Cell Biol. Allergen Acquires Elastagen - pharmasalmanac.com Allergan's Medical Aesthetics business - a comprehensive portfolio of facial aesthetics, body contouring and plastic and regenerative medicine products - is expected to grow at an 8-10 percent. Multimers may undergo further transitions, such as branching, to form spherules made of multimer aggregates (Tu et al., 2010). Mutations in LTBP4 cause a syndrome of impaired pulmonary, gastrointestinal, genitourinary, musculoskeletal, and dermal development. Bashir, M. M., Indik, Z., Yeh, H., Ornstein-Goldstein, N., Rosenbloom, J. C., Abrams, W., et al. (2016). Exp. doi: 10.1016/j.febslet.2015.08.029, Rodgers, U. R., and Weiss, A. S. (2004). Pharmacol. I thank the Elastagen team for their hard work and dedication in developing our innovative tropoelastin product pipeline and look forward to working with Allergan to take these products to market., Commenting on the transaction, Elastagens founding scientist Prof Anthony Weiss added:Our technology has come a long way from the lab bench at the University of Sydney towards developing products for patients around the world. Biochem. Domains in tropoelastin that mediate elastin deposition in vitro and in vivo. doi: 10.1016/j.cis.2010.10.003, Yeo, G. C., Tarakanova, A., Baldock, C., Wise, S. G., Buehler, M. J., and Weiss, A. S. (2016). Natl. Bonnans, C., Chou, J., and Werb, Z. Furthermore, tropoelastins hydrophobic and cross-linking domains are arranged in alternating patterns throughout the majority of the molecule, giving rise to both inter- and intra-domain level repetition. Cellular expression of tropoelastin mRNA splice variants. Caterpillar | Caterpillar to Relocate Global Headquarters to Dallas doi: 10.1002/bip.1981.360200611. Tropoelastin monomers undergo self-assembly upon reaching the transition temperature through the aggregation of their hydrophobic domains (Wise et al., 2014). Moreover, fibulins are essential for elastic fiber directionality, as fibroblasts with fibulin-4 and -5 knockdowns generate poorly formed elastic fibers (Yamauchi et al., 2010), and fibulin-4 / mice display aberrant, poorly cross-linked, and non-fibrous elastin (McLaughlin et al., 2006). Sci. KP domains are found closer toward the N-terminus, whereas KA domains are closer to the C-terminus and include alanine tracts (Indik et al., 1987). In addition, Elastagen has received significant support from Australian Federal Government grants and the NSW State Government Medical Devices Fund (MDF). A novel cell adhesion region in tropoelastin mediates attachment to integrin alphaVbeta5. KA domains were initially thought to form -helices and poly-proline II helices (PPII) due to the presence of cross-links which require a lysine arrangement that was postulated to be achieved via -helical configuration (Brown-Augsburger et al., 1995). The isoform-function theory is further reinforced by the presence of two different ELN genes within teleosts that are differentially expressed both spatially and temporally during development (Miao et al., 2007). Trends towards maximal association are apparent when each of these parameters is varied. Imaging 11:e007303. It was first hypothesized that tropoelastin assembles in a head-to-tail manner similar to that of other ECM proteins such as collagen, which assembles into fibrils that subsequently associate laterally to form sheets and thicker fibers (Kadler, 2017). (2018). Comparative genomics of elastin: sequence analysis of a highly repetitive protein. The N-terminal head caps an extended coil region that consists of domains 2-18. For many years it was difficult to study tropoelastin at an atomic scale, but the application of computational methods, such as full-atomistic molecular dynamics and elastic network models, in combination with powerful low-resolution structural studies, have expanded the field and delivered an enhanced understanding of the mechanisms that contribute to self-assembly. The first is an intracellular role as a tropoelastin chaperone and the second is as part of the elastin receptor complex (ERC). This content is for members only. doi: 10.1046/j.1432-1327.1999.00891.x, Yamauchi, Y., Tsuruga, E., Nakashima, K., Sawa, Y., and Ishikawa, H. (2010). Such models could be used in conjunction with the full molecular model of tropoelastin to examine the self-assembly of discrete regions to understand the impacts of amino acid substitutions in disease. For Elastagen contact: Robert Daniels, CEO +61 2 9209 4054. The understanding of tropoelastins structure has been hindered by numerous intrinsic properties of the molecule. N. Y. Acad. HS, which is present on cell surface proteoglycans (syndecans and glypicans), interacts strongly with tropoelastin (Cain et al., 2005). Elastin synthesis and fiber assembly. Developing elastic tissue. 276, 4457544580. 1, 2 Elastogenesis, the process of elastin formation, mainly occurs during the fetal and early neonatal development of organs such as blood vessels, lungs, and skin. Biochemistry 8, 28372845. Elastogenesis occurs during replacement fibrosis in human heart disease and can be accelerated in vitro via tropoelastin treatment. 252, 351365. Of most importance, the inability to acquire large quantities of pure tropoelastin historically presented a significant obstacle to experimentally characterizing its structure. Trifluoroethanol promotes helix formation by destabilizing backbone exposure: desolvation rather than native hydrogen bonding defines the kinetic pathway of dimeric coiled coil folding. doi: 10.1126/sciadv.1501145, Yeo, G. C., and Weiss, A. S. (2019). Figure 1. In vitro elastogenesis: instructing human vascular smooth muscle cells to generate an elastic fiber-containing extracellular matrix scaffold. doi: 10.1016/j.matbio.2006.09.011, Miao, M., Reichheld, S. E., Muiznieks, L. D., Huang, Y., and Keeley, F. W. (2013). Invest. Coacervation characteristics of recombinant human tropoelastin. Allergan announced that it would be accessing Elastagen's next generation Juvederm dermal filler injectable portfolio, which will now also boast its "key 'youth protein' tropoelastin". Transglutaminase-mediated cross-linking of tropoelastin to fibrillin stabilises the elastin precursor prior to elastic fibre assembly. 293, 1510715119. It's a major component of tissues in your body that require stretchiness, like your lungs, bladder, large blood vessels and some ligaments. Elastin is highly hydrophobic, extensively cross-linked, and is assembled into elastic fibers in a dynamic process involving cells, cell surface receptors, and numerous elastic fiber . The alignment of the tropoelastin aggregates . Tropoelastin. doi: 10.1016/j.biocel.2008.03.017, Wise, S. G., Yeo, G. C., Hiob, M. A., Rnjak-Kovacina, J., Kaplan, D. L., Ng, M. K., et al. Lyophilized Powder. Allergan's Acquisition of Elastagen - Global Legal Chronicle Calorim. (2006). J. Biol. 280, 3052630537. Overview of the computational and experimental methodologies that have recently contributed to our understanding of elastic fiber assembly. Elastin synthesis in arterial smooth muscle cell culture. doi: 10.1002/mabi.201800250, Tiedemann, K., Batge, B., Muller, P. K., and Reinhardt, D. P. (2001). The flexibility of the mid-region of the molecule was proposed to drive the overall elasticity of the resultant fibers. The N-terminal head caps an extended coil region that consists of domains 218. III. The amino acid sequence of domain 36 is unique; furthermore, its sequence confers a positively charged C-terminus comprising lysines between positively charged arginines, forming a RKRK sequence (Vrhovski et al., 1997). doi: 10.1073/pnas.1014280108. (1973). doi: 10.1038/246461a0, Haust, M. D., More, R. H., Bencosme, S. A., and Balis, J. U. Subtle balance of tropoelastin molecular shape and flexibility doi: 10.1007/978-3-319-71530-8_13-1, Wen, Q., Mithieux, S. M., and Weiss, A. S. (2020). Remarkably, optimal coacervation is found at 37 degrees C, 150 mM NaCl and pH 7-8. 126, 563574. doi: 10.1007/s10973-014-4254-9, Debelle, L., and Tamburro, A. M. (1999). The cross-linking domains are defined by lysines, which are responsible for the formation of durable bi-, tri-, and tetrafunctional cross-links within mature elastin. Effect of peptide sequence on the LCST-like transition of elastin-like peptides and elastin-like peptidecollagen-like peptide conjugates: simulations and experiments. doi: 10.1038/nrm3904, Bressan, G. M., Castellani, I., Giro, M. G., Volpin, D., Fornieri, C., and Pasquali Ronchetti, I. Tropoelastin, the soluble precursor to elastin, and the degradation products of fragmented elastic fibers also have important chemical signaling properties. doi: 10.1016/j.bbrc.2010.05.013, Elvin, C. M., Carr, A. G., Huson, M. G., Maxwell, J. M., Pearson, R. D., Vuocolo, T., et al. 79, 277284. The hydrophobic domains have been extensively studied and are responsible for facilitating tropoelastins ability to self-assemble (Vrhovski et al., 1997; Toonkool et al., 2001). Additionally, coarse-graining the full-atomistic model has allowed for the examination of mesoscale tropoelastin assembly and, in particular, deciphered the orientation of tropoelastin molecules that occurs during early stage assembly (inset image) (Tarakanova et al., 2019a). Biol. Novel Recombinant Tropoelastin Implants Restore Skin - PubMed The SAXS/SANS global shape of tropoelastin (Baldock et al., 2011) has been used to validate the full-atomistic computational model of tropoelastin through a geometric and topological comparison (Tarakanova et al., 2018). doi: 10.1074/jbc.M004265200, Kadler, K. E. (2017). 624, 137146. Coacervation of tropoelastin. Evidence for the presence of alpha-aminoadipic acid delta-semialdehyde and its aldol condensation product. Chem. 41, 494497. Proc. Biochimie 86, 173178. Bochicchio, B., Yeo, G. C., Lee, P., Emul, D., Pepe, A., Laezza, A., et al. In order to eliminate this limitation, human tropoelastin has been expressed in a recombinant bacterial system and the protein has been highly purified. Biopolymers 29, 16991706. Allergans success is powered by our global colleagues commitment to being Bold for Life. 67-kD elastin-binding protein is a protective companion of extracellular insoluble elastin and intracellular tropoelastin. Chem. The smallest amino acid, glycine is known to promote flexibility within local structures due to lack of steric hindrance, whereas prolines restrictive sidechain inhibits conformational sampling and disrupts the formation of prolonged secondary structures (Roberts et al., 2015). This acquisition and the development of a next generation of injectables based on this technology will ensure Allergan offers innovative filler products for years to come., Robert Daniels, Elastagen CEO, noted: Partnering with Allergan, a leader in medical aesthetics, is incredibly exciting. Fed. Arch. Fluorescently labelled mesenchymal stem cells growing on tropoelastin. The coacervate is made insoluble by irreversible crosslinking. In addition to the RKRK sequence, domain 36 contains tropoelastins sole two cysteines and only disulfide bond. Elastagens revolutionary technology is based on recombinant human tropoelastin, the precursor of elastin which is a key component of youthful skin. Specific instructions are found in the Directions for Use. Unlike hydrophobic domains, cross-linking domains in isolation are unable to self-assemble; thus, they have been studied in the context of the cross-linking of elastin-derived biomaterials (Annabi et al., 2017; Yue et al., 2017). Elastin binding protein (EBP) is a splice variant of -galactosidase, that recognizes the repetitive hydrophobic sequences (VGVAPG) of tropoelastin (Tajima et al., 1997). Tropoelastin interacts with microfibril components including fibrillin-1, fibulin-4, and -5, and other associated molecules such as latent transforming growth factor binding protein-4 (Visconti et al., 2003; McLaughlin et al., 2006; Urban et al., 2009; Yamauchi et al., 2010; Noda et al., 2013; Lockhart-Cairns et al., 2020). doi: 10.1073/pnas.1812951116, Yue, K., Li, X., Schrobback, K., Sheikhi, A., Annabi, N., Leijten, J., et al. (1987). Dissection of human tropoelastin: solution structure, dynamics and self-assembly of the exon 5 peptide. Circ. 22, 109121. They are ubiquitous across most vertebrates other than lower vertebrates such as species from the superclass Agnatha (jawless fish) (Debelle and Tamburro, 1999). Free energy determinants of secondary structure formation: I. alpha-Helices. Instead, tropoelastin domains 1418 and 36 (RKRK sequence) have been found to bind to both integrins. Partridge, S. M. (1966). doi: 10.1248/bpb.b13-00933, Ozsvar, J., Tarakanova, A., Wang, R., Buehler, M. J., and Weiss, A. S. (2019). Tropoelastin is the building block of elastin, a key component of the skin, arteries and lungs that gives tissue its elasticity. Hailed as a giant leap forward in hair rejuvenation, NULASTIN transforms the look of eyelashes up to 120% thicker and 61% longer. Biochemistry 52, 77317741. Interactions of fibrillin-1 with heparin/heparan sulfate, implications for microfibrillar assembly. 19:e1800250. 7:32. doi: 10.3389/fphar.2016.00032, Schmelzer, C. E. H., Heinz, A., Troilo, H., Lockhart-Cairns, M. P., Jowitt, T. A., Marchand, M. F., et al. doi: 10.1016/j.matbio.2019.06.010, Reichheld, S. E., Muiznieks, L. D., Stahl, R., Simonetti, K., Sharpe, S., and Keeley, F. W. (2014). doi: 10.1126/scitranslmed.aai7466, PubMed Abstract | CrossRef Full Text | Google Scholar, Avbelj, F. (2000). Even after being able to produce recombinant tropoelastin at scales suited to characterization studies, traditional techniques have not yet produced an experimentally verified atomistic structure (Martin et al., 1995; Tarakanova and Buehler, 2013). 589(19 Pt A), 24772486. After a period of collaboration with the Elastagen team, US biopharmaceutical giant Allergan acquired Elastagen in 2018 for over $350 million in total deal value. 37, 698702. Poly (Val-Gly-Gly-Leu-Gly). Tropoelastin promotes cell attachment and migration of several cell types including fibroblasts, endothelial cells and mesenchymal stem cells. More recently, it has been demonstrated that KA domains consist of random coil content prior to self-assembly and become more ordered as molecules aggregate, marrying the observations discussed above into a cohesive model within the context of assembly and the requirements of higher-order structures (Reichheld et al., 2014). Shape of tropoelastin, the highly extensible protein that controls human tissue elasticity. Domain 26 of tropoelastin plays a dominant role in association by coacervation. (1988). Bioeng. Allergan Highlights Key Growth Drivers for Medical Aesthetics - PR Newswire doi: 10.1046/j.1432-1327.1998.2580001.x, Wang, Z., Liu, L., Mithieux, S. M., and Weiss, A. S. (2020). The most commonly investigated isoform contains domain 26A and lacks domain 22, and is predominantly found in elastic tissues (Indik et al., 1987; Vrhovski et al., 1997). Weiss Lab Home doi: 10.1038/nature06669, Cox, B. 282, 1248412491. Biol. It has recently been suggested that fibrillins are capable of stabilizing tropoelastin, possibly for the purpose of selecting conformations that are favorable for elastin assembly (Lockhart-Cairns et al., 2020). Chem. Unsubstituted models are also critical to understanding self-assembly. Initially, in vitro coacervation is characterized by the rapid aggregation of tropoelastin. (2005). Together, these two properties can be tuned and exploited to give rise to an increasing number of novel biomaterials for tissue engineering and regenerative medicine, which have been recently reviewed elsewhere (Wang et al., 2020; Wen et al., 2020). Implications for microfibril and elastic fiber assembly. 69, 89102. Molecular model of human tropoelastin and implications of associated mutations. The prevention of early self-aggregation in vitro is thought to be mediated by chaperone proteins (Hinek and Rabinovitch, 1994; Miao et al., 2013). Biol. (1995). Molecular docking studies utilizing tropoelastin and the 3D structure of LOX1 (Vallet et al., 2018) may assist in our understanding as to whether the enzyme has a preference for modifying particular tropoelastin residues. Sci. Lysinonorleucine. Domains 12 to 16 of tropoelastin promote cell attachment and spreading Phase behavior and self-assembly of perfectly sequence-defined and monodisperse multiblock copolypeptides. Micron 41, 268272. Water structure and elastin-like peptide aggregation. 300, 13351359. 284, 22162230. A model two-component system for studying the architecture of elastin assembly in vitro. 286, 35943610. Colloid Interface Sci. J. Biomol. Isolation and characterization of human elastin cDNAs, and age-associated variation in elastin gene expression in cultured skin fibroblasts. Tropoelastin: a versatile, bioactive assembly module. doi: 10.1002/bip.22663, Murata, K., and Wolf, M. (2018). doi: 10.1073/pnas.84.16.5680, Jensen, S. A., Vrhovski, B., and Weiss, A. S. (2000). The authors wrote and submitted this manuscript in response to an invitation by the Editor. Targeted disruption of fibulin-4 abolishes elastogenesis and causes perinatal lethality in mice. An electron microscopic study. Biophys. Domains 12 to 16 of tropoelastin promote cell attachment and spreading through interactions with glycosaminoglycan and integrins alphaV and alpha5beta1. Polymorphisms in the human tropoelastin gene modify in vitro self-assembly and mechanical properties of elastin-like polypeptides. doi: 10.1002/bip.23007, Miao, M., Stahl, R. J., Petersen, L. F., Reintsch, W. E., Davis, E. C., and Keeley, F. W. (2009). Bioeng. 270, 1777817783. Novel Recombinant Tropoelastin Implants Restore Skin Extracellular A., Wachi, H., Davis, E. C., and Mecham, R. P. (2003). Positively charged lysine residues in domains 17 were identified to interact with negatively charged HS, most likely via ionic interactions (Lee et al., 2017). Tropoelastin is characterised by alternating hydrophobic and hydrophilic domains and is highly flexible. Fazio, M. J., Olsen, D. R., Kuivaniemi, H., Chu, M. L., Davidson, J. M., Rosenbloom, J., et al. Elastic fibers are an important component of the extracellular matrix, providing stretch, resilience, and cell interactivity to a broad range of elastic tissues. Structural analysis of photocrosslinkable methacryloyl-modified protein derivatives. Elastin is extensively cross-linked and difficult to break apart into monomers even under harsh conditions, thus, initial strategies included feeding animals a copper deficient diet to prevent lysyl oxidase (LOX) cross-linking of tropoelastin; however, this proved inefficient and time consuming (Wise and Weiss, 2009; Tarakanova et al., 2018). doi: 10.1016/0014-4800(65)90015-8, He, D., Chung, M., Chan, E., Alleyne, T., Ha, K. C. H., Miao, M., et al. The smooth muscle cell. doi: 10.1267/ahc.10026, Yang, A. S., and Honig, B. This suggests the ERCs primary signal pathways are involved in wound recognition through fragments of elastin, where EDPs are formed as a result of elastic tissue damage. Lab. J. Biochem. Tropoelastin was revealed to be an asymmetric molecule with distinct N- and C-terminal regions that are respectively referred to as the "head" and "foot" of the molecule. (1981). doi: 10.1016/j.biomaterials.2017.01.041, Tarakanova, A., Ozsvar, J., Weiss, A. S., and Buehler, M. J. Genet. This product is generally used in vitro as a substrate scaffold to enhance cell attachment, adherence and proliferation. Tropoelastin is a low complexity protein on both primary and secondary sequence levels. Tropoelastin is an ECM component primarily located in elastic tissues and has been shown to promote the expansion of hematopoietic stem cells (HSCs) and MSCs when used as a substrate coating or as part of the substrate bulk material ().The ECM is proposed to modulate stem cell phenotype and activity, including proliferation, via its chemistry, topography, and mechanical properties (). doi: 10.1002/jcp.20546, Kozel, B. Biochemistry 45, 95189530. With commercial operations in approximately 100 countries, Allergan is committed to working with physicians, healthcare providers and patients to deliver innovative and meaningful treatments that help people around the world live longer, healthier lives every day. PLoS One 7:e46130. Investig. Perturbation of either of these components greatly reduces tropoelastins ability to self-assemble in vitro and interact with the microfibril scaffold of elastic fibers (Nonaka et al., 2014), indicating that an intact domain 36 is required for correct assembly. This process is reversible and thermodynamically controlled and does not require protein cleavage. Tropoelastins hydrophobic domains are primarily responsible for facilitating coacervation (Tamburro et al., 1992; Miao et al., 2003; Muiznieks et al., 2003). 396, 870873. Transient tropoelastin nanoparticles are early-stage intermediates in the coacervation of human tropoelastin whose aggregation is facilitated by heparan sulfate and heparin decasaccharides. FASEB J. doi: 10.1371/journal.pone.0046130, Hedtke, T., Schrader, C. U., Heinz, A., Hoehenwarter, W., Brinckmann, J., Groth, T., et al. Natl. No use, distribution or reproduction is permitted which does not comply with these terms. To get started with texting, you will need: Your phone number The evolutionary background and functional consequences of the rs2071307 polymorphism in human tropoelastin. Rev. With leaps in the improvement of cryogenic electron microscopy to characterize flexible molecules, we predict that this approach will contribute to a deeper understanding of tropoelastin structure and self-assembly in the context of endogenous fiber formation and biomaterials fabrication. Acad. Fibrillin-1 interactions with heparin. Dermatol. 4, 508524. U.S.A. 115, 73387343. (2017). 21:063001. doi: 10.1088/0965-0393/21/6/063001, Tarakanova, A., Huang, W., Weiss, A. S., Kaplan, D. L., and Buehler, M. J. In contrast, higher temperatures allow the breaking of the hydrogen bonds of the ordered water, dissipating the clathrate shells and permitting the association of the hydrophobic domains (Yeo et al., 2011). A Study to Evaluate the Efficacy of ELAPR002f in Females and Males With Pathol. Additionally, elastin is remarkably durable as it is primarily deposited during prenatal development and childhood, and is rarely synthesized during adulthood. Allergan's Medical Aesthetics business - a comprehensive portfolio of facial aesthetics, body contouring and plastic and regenerative medicine products - is expected to grow at an 8-10 percent CAGR from 2017 to 2025. Biol. 33, 54685481. doi: 10.1016/j.ajhg.2009.09.013. Biomed. With this approach, Allergan has built one of the broadest development pipelines in the pharmaceutical industry. 13, 739743. The compositions include a coalescence-controlling agent in the form of a polysaccharide or polysaccharide derivative, in an amount effective for providing the substance with the properties of flow, enabling injection. Natl. doi: 10.1093/protein/13.11.739, Roberts, S., Dzuricky, M., and Chilkoti, A. (2006). eLife 6:e26526. Acad. Insights into the structure and dynamics of lysyl oxidase propeptide, a flexible protein with numerous partners. (2009). Differential expression of two tropoelastin genes in zebrafish. (1983). Elastin as a random-network elastomer: a mechanical and optical analysis of single elastin fibers. (2015). A., and Rucker, R. B. For example, the tetrafunctional cross-link, on which the model is based, is derived from porcine elastin (Brown-Augsburger et al., 1995). DEERFIELD, IL - Caterpillar Inc. (NYSE: CAT) today announced it will move its global headquarters to the company's existing office in Irving, Texas, from its current location in Deerfield, Illinois. Our Juvederm collection of fillers has sales of over $1 billion globally and is one of the fastest growing parts of our Aesthetics business, said Bill Meury, Chief Commercial Officer at Allergan. J. Biol. Eur. Biomacromolecules 20, 11781189. J. Biol. Bull. The hydrophobic domains contain repetitions and variations of Val-Pro-Gly-Val-Gly motifs (Figure 1), resulting in the aforementioned low complexity of sequence (Foster et al., 1973; Gray et al., 1973). Gene 154, 159166. 207, 8796. Primary structure of porcine tropoelastin. (2020). 15, 786801. Annabi, N., Zhang, Y. N., Assmann, A., Sani, E. S., Cheng, G., Lassaletta, A. D., et al. Tropoelastin is frequently described in the literature as an unstructured protein, mainly because models of elasticity invoke an element of disorder within the structure (4, 9, 10).While this concept appears to be the case at the fine, more subtle intramolecular level, chaos alone is unlikely to explain the ordered assembly of tropoelastin which culminates in the formation of organized . Elastases can be in the form of serine- (e.g., Ela-2), cysteine- (e.g., cathepsin I), or matrix metalloproteinases (MMP-2, -7, -9, and -12), and bioactive peptides include the VGVAPG peptide. (2017). Binding of EDPs to the ERC induces a number of biological effects including migration, adhesion, proliferation, protease expression, and secretion. Biochemistry 37, 1461314622. doi: 10.1074/jbc.M501390200, Chung, M. I., Miao, M., Stahl, R. J., Chan, E., Parkinson, J., and Keeley, F. W. (2006). (2005). Acta 761, 1722. This phenomenon is supported by in vitro peptide studies, which note that increasing the space between PG motifs or removing prolines results in more ordered structures (Rauscher et al., 2006). For more information, visit Elastagens website atwww.elastagen.com. Proc. Sci. The bifunctional cross-links can undergo further condensation to form tetrafunctional desmosine or isodesmosine (Partridge, 1966).