Treating Retinal Degeneration by Transcriptional Modulation
Inherited retinal dystrophies such as retinitis pigmentosa (RP) and leber congenital amaurosis (LCA) are incurable diseases that inexorably lead to blindness. Despite the identification of genes and the remarkable results obtained for treating recessive forms of retinal inherited diseases, the underlying pathological mechanisms, as well as the therapeutic strategies to treat dominant forms of retinal degenerations (autosomal dominant RP; adRP), have yet to be appropriately conceived and experimentally demonstrated.
The challenges for the proper design of effective therapeutic strategies are owed to the complexity of the underlying disease mechanisms and the genetic heterogeneity of adRPs, in the sense that a number of distinct mutations affects numerous individual genes.
Research in the Surace lab is aimed at developing novel strategies to modulate the expression of disease genes with artificial proteins (artificial transcriptional repressors). The system relies on the generation of DNA-binding proteins carrying effector domains, which in turn enable cell-specific control of endogenous levels of gene transcripts.
We have recently shown that artificial transcriptional repressors enable transcriptional gene silencing of rhodopsin, a gene associated with adRP, resulting in significant therapeutic benefits in a disease model of adRP treated with AAV vectors.
Gene Delivery Approaches to Developing Treatments for Inherited Neurodegeneration
Developing gene therapy strategies to treat inherited neurodegeneration by transforming experimental proof-of-concept into clinical trials is a multi-step process that includes therapeutic strategy design, the assessment of their efficacy, pre-clinical validation of safety and clinical study design.
In this process identifying efficient transfer systems to deliver therapeutic nucleic acids to the diseased cells is important. AAV vectors are particularly efficacious for delivering genes carrying therapeutic molecules to terminally differentiated neurons and glial cells (or neuronal and glial precursors) in an efficient, nontoxic and stable fashion. These vectors have proved successful in animal models and in human clinical trials.
More specifically, we are optimizing AAV vectors for retinal transduction efficiency, in terms of retinal cell-specific expression, time of onset and persistency and level (dosage) of transgene expression. In addition, we are fully assessing the safety profile of AAV vector-mediated retinal gene transfer in relevant pre-clinical models.
PostDoc: Francesca Punzo, Mario Renda
PhD student: Nicola de Prisco, Fabiola Curion
Fellow: Elena Marrocco, Salvatore Botta, Vanessa Attanasio, Mariangela Lupo, Martina Sofia, Maura Argenziano, Anna Manfredi
Mussolino C, Della Corte M, Rossi S, Viola F, Di Vicino U, Marrocco E, Neglia S, Doria M, Testa F, Giovannoni R, Crasta M, Giunti M, Villani E, Lavitrano M, Bacci ML, Ratiglia R, Simonelli F, Auricchio A, Surace EM (2011). AAV-mediated photoreceptor transduction of the pig cone-enriched retina. Gene Ther. 18(7):637-45. doi: 10.1038/gt.2011.3.
Mussolino C, Sanges D, Marrocco E, Bonetti C, Di Vicino U, Marigo V, Auricchio A, Meroni G, Surace EM (2011). Zinc-finger-based transcriptional repression of rhodopsin in a model of dominant retinitis pigmentosa. EMBO Mol Med. 3(3):118-28. doi: 10.1002/emmm.201000119.
Spampanato C, De Leonibus E, Dama P, Gargiulo A, Fraldi A, Sorrentino NC, Russo F, Nusco E, Auricchio A, Surace EM, Ballabio A (2011). Efficacy of a combined intracerebral and systemic gene delivery approach for the treatment of a severe lysosomal storage disorder. Mol Ther. 19(5):860-9. doi: 10.1038/mt.2010.299.
Bonetti C, Surace EM (2010). Mouse embryonic retina delivers information controlling cortical neurogenesis. PloS One. 5(12):e15211. doi: 10.1371/journal.pone.0015211.
Maguire AM, Simonelli F, Pierce EA, Pugh EN Jr, Mingozzi F, Bennicelli J, Banfi S, Marshall KA, Testa F, Surace EM, Rossi S, Lyubarsky A, Arruda VR, Konkle B, Stone E, Sun J, Jacobs J, Dell'Osso L, Hertle R, Ma JX, Redmond TM, Zhu X, Hauck B, Zelenaia O, Shindler KS, Maguire MG, Wright JF, Volpe NJ, McDonnell JW, Auricchio A, High KA, Bennett (2008). Safety and efficacy of gene transfer for Leber's congenital amaurosis. N Engl J Med. 358: 2240-2248. doi: 10.1056/NEJMoa0802315.