Treatment of neurological disorders

Abstract

This invention provides treatment compositions as well as systems and methods of determining and administering an effective amount of treatment for a neurological disorder. The treatment composition can contain a labeled interfering RNA (iRNA) agent capable of decreasing expression of a target RNA associated with the neurological disorder. The methods of the invention include determining an effective amount of a therapeutic composition by introducing a solution containing a tracer into the brain of a mammal. The tracing solution is monitored until a target volume of distribution at steady state distribution is substantially achieved, and the rate of delivery of the therapeutic composition is determined. The therapeutic composition can then be administered at the rate determined by use of the tracing solution.

What is claimed is: 
     
         1 - 27 . (canceled) 
     
     
         28 . A system useful in determining an effective amount of a therapeutic composition comprising an iRNA agent for treating a central nervous system disorder in a mammal comprising: a catheter configured to be implanted in the brain of the mammal, and a tracing composition comprising the iRNA agent labeled with a detectable label and wherein the iRNA agent comprises an antisense sequence that is substantially complementary to a target RNA in the brain such that that the iRNA agent is capable of decreasing the expression of the target RNA in the brain, and wherein the labeled iRNA agent comprises a detectable label, wherein the detectable label does not adversely affect the effectiveness of the labeled iRNA agent to decrease expression of the target RNA as compared to the iRNA agent without the label, and wherein the detectable label does not adversely effect the distribution of the labeled iRNA agent in the brain as compared to the labeled iRNA agent without the label. 
     
     
         29 . The system of  claim 28  wherein the label is carbon-14, the central nervous system disorder is Huntington's disease, and the target RNA is a huntingtin RNA. 
     
     
         30 . The system of  claim 28  wherein the catheter is implanted so as to deliver the tracing composition to regions of the brain by infusion methods selected from the group consisting of intrathecal, intraparenchymal, intracerebroventricular, intrastriatal, intraputamenal, intracaudate, and intracortical infusion. 
     
     
         31 . The system of  claim 28  further comprising an infusion pump operably connected to the catheter that pumps the tracing composition through the catheter to the brain and a controller for controlling the rate at which the tracing composition is delivered to the patient. 
     
     
         32 . The system of  claim 31  wherein the infusion pump includes a reservoir containing the tracing composition and wherein the pump is implantable and the reservoir is refillable. 
     
     
         33 . The system of  claim 28  further comprising means for monitoring distribution of the tracing composition during delivery by imaging the detectable label to determine whether a target volume of distribution at steady state is substantially achieved. 
     
     
         34 . A method of determining and delivering an effective amount of a therapeutic composition containing a therapeutic agent via a catheter to the brain of a mammal comprising the steps of: a. introducing the solution via the catheter to the brain; b. monitoring distribution of the solution during delivery by imaging the tracer in the solution to determine whether a target value of distribution at steady state is substantially achieved; c. if target volume of distribution at steady state is not substantially achieved, modifying the rate of delivery of the solution or the concentration of the tracer in the solution or both, until target volume of distribution at steady state is substantially achieved; d. determining a rate of delivery of the therapeutic composition and the concentration of the therapeutic agent in the therapeutic composition to substantially achieve target volume of distribution at steady state based on the rate of delivery and concentration of tracer of tracer resulting in the target volume of distribution at steady state being substantially achieved in step (b) or step (c); and e. delivering the therapeutic composition at the rate determined in step (d) with the concentration of therapeutic agent in the therapeutic composition determined in step (d) via the catheter to the brain of the mammal. 
     
     
         35 . The method of  claim 34 , wherein the step of monitoring the distribution of the solution and the tracer comprises imaging the brain of said mammal one or more times using one or more imaging means from the group comprised of magnetic resonance imaging (MRI) and X-ray based imaging. 
     
     
         36 . The method of  claim 34 , wherein the tracer comprises an iRNA agent labeled with a detectable label and wherein the iRNA agent comprises an antisense sequence that is substantially complementary to a target RNA in the brain so that the labeled iRNA agent is capable of decreasing expression of the target RNA in the brain and wherein the labeled iRNA agent comprises a detectable label, wherein the detectable label does not adversely affect the effectiveness of the labeled iRNA agent to decrease expression of the target RNA as compared to the iRNA agent without the label, and wherein the detectable label does not adversely effect the distribution of the labeled iRNA agent in the brain as compared to the labeled iRNA agent without the label.