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Loffredo, F

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Loffredo

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Loffredo, F

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    Publication
    Targeted Delivery to Cartilage Is Critical for In Vivo Efficacy of Insulin-like Growth Factor 1 in a Rat Model of Osteoarthritis
    (Wiley-Blackwell, 2014) Loffredo, F; Pancoast, JR; Cai, Lei; Vannelli, Todd; Dong, Jesse Z.; Lee, Richard; Patwari, Parth
    Objective: Acute articular injuries lead to an increased risk of progressive joint damage and osteoarthritis (OA), and no therapies are currently available to repair or protect the injured joint tissue. Intraarticular delivery of therapeutic proteins has been limited by their rapid clearance from the joint space and lack of retention within cartilage. The aim of this study was to test whether targeted delivery to cartilage by fusion with a heparin-binding domain would be sufficient to prolong the in vivo function of the insulin-like growth factor 1 (IGF-1). Methods: We produced a humanized and optimized recombinant HB-IGF-1 fusion protein. By injecting HB-IGF-1, IGF-1, or saline alone into the knee joints of adult Lewis rats, we tested whether fusion with a heparin-binding domain 1) altered the kinetics of retention in joint tissues, 2) prolonged functional stimulation as measured by radiolabel incorporation, and 3) enhanced efficacy in a rat model of surgically induced OA, using weekly injections. Results: Fusion of heparin-binding domain with IGF-1 prolonged retent on in articular and meniscal cartilage from <1 day to 8 days after injection. Unmodified IGF-1 had no functional effect 2 days after injection, whereas HB-IGF-1 stimulated meniscal cartilage at least 4 days after injection. HB-IGF-1, but not IGF-1, significantly slowed cartilage damage in a rat model of OA. Conclusion: Heparin-binding domain fusions can transform rapidly cleared proteins into potential intraarticular therapies by targeting them to cartilage.
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    Growth Differentiation Factor 11 Is a Circulating Factor that Reverses Age-Related Cardiac Hypertrophy
    (Elsevier BV, 2013) Loffredo, F; Steinhauser, Matthew; Jay, Steven M.; Gannon, Joseph; Pancoast, James R.; Yalamanchi, Pratyusha; Sinha, Manisha; Dall’Osso, Claudia; Khong, Danika; Shadrach, Jennifer; Miller, Christine; Singer, Britta S.; Stewart, Alex; Psychogios, Nikolaos; Gerszten, Robert; Hartigan, Adam J.; Kim, Mi-Jeong; Serwold, Thomas; Wagers, Amy; Lee, Richard
    The most common form of heart failure occurs with normal systolic function and often involves cardiac hypertrophy in the elderly. To clarify the biological mechanisms that drive cardiac hypertrophy in aging, we tested the influence of circulating factors using heterochronic parabiosis, a surgical technique in which joining of animals of different ages leads to a shared circulation. After 4 weeks of exposure to the circulation of young mice, cardiac hypertrophy in old mice dramatically regressed, accompanied by reduced cardiomyocyte size and molecular remodeling. Reversal of age-related hypertrophy was not attributable to hemodynamic or behavioral effects of parabiosis, implicating a blood-borne factor. Using modified aptamer-based proteomics, we identified the TGF-b superfamily member GDF11 as a circulating factor in young mice that declines with age. Treatment of old mice to restore GDF11 to youthful levels recapitulated the effects of parabiosis and reversed age-related hypertrophy, revealing a therapeutic opportunity for cardiac aging.
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    Restoring Systemic GDF11 Levels Reverses Age-Related Dysfunction in Mouse Skeletal Muscle
    (American Association for the Advancement of Science (AAAS), 2014) Sinha, Manisha; Jang, Y. C.; Oh, Juhyun; Khong, Danika; Wu, Elizabeth Y; Manohar, Rohan; Miller, Christine; Regalado, Samuel G.; Loffredo, F; Pancoast, James R.; Hirshman, Michael; Lebowitz, Jessica; Shadrach, Jennifer; Cerletti, Massimiliano; Kim, Mi Jeong; Serwold, Thomas; Goodyear, Laurie; Rosner, Bernard; Lee, Richard; Wagers, Amy
    Parabiosis experiments indicate that impaired regeneration in aged mice is reversible by exposure to a young circulation, suggesting that young blood contains humoral “rejuvenating” factors that can restore regenerative function. Here, we demonstrate that the circulating protein growth differentiation factor 11 (GDF11) is a rejuvenating factor for skeletal muscle. Supplementation of systemic GDF11 levels, which normally decline with age, by heterochronic parabiosis or systemic delivery of recombinant protein, reversed functional impairments and restored genomic integrity in aged muscle stem cells (satellite cells). Increased GDF11 levels in aged mice also improved muscle structural and functional features and increased strength and endurance exercise capacity. These data indicate that GDF11 systemically regulates muscle aging and may be therapeutically useful for reversing age-related skeletal muscle and stem cell dysfunction.