Gene therapy uses DNA to alter the behavior of cells to treat disease. In the 1990s, gene therapy was seen as a promising new treatment modality, unfortunately, the majority of clinical trials failed. However, after 25 years of research, there has been a promising revival of gene therapy for diseases with unmet treatment needs. Leading the way are Imlygic® and Glybera®, virus-based gene therapies approved for marketing by the U.S. Food and Drug Administration in 2015, and the European Medicines Agency in 2013, respectively. Following are hundreds of clinical trials worldwide for a wide range of indications including congenital blindness, Duchenne Muscular Dystrophy, and Alzheimer Diseases.
We are developing MiniPromoters for restricted expression of gene therapy. One safety lesson learned in the early gene therapy studies was that by restricting the expression of the virus to only the therapeutic target cells, off-target side effects could be minimized. Thus, it has been recognized that the use of cell-type specific promoters is a desirable and possibly required feature of future gene therapies. In addition, restricted expression may enable the consideration of a broader pallet of therapeutic molecules, as the concern of functional-toxic side effects is reduced.
Currently we are taking a two-pronged approach to gene therapy for the congenital blindness aniridia: augmentation gene therapy, and genome editing using CRISPR (clustered regularly interspaced short palindromic repeats) /cas9 (CRISPR-associated nuclease 9). For augmentation gene therapy, we are delivering to the eye additional PAX6, the gene mutated in aniridia, encoded in rAAV. Because PAX6 may need to be carefully regulated, we have designed MiniPromoters from the human PAX6 gene and tested them in the mouse eye (Hickmott et al., 2016 in revision). For genome-editing therapy, we are using the bacterial CRISPR/cas9 system. It will be delivered in rAAV to edit out the genomic mutation in vivo in a mouse model of aniridia.
de Leeuw, C.N., Dyka, F.M., Boye, S.L., Laprise, S., Zhou, M., Chou, A.Y., Borretta, L.J., McInerny, S.C., Banks, K.G., Portales-Casamar, E., Swanson, M.I., D'Souza, C.A., Boye, S.E., Jones, S.J.M., Holt, R.A., Goldowitz, D., Hauswirth, W.W., Wasserman, W.W., and Simpson, E.M. (2014). Targeted CNS delivery using human MiniPromoters and demonstrated compatibility with adeno-associated viral vectors. Mol Ther Methods Clin Dev 1, 1-15, Impact Factor Not Yet Assigned, Cited 5, PMID 24761428.
Corso-Díaz, X., Borrie, A.E., Bonaguro, R.J., Schuetz, J.M., Rosenberg, T., Jensen, H., Brooks, B.P., MacDonald, I., Pasutto, F., Walter, M., Gronskov, K., Brooks-Wilson, A.R., and Simpson, E.M. (2012). Absence of NR2E1 mutations in Patients with Aniridia. Molecular vision 18, 2770-2782, Impact Factor 1.987, Cited 3, PMID 23213277