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A long-acting prolactin to combat lactation insufficiency.

ABSTRACT: Human infants are born to breastfeed. While 50% of lactating persons struggle to make enough milk, there are no governmentally-approved drugs to enhance lactation¹. Here, we engineer a variant of the naturally-occurring driver of lactation, the hormone Prolactin, to increase its serum half-life and produce a viable drug candidate. Our engineered variant, Prolactin-eXtra Long-acting (Prolactin-XL), is comprised of endogenously active human prolactin fused to an engineered human IgG Fc domain designed to overcome the unique drug development challenges specific to the lactating person-infant dyad. Our Prolactin-XL has a serum half-life of 70.9h in mice, 2,625-fold longer than endogenously active prolactin alone (70.9h v. 0.027h). We demonstrate that Prolactin-XL increases milk production and restores growth of pups fed by dams with pharmacologically-ablated lactation. We show that Prolactin-XL-enhanced lactation is accompanied by reversible, lactocyte-driven changes in mammary gland morphology. This work establishes long-acting prolactins as a potentially powerful pharmacologic means to combat insufficient lactation.

SUBMITTER: Kready K

PROVIDER: S-EPMC10760067 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature

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A long-acting prolactin to combat lactation insufficiency.

Kready Kasia K Doiron Kailyn K Chan Katherine Redfield KR Way Jeffrey J Justman Quincey Q Powe Camille E CE Silver Pamela P

bioRxiv : the preprint server for biology 20231215

Human infants are born to breastfeed. While 50% of lactating persons struggle to make enough milk, there are no governmentally-approved drugs to enhance lactation<sup>1</sup>. Here, we engineer a variant of the naturally-occurring driver of lactation, the hormone Prolactin, to increase its serum half-life and produce a viable drug candidate. Our engineered variant, Prolactin-eXtra Long-acting (Prolactin-XL), is comprised of endogenously active human prolactin fused to an engineered human IgG Fc ...[more]

PMID: 38168384

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Project description:ImportanceCardiovascular events and mortality are the principal causes of excess mortality and health care costs for people with type 2 diabetes. No large studies have specifically compared long-acting insulin alone with long-acting plus short-acting insulin with regard to cardiovascular outcomes.ObjectiveTo compare cardiovascular events and mortality in adults with type 2 diabetes receiving long-acting insulin who do or do not add short-acting insulin.Design, setting, and participantsThis retrospective cohort study emulated a randomized experiment in which adults with type 2 diabetes who experienced a qualifying glycated hemoglobin A1c (HbA1c) level of 6.8% to 8.5% with long-acting insulin were randomized to continuing treatment with long-acting insulin (LA group) or adding short-acting insulin within 1 year of the qualifying HbA1c level (LA plus SA group). Retrospective data in 4 integrated health care delivery systems from the Health Care Systems Research Network from January 1, 2005, to December 31, 2013, were used. Analysis used inverse probability weighting estimation with Super Learner for propensity score estimation. Analyses took place from April 1, 2018, to June 30, 2019.ExposuresLong-acting insulin alone or with added short-acting insulin within 1 year from the qualifying HbA1c level.Main outcomes and measuresMortality, cardiovascular mortality, acute myocardial infarction, stroke, and hospitalization for heart failure.ResultsAmong 57 278 individuals (39 279 with data on cardiovascular mortality) with a mean (SD) age of 60.6 (11.5) years, 53.6% men, 43.5% non-Hispanic White individuals, and 4 years of follow-up (median follow-up of 11 [interquartile range, 5-20] calendar quarters), the LA plus SA group was associated with increased all-cause mortality compared with the LA group (hazard ratio, 1.27; 95% CI, 1.05-1.49) and a decreased risk of acute myocardial infarction (hazard ratio, 0.89; 95% CI, 0.81-0.97). Treatment with long-acting plus short-acting insulin was not associated with increased risks of congestive heart failure, stroke, or cardiovascular mortality.Conclusions and relevanceFindings of this retrospective cohort study suggested an increased risk of all-cause mortality and a decreased risk of acute myocardial infarction for the LA plus SA group compared with the LA group. Given the lack of an increase in major cardiovascular events or cardiovascular mortality, the increased all-cause mortality with long-acting plus short-acting insulin may be explained by noncardiovascular events or unmeasured confounding.

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A long-acting prolactin to combat lactation insufficiency.

Publications

A long-acting prolactin to combat lactation insufficiency.

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