Lipid-encapsulated mRNA encoding an extended serum half-life interleukin-22 ameliorates metabolic disease in mice

Susanna Canali; Alexander W Fischer; Mychael Nguyen; Karl Anderson; Lorna Wu; Anne-Renee Graham; Chiaowen Joyce Hsiao; Chinmayi Bankar; Nancy Dussault; Veronica Ritchie; Meagan Goodridge; Todd Sparrow; Allison Pannoni; Sze-Wah Tse; Vivienne Woo; Kaitlin Klovdahl; Jared Iacovelli; Eric Huang

doi:10.1016/j.molmet.2024.101965

Lipid-encapsulated mRNA encoding an extended serum half-life interleukin-22 ameliorates metabolic disease in mice

Mol Metab. 2024 Aug:86:101965. doi: 10.1016/j.molmet.2024.101965. Epub 2024 Jun 11.

Authors

Susanna Canali¹, Alexander W Fischer², Mychael Nguyen³, Karl Anderson⁴, Lorna Wu⁵, Anne-Renee Graham⁶, Chiaowen Joyce Hsiao⁷, Chinmayi Bankar⁸, Nancy Dussault⁹, Veronica Ritchie¹⁰, Meagan Goodridge¹¹, Todd Sparrow¹², Allison Pannoni¹³, Sze-Wah Tse¹⁴, Vivienne Woo¹⁵, Kaitlin Klovdahl¹⁶, Jared Iacovelli¹⁷, Eric Huang¹⁸

Affiliations

¹ Moderna, Inc., 325 Binney Street, Cambridge, MA 02142, USA. Electronic address: [email protected].
² Moderna, Inc., 325 Binney Street, Cambridge, MA 02142, USA. Electronic address: [email protected].
³ Moderna, Inc., 325 Binney Street, Cambridge, MA 02142, USA. Electronic address: [email protected].
⁴ Moderna, Inc., 325 Binney Street, Cambridge, MA 02142, USA. Electronic address: [email protected].
⁵ Moderna, Inc., 325 Binney Street, Cambridge, MA 02142, USA. Electronic address: [email protected].
⁶ Moderna, Inc., 325 Binney Street, Cambridge, MA 02142, USA. Electronic address: [email protected].
⁷ Moderna, Inc., 325 Binney Street, Cambridge, MA 02142, USA. Electronic address: [email protected].
⁸ Moderna, Inc., 325 Binney Street, Cambridge, MA 02142, USA. Electronic address: [email protected].
⁹ Moderna, Inc., 325 Binney Street, Cambridge, MA 02142, USA. Electronic address: [email protected].
¹⁰ Moderna, Inc., 325 Binney Street, Cambridge, MA 02142, USA. Electronic address: [email protected].
¹¹ Moderna, Inc., 325 Binney Street, Cambridge, MA 02142, USA. Electronic address: [email protected].
¹² Moderna, Inc., 325 Binney Street, Cambridge, MA 02142, USA. Electronic address: [email protected].
¹³ Moderna, Inc., 325 Binney Street, Cambridge, MA 02142, USA. Electronic address: [email protected].
¹⁴ Moderna, Inc., 325 Binney Street, Cambridge, MA 02142, USA. Electronic address: [email protected].
¹⁵ Moderna, Inc., 325 Binney Street, Cambridge, MA 02142, USA. Electronic address: [email protected].
¹⁶ Moderna, Inc., 325 Binney Street, Cambridge, MA 02142, USA. Electronic address: [email protected].
¹⁷ Moderna, Inc., 325 Binney Street, Cambridge, MA 02142, USA. Electronic address: [email protected].
¹⁸ Moderna, Inc., 325 Binney Street, Cambridge, MA 02142, USA. Electronic address: [email protected].

Abstract

Objective: Interleukin (IL)-22 is a potential therapeutic protein for the treatment of metabolic diseases such as obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease due to its involvement in multiple cellular pathways and observed hepatoprotective effects. The short serum half-life of IL-22 has previously limited its use in clinical applications; however, the development of mRNA-lipid nanoparticle (LNP) technology offers a novel therapeutic approach that uses a host-generated IL-22 fusion protein. In the present study, the effects of administration of an mRNA-LNP encoding IL-22 on metabolic disease parameters was investigated in various mouse models.

Methods: C57BL/6NCrl mice were used to confirm mouse serum albumin (MSA)-IL-22 protein expression prior to assessments in C57BL/6NTac and CETP/ApoB transgenic mouse models of metabolic disease. Mice were fed either regular chow or a modified amylin liver nonalcoholic steatohepatitis-inducing diet prior to receiving either LNP-encapsulated MSA-IL-22 or MSA mRNA via intravenous or intramuscular injection. Metabolic markers were monitored for the duration of the experiments, and postmortem histology assessment and analysis of metabolic gene expression pathways were performed.

Results: MSA-IL-22 was detectable for ≥8 days following administration. Improvements in body weight, lipid metabolism, glucose metabolism, and lipogenic and fibrotic marker gene expression in the liver were observed in the MSA-IL-22-treated mice, and these effects were shown to be durable.

Conclusions: These results support the application of mRNA-encoded IL-22 as a promising treatment strategy for metabolic syndrome and associated comorbidities in human populations.

Keywords: Lipid nanoparticle therapeutic; Messenger RNA; Metabolic disorders; Metabolic dysfunction-associated steatotic liver disease; Serum lipid parameters; interleukin-22.

MeSH terms

Animals
Disease Models, Animal
Half-Life
Interleukin-22*
Interleukins* / genetics
Interleukins* / metabolism
Lipids / blood
Liposomes
Liver / metabolism
Male
Metabolic Diseases* / genetics
Metabolic Diseases* / metabolism
Mice
Mice, Inbred C57BL*
Mice, Transgenic
Nanoparticles
Non-alcoholic Fatty Liver Disease / genetics
Non-alcoholic Fatty Liver Disease / metabolism
RNA, Messenger* / genetics
RNA, Messenger* / metabolism

Substances

Interleukin-22
Interleukins
RNA, Messenger
Lipids
Lipid Nanoparticles
Liposomes