Current Research Projects
I. Development of SMOs as Neuroprotective Compounds for Treatment of ALS and Epilepsy
Our major interest is in developing SMOs that reduce excitotoxicity and provide neuroprotection in the CNS as therapeutics for treating ALS (Lou Gehrig’s Disease) and Epilepsy. In these projects we work closely with Dr. Melanie Tallent (Pharmacology and Physiology) and Dr. Terry Heiman-Patterson (Neurology). The experimental paradigms used in these studies include: molecular engineering and optimization of SMOs, testing of SMO efficacy in cell culture or ex vivo systems, and evaluation of their efficacy in ameliorating pathology in pre-clinical animal models of the disease; including behavioral assessments.
II. Molecular engineering of Carriers for Improved Delivery of SMOs to Body Musculature and Across the Blood-Brain-Barrier
SMOs are regarded as extremely promising therapeutics for treating a variety of diseases including Duchenne Muscular Dustrophy (DMD) and Spinal Muscular Atrophy (SMA). However, a major limitation to their use is their poor delivery profile. Our group has focused on development of nanopolymers for improved delivery of SMOs to body musculature for treating DMD using the mdx mouse as a model (Figure below). However, more recently we have focused our efforts on the engineering and use of natural and synthetic peptides as improved SMO carriers for delivery of SMOs to body musculature and to the CNS after systemic delivery.
III. SMOs for Treating the Motor Neuron Degenerative Disease SMA
Our group has recently shown that SMO’s are broadly distributed and taken up into the nuclei of cells of the CNS after direct delivery to the cerebral spinal fluid and that they are biologically active and correct phenotype in a mouse model of the motor neuron disease SMA. See Figure below. We are currently working on improving the delivery of these SMOs across the BBB.
IV. SMOs for Treating Alzheimer’s Disease
In collaboration with Drs Melanie Tallent (Pharm/Physiol) and Keith Vosseller (Biochem & Molecular Biology) we have initiated a project aimed at the development of SMOs targeting several different proteins as potential therapeutics for treating Alzheimer’s Disease. Our group has recently shown that SMO’s are broadly distributed and taken up into the nuclei of cells of the CNS after direct delivery to the cerebral spinal fluid and that they are biologically active and correct phenotype in a mouse model of the motor neuron disease SMA. See Figure below.
V. SMOs as Cancer Therapeutics
In collaboration with Dr Mauricio Reginato (Biochem & Molecular Biology) we have initiated a project aimed at the development of SMOs targeting several different proteins as potential therapeutics for treating various cancers.
Glodde, M., Sirsi S.R., and G. J. Lutz. (2006) Physiochemical Properties of Low and High Molecular Weight PEG-Grafted Poly(ethylene imine) Copolymers and their Complexes with Oligonucleotides. Biomacromolecules 7(1):347-356.
Williams J. H., Sirsi, S. R., and G. J. Lutz. (2006) Induction of dystrophin expression by exon skipping in mdx mice following intramuscular injection of antisense oligonucleotides complexed with PEG-PEI copolymers. Molecular Therapy 14(1):88-96.
Sirsi, S. R., Schray, R. C., Williams J. H., Agisim M. E., and G. J. Lutz. (2008). Functionalized PEG-PEI copolymers complexed to exon skipping oligonucleotides improve dystrophin expression in mdx mice. Human Gene Therapy; 19(8):795-806.
Williams J. H., Sirsi, S. R., and G. J. Lutz. (2008). Nanopolymers improve delivery of exon skipping oligonucleotides and concomitant dystrophin expression in skeletal muscle of mdx mice. BMC Biotechnology; 2;8:35.
Williams, J. H., Schray, R. C., Patterson, C. A., Ayitey, S. O., Tallent, M. K., and G. J. Lutz. (2009) Oligonucleotide-Mediated SMN Expression in CNS Improves Phenotype in a Mouse Model of Spinal Muscular Atrophy. J. Neuroscience, 29(24):7633-8.