specific Aim 3, we will examine the synaptic neurotransmission from MC4R (+) neurons in the parafacial region to the rostral ventral respiratory group (rVRG) neurons that project to the phrenic motor nucleus using selective expression of ChR2 in Mc4r-Cre parafacial neurons, retrograde identification of spinally projecting rVRG neurons and patch clamp electrophysiology. CO2/pH chemosensitivity markers of RTN will be detected in MC4R(+) neurons projecting to rVRG. The proposal will provide a rationale for the therapeutic development of MCR4 agonists in OHS.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $892,874 )
2025	2025	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	National Center on Sleep Disorders Research	003	1	6/6/2025	SUPPLEMENT FOR EXPANSION	$0
2025	2025	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	National Center on Sleep Disorders Research	002	1	12/14/2024	SUPPLEMENT FOR EXPANSION	$0
2025	2025	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	National Center on Sleep Disorders Research	001	1	12/14/2024	SUPPLEMENT FOR EXPANSION	$43,644
2025	2025	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	National Center on Sleep Disorders Research	004	1	6/6/2025	SUPPLEMENT FOR EXPANSION	$0
2025	2025	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	National Center on Sleep Disorders Research	000	1	12/10/2024	SUPPLEMENT FOR EXPANSION	$41,866
2025	2025	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	National Center on Sleep Disorders Research	005	2	8/5/2025	NON-COMPETING CONTINUATION	$807,364
														Subtotal = $892,874

Issue Date FY: 2024 ( Subtotal = $807,364 )
2024	2024	GEORGE WASHINGTON UNIVERSITY (THE)	1918 F ST NW	WASHINGTON	DC	20052	DISTRICT OF COLUMBIA	USA	National Center on Sleep Disorders Research	000	1	7/22/2024	NEW	$807,364
														Subtotal = $807,364

Grand Total All Awards = $1,700,238

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Melanocortin 4 receptor agonists to treat sleep disordered breathing in obesity

Award Number: R01HL174409

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/22/2024

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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