| Parkinson's disease (PD) is a chronic age-related neurodegenerative disorder, characterized with resting tremor, bradykinesia and rigidity. Disease progression leads to degeneration and loss of dopamine secreting neurons, especially in the substantia nigra. As current therapeutic strategies for PD are restricted to treatment of symptoms rather than disease-modifying effect, there is a critical need to develop novel therapeutics that can stop the progressive loss of dopamine neurons. Disease-modifying biological therapeutic molecules, however, have restricted central nervous system (CNS) access due to the presence of the blood-brain barrier (BBB).;With the advent of gene therapy it has now become possible to target specific genes which have been either upregulated or down regulated in neurodegenerative disorders. Brain-derived neurotrophic factor (BDNF) belongs to the family of neurotrophins and has shown significant activity in protecting dopaminergic neurons and even promoting growth and differentiation. It has shown to inhibit apoptosis mediated cell death and neurodegeneration induced by neurotoxins. Studies have indicated that BDNF is expressed by dopaminergic neurons in the substantia nigra and ventral tegmental area. Low level of BDNF mRNA expression has been associated with depletion of dopaminergic neurons. Also BDNF has shown to improve cognition in patients with PD. The main delivery challenge is that BDNF does not cross the BBB easily, owing to its high molecular weight and low diffusion across the brain parenchyma. Thus effective strategies are required for the delivery of this molecule.;Plasmids can be used as gene delivery vectors due to its high stability as compared to other nucleic acid molecules. These plasmids when protected with the help of lipid moieties further enhances the stability of the delivery system. Cationic liposomes serve as efficient carriers since they are easily taken up by the brain as 10 compared to anionic and neutral liposomes. Plasmid was selected as a therapeutic agent since it offers several advantages over protein therapeutics like: better invivo and invitro stability, low immunogenecity and longer half life.;This MS dissertation project focuses on the formulation of a cationic liposomal drug delivery system encapsulating Plasmid DNA capable of expressing BDNF and delivering it to mammalian cells to evaluate the transfection efficiency of the liposomes and also assess the upregulation in BDNF mRNA levels. Further it also examines the potential of BDNF plasmid to protect the cells from neurodegeneration in an invitro PD cell model. |
