Gene Therapy

Genes are the DNA-based blueprint of the human body and provide the information cells use to grow and function. In some cases, the cellular expression of aberrant proteins is caused by corrupted or missing genes, or by faulty modifications to the downstream products of genes. Traditional pharmaceutical-based treatments typically modify components of the cell or its environment to induce a therapeutic response. Gene therapy, however, is focused on utilizing viral-based technologies that deliver therapeutic genes to human cells or tissues to directly correct the genetic defect. These viral-based technologies, known as vectors, have naturally evolved capabilities to deliver therapeutic genetic material to living cells in a safe and effective way.

Congestive Heart Failure (CHF)

Heart disease is the leading cause of death worldwide, with congestive heart failure (CHF) being the final stage of many heart diseases. CHF is a condition in which the heart is unable to supply sufficient amounts of blood and oxygen to the body. CHF can result from conditions that weaken the heart muscle, cause stiffening of the heart muscles, or increase oxygen demand by the body tissues beyond the heart’s capability to deliver. Approximately five million patients in the U.S. suffer from CHF, which is one of the most common reasons patients 65 and older are hospitalized. There is no cure for CHF short of a heart transplant. Only 2,300 heart transplants are performed annually. Device-based treatments, such as left ventricular assist devices (“LVADs”), are used to treat CHF patients, but these are short-term solutions and carry significant safety risks. Both LVAD and heart transplants are highly invasive procedures for which Medicare reimburses at a rate of $200,000 per patient.

Biological NanoParticles

Biological NanoParticles (BNPs) are derived from the Adeno-Associated Virus (“AAV”), a non-pathogenic virus that exists in humans. Use of BNPs prolongs the half-life of the drug substance being delivered and enables minimally invasive, targeted delivery. BNPs are modified from naturally derived AAV to target gene delivery to specific tissues, thus minimizing off-target expression, and to reduce the effects of pre-existing AAV neutralizing antibodies. These design features minimize the amount of virus required for therapeutic effect and allow titration of dosages. BNPs have been safely used in human clinical trials for the treatment of Duchenne muscular dystrophy.

Self-Complementary Vectors

Self-complementary vectors enhance the benefits of naturally derived AAV vectors by enabling faster therapeutic protein expression (quicker therapeutic benefit), reducing the amount of virus required for therapeutic effect (potential increased safety), and allowing dose titration. The self-complementary AAV vector technology has been validated by St. Jude Children’s Research Hospital and Baxter in various human clinical trials for the treatment of Hemophilia B, demonstrating safe, sustained therapeutic expression of factor IX.

Related Team Publications

  • Cai WF, Liu GS, Lam CK, Florea S, Qian J, Zhao W, Pritchard T, Haghighi K, Lebeche D, Lu LJ, Deng J, Fan GC, Hajjar RJ, Kranias EG. Up-regulation of micro-RNA765 in human failing hearts is associated with post-transcriptional regulation of protein phosphatase inhibitor-1 and depressed contractility. Eur J Heart Fail. 2015;17(8):782-93. doi: 10.1002/ejhf.323. PubMed PMID: 26177627
  • Carr AN, Schmidt AG, Suzuki Y, del Monte F, Sato Y, Lanner C, Breeden K, Jing SL, Allen PB, Greengard P, Yatani A, Hoit BD, Grupp IL, Hajjar RJ, DePaoli-Roach AA, Kranias EG. Type 1 phosphatase, a negative regulator of cardiac function. Mol Cell Biol. 2002;22(12):4124-35. PubMed PMID: 12024026; PMCID: PMC133876.
  • Fish KM, Ladage D, Kawase Y, Karakikes I, Jeong D, Ly H, Ishikawa K, Hadri L, Tilemann L, Muller-Ehmsen J, Samulski RJ, Kranias EG, Hajjar RJ. AAV9.I-1c delivered via direct coronary infusion in a porcine model of heart failure improves contractility and mitigates adverse remodeling. Circ Heart Fail. 2013;6(2):310-7. doi: 10.1161/CIRCHEARTFAILURE.112.971325. PubMed PMID: 23271792; PMCID: PMC3605211.
  • Haghighi K, Pritchard TJ, Liu GS, Singh VP, Bidwell P, Lam CK, Vafiadaki E, Das P, Ma J, Kunduri S, Sanoudou D, Florea S, Vanderbilt E, Wang HS, Rubinstein J, Hajjar RJ, Kranias EG. Human G109E-inhibitor-1 impairs cardiac function and promotes arrhythmias. J Mol Cell Cardiol. 2015;89(Pt B):349-59. doi: 10.1016/j.yjmcc.2015.10.004. PubMed PMID: 26455482; PMCID: PMC4689614.
  • Ishikawa K, Fish KM, Tilemann L, Rapti K, Aguero J, Santos-Gallego CG, Lee A, Karakikes I, Xie C, Akar FG, Shimada YJ, Gwathmey JK, Asokan A, McPhee S, Samulski J, Samulski RJ, Sigg DC, Weber T, Kranias EG, Hajjar RJ. Cardiac I-1c overexpression with reengineered AAV improves cardiac function in swine ischemic heart failure. Mol Ther. 2014;22(12):2038-45. doi: 10.1038/mt.2014.127. PubMed PMID: 25023328; PMCID: PMC4429688.
  • Lipskaia L, Bobe R, Chen J, Turnbull IC, Lopez JJ, Merlet E, Jeong D, Karakikes I, Ross AS, Liang L, Mougenot N, Atassi F, Lompre AM, Tarzami ST, Kovacic JC, Kranias E, Hajjar RJ, Hadri L. Synergistic role of protein phosphatase inhibitor 1 and sarco/endoplasmic reticulum Ca2+ -ATPase in the acquisition of the contractile phenotype of arterial smooth muscle cells. Circulation. 2014;129(7):773-85. doi: 10.1161/CIRCULATIONAHA.113.002565. PubMed PMID: 24249716.
  • Lompre AM, Hajjar RJ, Harding SE, Kranias EG, Lohse MJ, Marks AR. Ca2+ cycling and new therapeutic approaches for heart failure. Circulation. 2010;121(6):822-30. doi: 10.1161/CIRCULATIONAHA.109.890954. PubMed PMID: 20124124; PMCID: PMC2834781.
  • Nicolaou P, Hajjar RJ, Kranias EG. Role of protein phosphatase-1 inhibitor-1 in cardiac physiology and pathophysiology. J Mol Cell Cardiol. 2009;47(3):365-71. doi: 10.1016/j.yjmcc.2009.05.010. PubMed PMID: 19481088; PMCID: PMC2716438.
  • Nicolaou P, Rodriguez P, Ren X, Zhou X, Qian J, Sadayappan S, Mitton B, Pathak A, Robbins J, Hajjar RJ, Jones K, Kranias EG. Inducible expression of active protein phosphatase-1 inhibitor-1 enhances basal cardiac function and protects against ischemia/reperfusion injury. Circ Res. 2009;104(8):1012-20. doi: 10.1161/CIRCRESAHA.108.189811. PubMed PMID: 19299645; PMCID: PMC2752882.
  • Pathak A, del Monte F, Zhao W, Schultz JE, Lorenz JN, Bodi I, Weiser D, Hahn H, Carr AN, Syed F, Mavila N, Jha L, Qian J, Marreez Y, Chen G, McGraw DW, Heist EK, Guerrero JL, DePaoli-Roach AA, Hajjar RJ, Kranias EG. Enhancement of cardiac function and suppression of heart failure progression by inhibition of protein phosphatase 1. Circ Res. 2005;96(7):756-66. doi: 10.1161/01.RES.0000161256.85833.fa. PubMed PMID: 15746443.
  • Pritchard TJ, Kawase Y, Haghighi K, Anjak A, Cai W, Jiang M, Nicolaou P, Pylar G, Karakikes I, Rapti K, Rubinstein J, Hajjar RJ, Kranias EG. Active inhibitor-1 maintains protein hyper-phosphorylation in aging hearts and halts remodeling in failing hearts. PLoS One. 2013;8(12):e80717. doi: 10.1371/journal.pone.0080717. PubMed PMID: 24312496; PMCID: PMC3846572.