Increasing IKAP expression by mRNA splicing modification improves phenotype in a mouse model of Familial Dysautonomia. E. Morini1, P. Dietrich2, M. Salani1, F. Urbina1, M. Nilbratt1, I. Dragatsis2, S. Slaugenhaupt1 1) Center for Human Genetic Research, Massachusetts General Hospital/Harvard Medical School, Boston, MA; 2) Department of Physiology, The University of Tennessee Health Science Center.

   Familial dysautonomia (FD) is a recessive neurodegenerative disease caused by a splice mutation in the IKBKAP gene which leads to variable skipping of exon 20. We found that kinetin can correct the IKBKAP splicing defect and increase the amount of normal mRNA and protein in FD cell lines. We have also shown that kinetin can increase the level of functional IKAP protein in mice following oral dosing in all tissues tested, including brain. Despite these remarkable advances we lacked an animal model in which to test the effect of increasing IKAP protein on the FD phenotype. In order to create a phenotypic model of FD in which we could also manipulate mRNA splicing, we introduced an FD transgene (TgFD9), which contains the human IKBKAP gene with the major FD splice mutation, into the Ikbkapdelta20/flox mouse model by sequential mating. The introduction of the human IKBKAP transgene attenuates the severe FD phenotype that we observed in the Ikbkapdelta20/flox mouse and recreates the same tissue-specific mis-splicing defect seen in FD patients. Characterization of this new mouse model, FD9/ Ikbkapdelta20/flox, recapitulates several phenotypic features observed in FD patients, including reduced growth rate, reduction in the number of fungiform papillae on the tongue, spinal abnormalities, and reduction in the volume of the sympathetic stellate and dorsal root ganglia. Our results demonstrate that the new TgFD9/ Ikbkapdelta20/flox mouse accurately models both the disease phenotype and the tissue-specific mRNA mis-splicing defect seen in FD patients. The creation of this new model has allowed us to initiate a preclinical trial of kinetin and will permit testing of other strategies aimed at either targeting mRNA splicing or increasing expression of IKBKAP. We have initiated in parallel three different preclinical trials to evaluate the efficacy of kinetin: 1) administration of kinetin to dams prior to mating and throughout gestation; 2) administration of kinetin to dams immediately following birth and pups weaned onto kinetin chow; 3) administration of kinetin to mice beginning at weaning age. Our preliminary results show that kinetin leads to significantly improved IKBKAP splicing and has beneficial effects on the overall growth of FD embryos and adult mice. The completion of this study will allow us to fully evaluate the spectrum of benefits that modification of IKAP protein levels by kinetin and other drugs and/or mechanisms may offer FD patients.

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