Waisman Center

Research in my laboratory focuses on three areas.

Gene delivery to retinal cells (blue stain)
1) Several diseases of the eye, as well as the brain/central nervous system involve the death of nerve cells. These include retinal degeneration, glaucoma, Alzheimer’s, Parkinson’s and traumatic injury. We are using gene therapy methods to develop therapeutic approaches to treating these diseases and have shown that delivery of a gene that blocks photoreceptor cell death keeps these cells alive in an animal model of disease. We are currently testing protection of the neurons lost in glaucoma and refining the gene delivery system to improve the effect. We are also developing gene delivery strategies for ocular tumors and have shown that introduction of the vector (specific DNA delivered to tumor cells) alone reduces tumor size. This is likely due to the induction of a host (cells to which the gene is delivered) antitumor response, which we are characterizing with the hope that we can add a gene that will augment the host response.

Herpes simplex virus
2) Herpes simplex virus (HSV) causes blinding keratitis (inflammation of the cornea) and we are interested in identifying genes in the virus that contribute to severe infection. Recently, we demonstrated that multiple genes are involved and have identified a number of novel mutations in several viral proteins. The work now focuses on explaining how the mutations act to influence the severity of the disease.

Structure of an antiviral peptide
3) We have an active program of antiviral drug discovery and development and have worked with several companies. We have also identified two novel antivirals. One, isolated from an edible mushroom that grows in Wisconsin, consists of a protein coupled to a peptide. This novel substance appears to block several previously unknown steps in viral infection and we are currently studying the mechanism. The second group of antivirals is a series of peptides that block virus entry into cells. The peptides block HSV, Papillomavirus and HIV, so we are currently developing the peptides as novel microbicides to block sexually transmitted viral infections. The peptides are also being used to study the poorly-understood process of viral entry.

Brandt CR, Imesch PD, Robinson NL, Syed N, Untawale S, Darjatmoko S, Chappell RJ, Heizelman P, Albert DM. Treatment of spontaneously arising retinoblastoma tumors in transgenic mice with an attenuated Herpes simplex virus mutant. Virology 229:283-291, 1997.

Liu X, Brandt CR, Gabelt BT, Bryar PJ, Smith ME, Kaufman PL. Herpes simplex virus mediated gene delivery to primate ocular tissues. Exp Eye Res 69:385-395, 1999.

Spencer B, Agarwala S, Smith M, Miskulin M, Brandt CR. Herpes simplex virus mediated gene delivery to the rodent visual system. Invest Ophthalmol Vis Sci 41:1392-1401, 2000.

Bultmann H, Busse JS, Brandt CR. A modified FGF4 signal peptide inhibits entry of Herpes simplex Type I virus. J Virol 75:2634-2645, 2001.

Spencer B, Agarwala S, Gentry L, Brandt CR. HSV-1 vector-delivered FGF2 to the retina is neuroprotective, but does not preserve functional responses. Mol Ther 3:746-756, 2001.

Liu X, Cai S, Glasser A, Volberg T, Polansky JR, Fauss D, Brandt CR, Geiger B, Kaufman PK. Effect of H-7 on cultured human trabecular meshwork cells. Mol Vis 7:145-153, 2001. http://www.molvis.org/molvis/v7/a21

Visalli RJ, Brandt CR. Mutation of the herpes simplex virus-1 KOS UL45 gene reveals dose dependent effects on central nervous system growth. Arch Virol 147:519-532, 2002.

Filla MS, Liu X, Nguyen TD, Polansky JR, Brandt CR, Kaufman PL, Peters DP. TIGR/MYOC localizes to trabecular meshwork extracellular matrix in vitro and binds to fibronectin. Invest Ophthalmol Vis Sci 43:151-161, 2002.

Bultmann H, Brandt CR. Peptides containing membrane transiting motifs inhibit virus entry. J Biol Chem 277:36018-36023, 2002.

Spear MA, Schuback D, Miyata K, Grandi P, Sun F, Yoo L, Nguyen A, Brandt CR, Breakefield XO. HSV-1 amplicon peptide display vector. J Virol Methods 107:71-79, 2002.

Brandt CR, Kolb AW, Shah DD, Pumfery AM, Kintner RL, Jaehnig E, Van Gompel JJ. Multiple determinants contribute to the virulence of HSV ocular and CNS infection and identification of serine 34 of the US1 gene as an ocular disease determinant. Invest Ophthalmol Vis Sci 44:2657-2668, 2003.

Liu X, Huang C-Y, Cai S, Polansky JR, Kaufman PL, Brandt CR. Transformation of human trabecular meshwork cells with SV40 TAg alters promoter utilization. Curr Eye Res 25:347-353, 2003.

Liu X, Wu Z, Sheibani N, Brandt CR, Polansky JR, Kaufman PL. Low dose Latrunculin-A inhibits dexamethasone-induced changes in the actin cytoskeleton and alters extracellular matrix protein expression in cultured human trabecular meshwork cells. Exp Eye Res 77:181-188, 2003.

Huang C-Y, Brandt CR. Rapid in vivo isolation of gene expression elements using an HSV amplicon system. J Virol Methods 113:1-12, 2003.

Brandt CR, Kolb AW. Tyrosine 116 of the herpes simplex virus IE alpha22 protein is an ocular virulence determinant and potential phosphorylation site. Invest Ophthalmol Vis Sci 44:4601-4607, 2003.

Kolb AW, Brandt CR.  Enhanced isolation of low frequency herpes simplex virus recombinants using green-fluorescent protein and FACS.  J Virol Methods 115:73-81, 2004.

Cullinan AE, Brandt CR.  Cytokine induced apoptosis in human retinoblastoma cells.  Mol Vis 10:315-322, 2004.  http://www.molvis.org/molvis/v10/a40

Cullinan AE, Lindstrom MJ, Sabet S, Albert DM, Brandt CR.  Antitumor effects of modified herpes simplex virus depend on the attenuating viral mutation in a murine retinoblastoma model.  Curr Eye Res 29:103-117, 2004.

Dr. Brandt's Medical Microbiology Web Page