/Most infants currently rely on infant formula (IF) to meet their nutritional needs. However, existing infantformula is functionally inferior because it lacks breast milk bioactive proteins that are crucial to infant healthand development. Consequently, formula-fed infants have increased risk of morbidity and mortality. Currenttechnology limits the ability to add bioactive milk proteins to infant formula because manufacturingprocesses are resource intensive, costly, and difficult to scale. Thus, scalable technology to improvebioactive availability for fortification of infant formula is needed. Towards this goal, TurtleTree hasdeveloped precision fermentation technology to produce recombinant bovine lactoferrin (rbLf), a criticalbioactive milk protein demonstrated to support gut health and immune function in infants. Not only willTurtleTree's technology allow for inclusion of lactoferrin in all infant formulas, but the use of precisionfermentation will also dissociate bioactive milk protein production from animal agriculture, as required forcow's milk-derived lactoferrin (cMDLf), and the associated environmental stressors. In this proposal, weaim to answer two specific questions that will validate our ability to apply precision fermentation technologyfor infant health and commercialize rbLf as an ingredient for addition to infant formula: 1) Does the uniqueglycosolation profile of rbLf impact the protein's immunomodulatory and gut function as compared tocMDLf? 2) Does rbLf improve gut health in an infant preclinical mouse model? Preliminary data supportingthis proposal demonstrates the N-linked glycan profile is the only substantially unique structural element ofrbLf, characterized by dominance of high-mannose type glycans (~99%) compared to cMDLf (~45%). Thus,we reason a proper evaluation of rbLf requires focused studies on physiological systems sensitive to glycanalterations, notably immune interactions (Aim 1) and gut development (Aim 2). Comparative resultsbetween differentially glycosylated lactoferrin treatment groups will distinguish glycan effects. In Aim 1, wewill assess the role of lactoferrin N-linked glycosylation on immunomodulation mediated by the mannosereceptor in order to understand glycan effect. In Aim 2, we will execute an intervention of orally-deliveredrbLf to improve dysregulated gut health in infant mouse pups. With the successful completion of both aims,we expect to demonstrate rbLf promotes immune and gut interactions that maintain biological activity andefficacy as compared to cMDLf. The scope of work is designed to support regulatory approval and expediteTurtleTree's path to market for the safe and effective application of advancing infant health.
Public Health Relevance Statement: Project Narrative
In an increasingly modernized world, more parents are turning to infant formula over breastfeeding to feed
their infants, but this practice is taking a toll on infant health. Reliable and scalable methods to produce
biologically active milk components found in breastmilk are pivotal to ensuring that formula-fed infants grow
up to be just as healthy as breastfed infants. Towards this goal, this proposal will validate the safety and
functionality of TurtleTree's precision fermentation-derived lactoferrin, which the company intends to market
as an infant formula ingredient to support immunity and gut health.
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