Significant Behavioral Recovery in Parkinson's Disease Model by Direct Intracerebral Gene Transfer Using Continuous Injection of a Plasmid DNA–Liposome Complex

Abstract

As an alternative to virus-mediated gene transfer, we previously demonstrated a simple, safe, and efficient transfer of foreign gene into the central nervous system using continuous injection of a plasmid DNA-cationic liposome complex. To explore whether this approach can be applied to the treatment of certain neurological disorders, we used an experimental model of Parkinson's disease (PD) in the present study. Following continuous injection for 7 days, tyrosine hydroxylase (TH) and aromatic L-amino acid decarboxylase (AADC) genes carried by a bovine papilloma virus-based plasmid vector were efficiently introduced into glial cells in the striatum of 6-hydroxydopamine-lesioned rats. Significant recovery in apomorphine-induced rotational behavior of PD models was obtained by transfection of TH gene and this effect continued for up to 5 weeks after injection. Moreover, cotransfection of TH with AADC genes was readily accomplished by this procedure and resulted in a greater and longer-lasting improvement of apomorphine-induced rotational behavior than was achieved by transfection of TH gene alone. We suggest that this approach is a controllable and manageable alternative to other methods of gene therapy for the treatment of PD.

Liposome-mediated NGF gene transfection following neuronal injury: potential therapeutic applications

“…Similar protection has been reported when exogenous NGF is infused into the ventricles following traumatic brain injury. 11 Recent studies have suggested that cationic liposomemediated gene transfer of therapeutically relevant genes has potential for treatment of neurological disorders such as Parkinson's disease 53 and epileptic seizures. 54,55 This paper provides new evidence that liposome-mediated gene transfer can produce nine-to 12-fold increases of secreted transgene products in the CSF and that these increases are associated with reductions in neuronal damage following traumatic brain injury.…”

Repeated intrathecal administration of plasmid DNA complexed with polyethylene glycol-grafted polyethylenimine led to prolonged transgene expression in the spinal cord

“…One way to achieve repeated CNS administration is to implant a cannula connected to a subcutaneous reservoir that provides continuous infusion of a therapeutic gene. 10,11 For gene delivery into the spinal cord, a less invasive method, thus potentially allowing multiple administrations, is lumbar intrathecal injection into the cerebrospinal fluid (CSF). Lumbar puncture poses little danger to the spinal cord as the relative wide subarachnoid space at the site allows a certain degree of mobility of nerves within the CSF, thus avoiding damage caused by needle puncture.…”

Gene therapy in the CNS

“…Procedures include direct transfer in vivo of the TH cDNA to striatal cells via viral vectors, 54,135,[142][143][144] transplanting cells which have been transduced ex vivo to express TH, 87,[145][146][147][148][149][150] and administration of a DNA-liposome complex encoding TH. [151][152][153] More recently the full pathway of DA synthesis been included in this approach, with the additional transfer of the synthetic enzyme GTPcyclohydrolase (GTPCH) to generate the TH cofactor, tetrahydrobiopterin, 55,[154][155][156] as well as transfer of aromatic amino acid decorboxylase (AADC) to facilitate conversion of L-Dopa to DA. [157][158][159] Together these genes may maximize production of DA in the striatum.…”