GENE TRANSFER/THERAPY

Our laboratory focuses on basic biomedical research and clinical translation directed towards amelioration of inherited and acquired disorders. We are especially interested in rational applications that interplay with the hematopoietic system.

Current laboratory projects:

Cancer Immunotherapy
Immunotherapy offers the potential to eliminate localized cancers, tumor stem cells, and also metastatic disease. One set of projects here involves transfer of sequences for cytokines and shRNAs into tumor cells directly to modulate specific anti-cancer immune responses. Another set of projects involves the generation of novel monoclonal antibodies and then subsequent chimeric antigen receptors (CARs) against tumor-specific antigens in order to impact T cell- and NK cell-based immune responses.

Prostate Biomarkers and Biology
Through comprehensive proteomic screens of samples from patients with aggressive versus indolent prostate cancer, we have identified novel factors that may be involved in prostate cancer initiation and progression. Projects here will involve detailed examination of the role of these factors and the effects of modulation of their expression on in vitro and in vivo outcomes.

Modulation of Acid Ceramidase Expression
Acid ceramidase (AC) plays a key role in regulating the balance between cellular ceramide and sphingosine-1-phosphate. Depending on the context, these lipids either promote apoptosis or promote cell proliferation. Projects here involve generating models with increased or decreased levels of AC activity and determining biological outcomes as related to a variety of cell types and tissues.

Fabry Disease
We have been working for a number of years on the development and implementation of clinical gene therapy trials targeting hematopoietic stem cells for the sustained systemic correction of Fabry disease.

Graduate Students:

Selected References:

 -Amarnath S, Mangus CW, Wang JC, Wei F, He A, Kapoor V, Foley JE, Massey PR, Felizardo TC, Riley JL, Levine BL, June CH, Medin JA, Fowler DH. The PDL1-PD1 Axis Converts Human TH1 Cells into Regulatory T Cells. Sci Transl Med. 2011 Nov 30;3(111):111ra120.

-Berthod F, Symes J, Tremblay N, Medin JA, Auger FA. Spontaneous fibroblast-derived pericyte recruitment in a human tissue-engineered angiogenesis model in vitro. J Cell Physiol. 2011 Jul 18. doi: 10.1002/jcp.22943. [Epub ahead of print]

-Hirayama S, Sato M, Liu M, Loisel-Meyer S, Yeung JC, Wagnetz D, Cypel M, Zehong G, Medin JA, Keshavjee S. Local long-term expression of lentivirally delivered IL-10 in the lung attenuates obliteration of intrapulmonary allograft airways. Hum Gene Ther. 2011 Nov;22(11):1453-60. Epub 2011 Jul 12.

-Felizardo TC, Wang JC, McGray RA, Evelegh C, Spaner DE, Fowler DH, Bramson JL, Medin JA. Differential immune responses mediated by adenovirus- and lentivirus-transduced DCs in a HER-2/neu overexpressing tumor model. Gene Ther. 2011 Oct;18(10):986-95. doi: 10.1038/gt.2011.53. Epub 2011 Apr 14.

-Tsunooka N, Hirayama S, Medin JA, Liles WC, Keshavjee S, Waddell TK. A novel tissue-engineered approach to problems of the postpneumonectomy space. Ann Thorac Surg. 2011 Mar;91(3):880-6.

-Yoshimitsu M, Higuchi K, Miyata M, Devine S, Mattman A, Sirrs S, Medin JA, Tei C, Takenaka T. Identification of novel mutations in the ?-galactosidase A gene in patients with Fabry disease: pitfalls of mutation analyses in patients with low ?-galactosidase A activity. J Cardiol. 2011 May;57(3):345-53. Epub 2011 Feb 17.

-Siegers GM, Dhamko H, Wang XH, Mathieson AM, Kosaka Y, Felizardo TC, Medin JA, Tohda S, Schueler J, Fisch P, Keating A. Human V?1 ?? T cells expanded from peripheral blood exhibit specific cytotoxicity against B-cell chronic lymphocytic leukemia-derived cells. Cytotherapy. 2011 Jul;13(6):753-64. Epub 2011 Feb 11.

-Siegers GM, Felizardo TC, Mathieson AM, Kosaka Y, Wang XH, Medin JA, Keating A. Anti-leukemia activity of in vitro-expanded human gamma delta T cells in a xenogeneic Ph+ leukemia model. PLoS One. 2011 Feb 3;6(2):e16700.

-Walia JS, Neschadim A, Lopez-Perez O, Alayoubi A, Fan X, Carpentier S, Madden M, Lee CJ, Cheung F, Jaffray DA, Levade T, McCart JA, Medin JA. Autologous transplantation of lentivector/acid ceramidase-transduced hematopoietic cells in nonhuman primates. Hum Gene Ther. 2011 Jun;22(6):679-87. Epub 2011 Mar 25.

-Wang AY, Crome SQ, Jenkins KM, Medin JA, Bramson JL, Levings MK. Adenoviral-transduced dendritic cells are susceptible to suppression by T regulatory cells and promote interleukin 17 production. Cancer Immunol Immunother. 2011 Mar;60(3):381-8. Epub 2010 Dec 14.

-Romieu-Mourez R, François M, Abate A, Boivin MN, Birman E, Bailey D, Bramson JL, Forner K, Young YK, Medin JA, Galipeau J.
Mesenchymal stromal cells expressing ErbB-2/neu elicit protective antibreast tumor immunity in vivo, which is paradoxically suppressed by IFN-gamma and tumor necrosis factor-alpha priming. Cancer Res. 2010 Oct 15;70(20):7742-7. Epub 2010 Oct 5.

-Lee CJ, Fan X, Guo X, Medin JA. Promoter-specific lentivectors for long-term, cardiac-directed therapy of Fabry disease. J Cardiol. 2011 Jan;57(1):115-22. Epub 2010 Sep 16.

-Likar Y, Zurita J, Dobrenkov K, Shenker L, Cai S, Neschadim A, Medin JA, Sadelain M, Hricak H, Ponomarev V. A new pyrimidine-specific reporter gene: a mutated human deoxycytidine kinase suitable for PET during treatment with acycloguanosine-based cytotoxic drugs. J Nucl Med. 2010 Sep;51(9):1395-403.

-Higuchi K, Yoshimitsu M, Fan X, Guo X, Rasaiah VI, Yen J, Tei C, Takenaka T, Medin JA. Alpha-galactosidase A-Tat fusion enhances storage reduction in hearts and kidneys of Fabry mice. Mol Med. 2010 May-Jun;16(5-6):216-21. Epub 2010 Feb 17.