Jingsong Cao

Oversee the preclinical R&D pipeline programs especially in the area of rare genetic diseases

Oversee the bioassay development and preclinical pharmacology research for AAV-based therapies

Directing, designing, and executing the in vitro and in vivo preclinical studies for mRNA-based therapeutic targets for monogenetic liver and cardiovascular metabolic diseases • Led the in vitro and in vivo preclinical biology studies for Gsd1a program, including all IND-enabling pharmacology studies. Took the program from concept inception to phase I clinical development with promising early efficacy in patients. • Established biochemical, cell-based, ex vivo, and in vivo assays/tools in support of discovery and development of mRNA-based therapies to treat a variety of metabolic liver and cardiovascular diseases related to dysregulations in glucose, lipid, or amino acid homeostatis. Achieved preclinical proof of in vivo efficacy for treating these diseases in clinically relevant animal models. • Applied bioinformatics-aided protein and nucleotide engineering approach in identifying mRNA-based therapies with enhanced pharmacology. • Directed and oversaw collaborations with external academic labs and CROs.

Directed and executed the in vitro and in vivo preclinical studies of mRNA-based therapeutic targets for monogenetic liver diseases. Related publications - 1. Cao J, Markel A, Hanahoe E, Ketova T, Mihai C, Zalinger Z, Marquardt D, Amato NJ, Cheng Y, Reid DW, Dousis A, Giangrande PH, Schultz JR, Martini PGV, and Finn PF. Amino acid substitution at position 298 of human glucose-6 phosphatase-α significantly impacts its stability in mammalian cells. Amino Acids. 2023; 55(5):695-708. 2. Cao J#, Choi M#, Guadagnin E, Soty M, Silva M, Verzieux V, Weisser E, Markel A, Zhuo J, Liang S, Yin L, Frassetto A, Graham A, Burke K, Ketova T, Mihai C, Zalinger Z, Levy B, Besin G, Wolfrom M, Tran B, Tunkey C, Owen E, Sarkis J, Dousis A, Presnyak P, Pepin C, Zheng W, , Ci L, Hard M, Miracco E, Rice L, Nguyen V, Zimmer M, Rajarajacholan U, Finn P, Mithieux G, Rajas F, Martini1 P, Giangrande P. Systemic human G6PC mRNA therapy restores euglycemia and prevents liver tumor formation in a mouse model of glycogen storage disease type 1a (GSD1a). Nat Commun. 2021 May 25;12(1):3090. (#: equal contribution). 3. Wei G#, Cao J#, Huang P#, An P, Badlani D, Zhao S, Wang D, Zhuo J, Lin Y, Frassetto A, Markel A, Presnyak V, Gandham S, Hua S, Lukacs C, Finn P, Giangrande PH, Martini PGV, and Popov Y. Synthetic human ABCB4 mRNA therapy rescues severe liver disease phenotype in a BALB/c.Abcb4 -/- mouse model of PFIC3. J Hepatol. 2021 Jun;74(6):1416-1428. (#: equal contribution). 4. Cao J, An D, Galduroz M, Zhuo J, Liang S, Eybye M, Frassetto A, Kuroda E, Funahashi A, Santana J, Mihai C, Benenato KE, Kumarasinghe ES, Sabnis S, Salerno T, Coughlan K, Miracco EJ, Levy B, Besin G, Schultz J, Lukacs C, Guey L, Finn P, Furukawa T, Giangrande PH, Saheki T, Martini PGV. mRNA Therapy Improves Metabolic and Behavioral Abnormalities in a Murine Model of Citrin Deficiency. Mol Ther. 2019 Jul 3;27(7):1242-1251.

• Directing biological and pharmacological efforts in Eternity Bioscience Inc, which is dedicated in discovering novel therapies for human diseases including cancer, inflammation, and metabolic diseases. • Discovered novel, potent, and selective small molecule compounds targeting MAPK and BTK pathways, and Ezh2 epigenetic regulators. Advanced 3 candidate compounds into clinical development for treatment of cancer and autoimmune diseases. Related publication at Eternity Biosciences - 5. Lu B, Shen X, Zhang L, Liu D, Zhang C, Cao J, Shen R, Zhang J, Wang D, Wan H, Xu Z, Ho MH, Zhang M, Zhang L, He F, Tao W. Discovery of EBI-2511: A Highly Potent and Orally Active EZH2 Inhibitor for the Treatment of Non-Hodgkin's Lymphoma.ACS Med Chem Lett. 2018 Jan 29;9(2):98-102. 6. Lu B, Huang S, Cao J, Hu Q, Shen R, Wan H, Wang D, Yuan J, Zhang L, Zhang J, Zhang M, Tao W, Zhang L. Discovery of EBI-1051: A novel and orally efficacious MEK inhibitor with benzofuran scaffold. Bioorg Med Chem. 2018 Feb 1;26(3):581-589. 7. Liu W, Guo W, Hang N, Yang Y, Wu X, Shen Y, Cao J, Sun Y, Xu Q. MALT1 inhibitors prevent the development of DSS-induced experimental colitis in mice via inhibiting NF-κB and NLRP3 inflammasome activation. Oncotarget. 2016 May 24;7(21):30536-49. 8. Zhang J, Lu B, Liu D, Shen R, Yan Y, Yang L, Zhang M, Zhang L, Cao G, Cao H, Fu B, Gong A, Sun Q, Wan H, Zhang L, Tao W, Cao J. EBI-907, a novel BRAF(V600E) inhibitor, has potent oral anti-tumor activity and a broad kinase selectivity profile. Cancer Biol Ther. 2016;17(2):199-207. 9. Lu B, Cao H, Cao J, Huang S, Hu Q, Liu D, Shen R, Shen X, Tao W, Wan H, Wang D, Yan Y, Yang L, Zhang J, Zhang L, Zhang L, Zhang M. Discovery of EBI-907: A highly potent and orally active B-Raf(V600E) inhibitor for the treatment of melanoma and associated cancers. Bioorg Med Chem Lett. 2016 Feb 1;26(3):819-823.

Responsible for identification, validation and progression of new drug targets for the treatment of metabolic diseases including type 2 diabetes, obesity, and hyperlipidemia; supporting the cell pharmacology activities in drug discovery programs spaning all testing stages in the area of cardiovascular and metabolic diseases.

Identification and validation of novel targets for obesity and diabetes; development of in vitro and cell-based assays for a variety of classes of targets, including metabolic enzymes, GPCR, and transporters.

• Led the development of DGAT1, ACC2, and SCD1 programs. Structurally diversified, potent, selective, cell-permeable, and in-vivo-effective small molecules inhibitors were identified. Developed HTS-amenable biochemical and cell-based assays for these programs. DGAT1 program has been transited to clinical development. • Cloned and identified two long-sought-after genes encoding microsomal acyl-CoA:glycerol 3-phosphate acyltransferase, GPAT3 and GPAT4. Generated and characterized GPAT3 KO mice. • Identified a novel brain isoform of lysophospholipid acyltransferase, LPEAT2, which may play important role in phospholipids formation in neuronal system. • New target identification and validation for metabolic disorders using bioinformatics, transcriptional profiling, and pathway mining approaches. Related publications - 10. Cao J et al. Mice Deleted for GPAT3 Have Reduced GPAT Activity in White Adipose Tissue and Altered Energy and Cholesterol Homeostasis in Diet-induced Obesity. Am J Physiol Endocrinol Metab. 2014; 306(10): E1176-87. 11. Cao J et al. Targeting Acyl-CoA:diacylglycerol acyltransferase 1 (DGAT1) with small molecule inhibitors for the treatment of metabolic diseases. J Biol Chem. 2011; 286(48):41838-51. 12. Shan D, et al, and Cao J*. GPAT3 and GPAT4 are regulated by Insulin-stimulated phosphorylation and play distinct roles in adipogenesis. J Lipid Res. 2010; 51(7):1971-81. 13. Gimeno RE and Cao J. Mammalian glycerol-3-phosphate acyltransferases (GPATs): new genes for an old activity. J Lipids Res 2008; 49(10):2079-88. 14. Cao J et al. Molecular Identification of a novel mammalian brain isoform of acyl-CoA:lysophospholipid acyltransferase with prominent ethanolamine lysophospholipids acylating activity, LPEAT2. J Biol Chem. 2008; 283(27):19049-57. 15. Cao J et al. Molecular identification of microsomal acyl-CoA:glycerol-3-phosphate acyltransferase, a key enzyme in de novo triacylglycerol synthesis. Proc Natl Acad Sci U S A. 2006;103(52):19695-700.

Cloned and characterized several important genes encoding triglycerides and glycerophospholipid acyltransferase, including the MGAT2 enzyme that controls fat absorption. Related publications - 16. Zhang J, Xu D, Nie J, Cao J, Zhai Y, Tong D, Shi Y. Monoacylglycerol acyltransferase-2 is a tetrameric enzyme that selectively heterodimerizes with diacylglycerol acyltransferase-1. J Biol Chem. 2014 Apr 11; 289(15):10909-18. 17. Cao J, Shen W, Chang Z, Shi Y. ALCAT1 Is A Polyglycerophospholipid Acyltransferase Potently Regulated by Adenine Nucleotide and Thyroid Status. Am J Physiol Endocrinol Metab. 2009; 296(4):E647-53. 18. Cao J, Cheng L, Shi Y. Catalytic properties of MGAT3, a putative triacylgycerol synthase. J Lipid Res. 2007; 48(3):583-91. 19. Cao J, Liu Y, Lockwood J, Burn P, and Shi Y. A novel cardiolipin remodeling pathway revealed by a gene encoding the ER-associated lysocardiolipin acyltransferase in mouse. J Biol Chem. 2004; 279(30):31727-34. 20. Cao J, Hawkins E, Brozinick J, Liu X, Zhang H, Burn P, Shi Y, A Predominant Role of MGAT2 in Dietary Fat Absorption Implicated by Tissue Distribution, Subcellular Localization, and Up-regulation by High Fat Diet. J Biol Chem 2004; 279 (18):18878-86. 21. Yang Y†, Cao J†, and Shi Y. Identification and characterization of a gene encoding human LPGAT1, an ER-associated lysophosphatidylglycerol acyltransferase. (†equal contribution). J Biol Chem. 2004; 279(53):55866-74. 22. Cao J, Lockwood J, Burn P, and Shi Y, Cloning and functional characterization of a mouse intestinal acyl-CoA:monoacylglycerol acyltransferase, MGAT2. J Biol Chem 2003; 278 (16): 13860-13866. 23. Cao J, Burn P, and Shi Y, Properties of the mouse intestinal acyl-CoA:monoacyl-glycerol acyltransferase, MGAT2. J Biol Chem 2003; 278 (28): 25657-25663. 24. Lockwood J, Cao J, Burn P, Shi Y, A Human Intestinal Monoacylglycerol Acyltransferase: Differential Features in Tissue Expression and Activity. Am J Physiol Endocrinol Metab. 2003;285(5):E927-37.

Studied the regulation and function of bile acid and organic anion transporters in liver and intestine. Related publications - 25. Cao J et al. Estradiol represses prolactin-induced expression of Na+/taurocholate cotransporting polypeptide through interaction of estrogen receptor and Stat5a in liver cells. Endocrinology 2004; 145 (4): 1739-1749. 26. Jones BR et al and Cao J et al. The role of protein synthesis and degradation in the post-transcriptional regulation of rat multidrug resistance-associated protein 2 (Mrp2, Abcc2). Mol Pharmacol. 2005; 68(3):701-10. 27. Crocenzi FA, Mottino AD, Cao J, Veggi LM, Sanchez PEJ, Vore M, Coleman R, and Roma MG. Estradiol-17beta-D-glucuronide-induces endocytic internalization of bsep in the rat. Am J Physiol – Gastrointestinal and Liver Physiology 2003; 285(2):G449-59. 28. Cao J et al. Expression of rat hepatic multidrug resistance-associated proteins and organic anion transporters in pregnancy. Am J Physiol – Gastrointestinal and Liver Physiology 2002; 283 (3): G757-66. 29. Mottino AD and Cao J et al. Altered localization and activity of canalicular multidrug resistance-associated protein 2 in estradiol-17beta-D-glucuronide-induced cholestasis. Hepatology 2002; 35 (6): 1409-19. (Featured in Cover of the Issue of Hepatology). 30. Cao J et al. Differential regulation of hepatic bile salt and organic anion transporters in pregnant and postpartum rats and the role of prolactin. Hepatology 2001; 33: 140-147. 31. Cao J et al. Prolactin, placental lactogen, and growth hormone induce Na+/taurocholate cotransporting polypeptide gene expression by activating Stat5 in liver cells. Endocrinology 2001; 142 (10): 4212-4222. 32. Mottino AD et al, Cao J, and Vore M. Am J Physiol 2002; 282: G41-G50. 33. Gowri PM and Cao J et al. J Biol Chem 2001; 276: 10485-10491. 34. Mottino AD et al, Cao J and Vore M. Am J Physiol 2001; 280: G1261-G1273.

Attended several core undergraduate and graduate courses in genetics and molecular biology offered by MIT and the MIT/Harvard health sciences and technology program. Earned a fellowship certificate from the program.

Related publications - 35. Xu Q, Cao J, and Zhang X. Inflamm Res 2002; 51: 44-50. 36. Wu F, Cao J, Jiang J, Yu B, Xu Q. J Pharm Pharmacol 2001; 53 (5): 681-8. 37. Cao J, et al. Inflamm Res 2000; 49: 578-583. 38. Chen X, Cao J and Xu Q. Inflamm Res 2000; 49: 571-577. 39. Cao J, et al. Pharmacol Res 1999; 39: 97-102. 40. Cao J, et al. Pharmacological Bulletin 1999; 15: 124-127. 41. Xu Q, Cao J, Wu F, Hayakawa Y, Saiki I and Koda A. Liver 1999; 19: 473-480. 42. Xu Q, Wu F, Cao J et al. Eur J Pharmacol 1999; 377: 93-100. 43. Chen T, Li J, Cao J et al. Planta Med 1999; 65: 56-59. 44. Xu Q, Cao J et al. Pharm Pharmacol Comm 2000; 6: 41-47. 45. Xu Q, Jiang J, Cao J et al. Life Sci 1998; 62: 1281-1292. 46. Cao J, et al. Journal of China Pharmceutical University 1998; 29: 383-386. 47. Xu Q et al, Cao J. Life Sci 1997; 60: 2417-25. 48. Xu Q et al, Cao J, Chen X. Pharmacol Res 1997; 35: 273-278.