Cell Biology

Faculty and Research Interests

Paola Leone, PhD

Associate Professor
Science Center 253
856-566-6334
leonepa@umdnj.edu

Education

University of Padua, PhD (Neuroscience), 1988.

Research Interests

My laboratory is collecting and analyzing data on a human gene therapy protocol for Canavan disease (CD) that began in 2001. This Phase I Study was designed to deliver a standard dose of adeno-associated viral (AAV) vector to each patient’s brain at six separate sites, chosen to maximize spread of the vector through the affected regions and provided supportive evidence for efficacy of gene replacement. Approximately 900 billion copies of the human aspartylacylase gene (ASPA) were surgically administered to the brain of thirteen patients, using AAV containing aspartylacylase cDNA (AAV-ASPA). Pre- and post-surgical assessments utilized non-invasive biochemical, radiological, and neurological or cognitive tests. Outcome measures are quantitative N-Acetyl-Aspartate levels in brain, magnetic resonance brain signal changes, and standardized clinical assessments.

There is currently no single pathogenic model able to account for the severe degeneration of the brain seen in CD.  For decades now, hypotheses have centered on discrete biochemical functions that are unable to be refuted or verified due to the unavailability of the appropriate tools or of evidence to the contrary. Basic research is the foundation of therapeutic development, and only by understanding CD can we hope to develop an effective therapy. Over the past 6 years, or laboratory has attacked the unknowns inherent in the current definition of CD and identified a possible mechanism that would account for the severity of the Canavan phenotype. We have invested resources into an investigation of this mechanism, and will continue to do so with the ultimate aim of developing a targeted therapy.
Two developments in the field of Canavan research are central to the genesis of our work over this period. First of all, the identification of dysregulated development of white matter producing cells in a rat model of Canavan disease has pointed the way towards the development of stem cells for therapeutic development. The second major recent development has been the identification of a novel mutation to the aspa gene that is associated with a remarkably mild phenotype. This discovery was hugely significant because although the mutated ASPA protein satisfied the primary diagnostic criterion of loss of enzyme activity, patients that have this mutation do not appear to develop a severely degenerative condition. The significance of this discovery can not be overstated, as it suggests that the ASPA enzyme has functions that are currently unknown, and that these functions may be central to the manifestation of the degeneration seen in Canavan patients. Our research has been able to demonstrate functional differences between this novel mutation and other more common mutations in the way that they interact with neurons in the brain. ASPA is normally found only in cells that produce white matter, or myelin and the ability of ASPA within such cells to influence the function of surrounding neurons is an exciting development as it is consistent with the global developmental defect we have observed in our animal model. We are currently attempting to define this mechanism as it is likely to be a significant factor in the ability of transplanted cells to survive in the Canavan brain, and is therefore central to the successful development of an effective therapy.
In summary my laboratory is studying & characterizing the Canavan rat model for Canavan Disease (CD) “tremor rat”. These studies run in parallel with the characterization of oligodendrocytes developments in the human brain.  Furthermore we are also studying the effect of common & novel CD genetic mutations on development.

PublicationS

1. Kaplitt, M.G., Leone, P., Xiao, X., Pfaff, D.W., O’Malley, K.L., Samulski, R.J., and During, M.J. (1994) Adeno-associated virus vectors yield long-term expression of potentially therapeutic genes in the mammalian brain.  Nature Genetics, 8: 148-154.
2. During, M.J. and Leone, P. (1995) Adeno-associated virus vectors for gene therapy for neurodegenerative disorders. Clinical Neuroscience, 3, 292-300.
3. Freese, A., Kaplitt, M.G., O’Connor, W.M., Abbey, M., Langer, D., Leone, P., During,M.J. (1997) Direct gene transfer into human epileptogenic hippocampal tissue with an adeno-associated virus vector - implications for a gene therapy approach to epilepsy. Epilepsia, 38: 759-766.
4. During, M.J. and Leone, P. (1997) Targets for Gene Therapy of Parkinson’s Disease: Growth Factors, signal transduction and promoters. Exp. Neurol., 144, 74-81. 7.
5. During, M.J., Samulski, R.J., Leone, P., Kaplitt, M.G., Freese, A. Xiao, X., Elsworth, J.D., Roth, R.H., Sladek, J.R.Jr., O'Malley, K.L. and Redmond, D.E. (1998) In vivo expression of therapeutic human genes for dopamine  production in the caudates of MPTP-treated monkeys using an AAV vector. Gene Therapy  5, 820-827.
6. During, M.J., Xu, R., Young, D., Kaplitt, M.G., Sherwin, R.S., and Leone, P. (1998) Peroral gene therapy of lactose intolerance using an AAV vector. Nature Medicine, 4, 1131-1135.
7. Young, D.D., Lawlor, P., Leone, P., Dragunow, M., During, M.J. (1999) Environmental enrichment inhibits spontaneous neuronal apoptosis and prevents neuronal injury in the rat. Nature Medicine, 5, 448-453.
8. Leone, P., Janson, C.G., McPhee, S.J., During, M.J. (1999) Global CNS Gene Transfer for Childhood Neurogenetic  Enzyme Deficiency: Canavan Disease. Current Opinions in Molecular Therapeutics, 1:4, 487-492.
9. Leone, P., McPhee, S.W., Janson, C.G., Davidson, B.L., Freese, A., During, M.J. (2000) Multisite partitioned delivery of human tyrosine  hydroxylase  gene with phenotypic recovery in Parkinsonian rats. Neuroreport, 2:6, 1145-1151.
10. During, M.J., Symes, C.A., Lawlor, P.A., Lin, J., Dunning, J., Fitzsimons, H.L., Poulsen, D., Leone, P., Xu, R., Dicker, B.L., Lipski, J., Young, D. (2000) Targeted autoimmunity: a genetic NMDAR1 vaccine with efficacy in experimental stroke and epilepsy. Science, 287, 1453-1460.
11. Leone, P., Janson, C.G., Bilianiuk, L., Wang, Z., Huang, L., Sorgi, F., Matalon, R., Kaul, R., Zeng, Z., Freese, A., McPhee S.W., Mee, E., During, M.J. (2000) Aspartoacylase gene transfer to the mammalian central nervous system with therapeutic implication for Canavan Disease.  Ann. of Neurol, 48:1, 27-38. 20.
12. Telfeian, A.E., Federoff, H.J., Leone, P., During, M.J., Williamson, A. (2000) Overexpression of GluR6 in rat hippocampus produces seizures and spontaneous nonsynaptic bursting in vitro.  Neurobiology of Disease, 4, 362-374.
13. Janson CG, McPhee SW, Leone P., Freese A, During MJ. (2001) Viral-based gene transfer to the mammalian CNS for functional genomic studies. Trends Neurosci. 1;24(12):706-12..
14. Janson CG, Ramesh T.M., During, M.J., Leone, P., Heywood, J.(2001) Human intrathecal transplantation of peripheral blood stem cells in amyotrophic lateral sclerosis. Hematotherapy & Stem Cell Research 10:6, 913-16.
15. Abi-Saab W.M., Maggs D.G., Jones T, Jacob R, Srihari V., Thompson J., Kerr D, Leone P, Krystal J.H., Spencer D.D., During MJ, Sherwin R.S. (2002) Striking Differences in Glucose and Lactate Levels Between Brain Extracellular Fluid and Plasma in Conscious Human Subjects: Effects of Hyperglycemia and Hypoglycemia. J Cereb Blood Flow Metab. (3): 271-279.
16. Janson, C.G, McPhee, S.W.J., Bilaniuk, L., Haselgrove, J., Testaiuti, M., Freese, A., Wang, D.J., Shera, D., Hurh P., Rupin J., Saslow, E., Goldfarb, O., Goldberg, M., Larijani, G., Sharrar, W., Camp A., Liouterman, L., Kolodny, E., Samulski, J., Leone, P. (2002) Gene Therapy of Canavan Disease: AAV-2 Vector for Neurological Delivery of Aspartoacylase Gene (ASPA) to the Human Brain. Human Gene Therapy, 13: 1391-1412.
17. Zeng, B., Wang, Z-H., Ribeiro, L.A., Leone, P., De Gasperi, R., Kim, S-J., Raghavan, S., Ong, E., Naum, M., Pastores, G.M., Kolodny, E.H. (2002) Identification and Characterization of Novel Mutations of the Aspartoacylase Gene in Non-Jewish Patients with Canavan Disease. Journal of Inherited Metabolic Diseases. 25: 557-570.
18. Boulis, N.M., Noordmans, A.J., Song, D.K., Imperiale, M.J., Rubin, A., Leone, P., During, M., Feldman, E. (2003) Adeno-Associated Viral Vector Gene Expression in the Adult Rat Spinal Cord Following Remote Vector Delivery. Neurobiology of Disease. 14(3): 535-41
19. McPhee, S.W.J., Francis, J.S., Janson, C.G., Serikawa, T., Ong, E.O., Kolodny, E.H., Hyland, K., Young, D., During, M.J., Freese, A., Leone, P. (2004) Effects of AAV-2 mediated aspartoacylase gene transfer in the tremor rat model of Canavan disease. Molecular Brain Research. 135(1-2):112-21 20.
20. Inoue, H., Osawa, I. , Murakami, T., Kimura, A., Hakamata Y., Sato, Y., Kaneko,T., Okada, T., Ozawa, K., Francis J., Leone, P., and Kobayashi, E. (2005) Development of Inbred Transgenic Strains of Rats with LacZ or GFP. Biochemical & Biophysical Research Communication. 329(1): 288-95.
21. Assadi, M., Janson, C.G., Bilaniuk, L., Shera D., Leone, P. (2005) Case Report: Lithium Citrate for Canavan Disease. Pediatric Neurology. 33:235-243.
22. Tavazzi, B., Lazzarino, G., Leone, P., Amorini, A.M., Bellia, Janson, G.J., Di Pietro, V., Ceccarelli, L., Donizelli, S., Francis, J.S.,  F., Giardinia, B. (2005) Sensitive and reproducible high performance liquid chromatographic separation of N-Acetyl Aspartate, N-Acetyl Glutamate and N-Acetyl-Aspartyl Glutamate suitable for the biochemical evaluation of Canavan Disease patients. Clinical Biochemistry. 38(11): 997-1008
23. Janson, C.G., Kolodny, E.H., Bilaniuk, L., Shera, D., Goldfarb, O., Zeng, B-J., Leone, P. (2005) Mild-onset presentation of Canavan disease associated with novel G212A point mutation in aspartoacylase gene. Annals of Neurology. 59(2):428-31
24. McPhee, S.W.J., Janson, C.G., Francis, J., Samulski, R.J., Freese, A., Shera, D., Leone, P. (2006)  Immunological Profile of Canavan Patients Treated With AAV-2 Vectors. Journal of Gene Medicine. 8(5):577-88
25. Francis, J.S., McPhee, S.W.J., Olariu, A., Janson, C.G., Leone, P. (2006) A Role for Aspartoacylase in the Regulation of BDNF and the Timing of Postnatal Oligodendrogenesis. Journal of Neuroscience Research. 84(1): 151-69
26. Zeng, B-J., Wang, Z-H; Torres, P.A.,  Pastores, G.,  Leone, P.  Raghavan, S.S., Kolodny E.H. Rapid Detection of Three Large Novel Deletions of the Aspartoacylase Gene In Non-Jewish Patients With Canavan Disease (2006). Molecular Genetics and Metabolism. 89(1-  2):156-63
27. Zeng, B.J., Pastores G.M., Leone, P., Raghavan, S., Wang Z.H., Ribeiro, L.A., Torres, P., Ong E., Kolodny, E.H. Mutation Analysis of the Aspartoacylase Gene in non-Jewish Patients in Canavan Disease (2006). Advances in Experimental Medicine and Biology. 576:165-73
28. Janson CG, McPhee SWJ, Francis J, Shera D, Assadi M, Hurh P, Haselgrove J, Wang DJ, Bilaniuk L, Freese A, Leone P. (2006) Natural History of Canavan Disease Revealed by Serial MRI and Proton Magnetic Resonance Spectroscopy (1H-MRS). Neuropediatrics. 84(1): 151-69
29. Francis, J.S., Olaris, A., McPhee, S.W.J., Kobayashi, E, Leone, P. (2007) GFP-transgenic Lewis rats as a cell source for oligodendrocyte replacement. Journal of Experimental Neurology. 205(1):177-89.
30. Aghai, Z.H.,  Kode, A.,  Saslow J.G., Nakhla T.,  Farhath, S., Stahl, G.E., Eydelman R., Louise Strande, L.,  Leone, P., Rahman, I. (2007) Azithromycin Suppresses Activation of Nuclear Factor-kappaB and Synthesis of Pro-inflammatory Cytokines in Tracheal Aspirate Cells from Premature Infant. Pediatric Research. 62(4):483-8.
31. Aghai, Z. H.,  Faqiri, S., Saslow, J.G., Nakhla,  T.,  Farhath, S., Kumar,  A., Eydelman, R.,  Strande,  L., Stahl, G.E.,  Leone P., and Bhandari. V. (2008) Angiopoietin 2 is Increased in Tracheal Aspirates From Premature Infants Developing Bronchopulmonary Dysplasia. Journal of Perinatology. 28(2):149-55.
32. Assadi, M., Basemen S., Janson C.J., Wang D-J., Bilaniuk L., Leone P. (2008) Serial 1H-MRS in GM2 Gangliosidoses. European Journal of Pediatrics,. 167 (3):347-52.
33. Assadi, M., Campellone, J.V., Janson C.G., Veloski, J.J., Schwartzman R.J., Leone, P. (2008) treatment of Spinocerebellar Ataxia with Buspirone. Journal of Neurological Sciences. 260(1-2):143-146.
34. Assadi, M., Leone, P., Veloski J.J., Schwartzman R.J. Janson C.G., Campellone J.V.(2008)  Validating an Ataxia Functional Composite Scale in Spinocerebellar Ataxia. Jou rnal of Neurological Science 268(1-2):  136-9.
35. Wang J., Leone P., Wu G., Francis J.S., Li H., Jain M.D., Serikawa t., Ledeen R.W. (2008) Myelin Lipid Abnormalities in the Aspartoacylase-Deficient Tremor Rat. Neurochemical Research. In press

Positions and Honors

1992–97, Research Scientist/Lab Director Yale University, New Haven, CT

1997–98, Visiting Scientist, University of Auckland, Auckland, New Zealand

1998–01, Assist. Professor, Dept. Neurosurgery, Thomas Jefferson Univ., Philadelphia, PA

2001–2007, Assoc. Professor, Dept. Surgery, UMDNJ/RWJ Medical School, Camden, NJ

2001–2007, Director, Cell and Gene Therapy Center, UMDNJ/Cooper Hospital, Camden, NJ

2002–2007, Assoc. Prof, Dept. Mol. Gen., Microb., Immun., UMDNJ/RWJMS, New Brunswick, NJ

2006–2007, Director Surgical Research, Cooper University Hospital, Camden, NJ

2007–present, Associate Professor, UMDNJ-SOM, Stratford, NJ

2007–present, Director, Cell and Gene Therapy Center, Stratford, NJ