Methods of treating amyotrophic lateral sclerosis

Abstract

Disclosed are methods for inhibiting the progression of Amyotrophic Lateral Sclerosis (ALS). The methods include administering to a patient suffering from ALS a composition comprising either deuterated linoleic acid or an ester or deuterated arachidonic acid or an ester thereof.

1 . A method for reducing disease progression of ALS in a patient, the method comprising:
 administering an effective amount of a deuterated arachidonic acid, an ester thereof, or a prodrug thereof, to reduce said disease progression in said patient;   wherein a therapeutic concentration of deuterated arachidonic acid in the motor neurons is sufficient to reduce disease progression, wherein said reduction is measured to be at least about 30% reduction relative to the rate of disease progression during the natural history of the patient.   
     
     
         2 . The method of  claim 1 , wherein the therapeutic concentration of deuterated arachidonic acid is determined by its concentration in red blood cells. 
     
     
         3 . The method of  claim 1 , wherein a percent reduction in the rate of disease progression is determined by:
 measuring a natural rate of disease progression in a patient or an average natural rate of disease progression in a cohort of patients;   measuring the rate of disease progression in said patient or cohort of patients during a period of compliance with the administering step; and   calculating the difference between the natural rate and the rate during the period of compliance, dividing the difference by the rate of disease progression during the natural history of the patient, and multiplying by 100.   
     
     
         4 . The method of  claim 1 , wherein said prodrug of a deuterated arachidonic acid or ester thereof is a deuterated linoleic acid or ester thereof. 
     
     
         5 . The method of  claim 4 , wherein said deuterated linoleic acid or ester thereof is 11,11-D2-linoleic acid or ester thereof. 
     
     
         6 . The method of  claim 1 , wherein the deuterated arachidonic acid or ester thereof is 13,13-D2-arachidonic acid. 
     
     
         7 . The method of  claim 6 , wherein the therapeutic concentration of 13,13-D2-arachidonic acid is determined by its concentration in red blood cells. 
     
     
         8 . The method of  claim 7 , wherein the concentration of 13,13-D2-arachidonic acid in red blood cells is at least about 3% based on the total number of fatty acids contained in the red blood cells. 
     
     
         9 . The method of  claim 1 , wherein the deuterated arachidonic acid or ester thereof is 7,7,10,10,13,13-D6-arachidonic acid or ester thereof. 
     
     
         10 . The method of  claim 9 , wherein the concentration of 7,7,10,10,13,13 in the red blood cells is at least about 0.5% based on the total number of fatty acids contained therein. 
     
     
         11 . The method according to  claim 5 , wherein 11,11-D2-linoleic acid or an ester thereof is administered to the patient with a dosing regimen that comprises a primer dose and a maintenance dose, the method further comprising:
 a) administering said primer dose to said patient at least about 7 grams of 11,11-D2-linoleic acid or an ester thereof wherein said first dosing component is continued for a period of at least 24 days to provide a therapeutic concentration of 13,13-D2-arachidonic acid in red blood cells thereby reducing the rate of disease progression;   b) subsequent to the period of at least 24 days of administering said primer dose administering the maintenance dose to said patient, said maintenance dose comprising about at least 3 grams of 11,11-D2-linoleic acid or an ester thereof to maintain a therapeutic concentration of 13,13-D2-arachidonic acid provided that said maintenance dose is less than said primer dose.   
     
     
         12 . The method of  claim 11 , which further comprises;
 c) monitoring the concentration of 13,13-D2-arachidonic acid in the patient to ensure that the patient maintains a therapeutic concentration of 13,13-D2-arachidonic acid; and   d) increasing the dosing of 11,11-D2-linoleic acid or an ester thereof when said concentrations of 13,13-D2-arachidonic acid is deemed to be less than a therapeutic concentration.   
     
     
         13 . The method of  claim 12 , which further comprises restricting the patient's consumption of excessive dietary polyunsaturated fatty acids during administration of said primer and said maintenance doses. 
     
     
         14 . The method according to  claim 5 , wherein the method comprises administering 11,11-D2-linoleic acid or an ester thereof to the patient with a dosing regimen that comprises a primer dose and a maintenance dose:
 a) said primer dose comprises about 9 grams of 11,11-D2-linoleic acid or an ester thereof wherein said primer dose is continued for about 30 days to 45 days to provide a therapeutic concentration of 13,13-D2-arachidonic acid thereby reducing the rate of disease progression; and   b) subsequent to the about 30 days to 45 days of administering said primer dose, administering said maintenance dose of about 5 grams of 11,11-D2-linoleic acid or an ester thereof to maintain a therapeutic concentration of 13,13-D2-arachidonic acid in the motor neurons.   
     
     
         15 . The method of  claim 14 , which further comprises:
 c) monitoring the concentration of 13,13-D2-arachidonic acid in the patient to ensure that the patient maintains a therapeutic concentration of 13,13-D2-arachidonic acid; and   d) increasing the dosing of 11,11-D2-linoleic acid or an ester when said concentrations of 13,13-D2-arachidonic acid is determined to be less than a therapeutic concentration.   
     
     
         16 . The method of  claim 15 , which further comprises restricting the patient's consumption of excessive dietary polyunsaturated fatty acids during said first and second dosing components. 
     
     
         17 . The method according to  claim 6 , wherein the method comprises administering 13,13-D2-arachidonic acid or an ester thereof to the patient with a dosing regimen that comprises a primer dose and a maintenance dose:
 a) said primer or periodic dose comprises about up to about 7 grams of 13,13-D2-arachidonic or an ester thereof wherein said primer dose is continued for about 30 days to 45 days to provide a therapeutic concentration of 13,13-D2-arachidonic acid thereby reducing the rate of disease progression; and   b) subsequently following said primer dose with said maintenance dose which is from about 30 to 65% of the amount of 13,13-D2 arachidonic acid or ester thereof administered in said primer dose.   
     
     
         18 . The method of  claim 17 , which further comprises:
 c) monitoring the concentration of 13,13-D2-arachidonic acid in the patient to ensure that the patient maintains a therapeutic concentration of 13,13-D2-arachidonic acid; and   d) increasing the dosing of 13,13-D2-arachidonic acid or an ester when said concentrations of 13,13-D2-arachidonic acid is deemed to be less than a therapeutic concentration.   
     
     
         19 . The method of  claim 18 , which further comprises restricting the patient's consumption of excessive dietary polyunsaturated fatty acids during said first and second dosing components. 
     
     
         20 . The method according to  claim 9 , wherein the method comprises administering 7,7,10,10,13,13-D6 arachidonic acid or an ester thereof to the patient with a dosing regimen that comprises a primer dose and a maintenance dose:
 a) said primer dose comprises administering to said patient at least about 0.5 grams of 7,7,10,10,13,13-D6 arachidonic acid or an ester thereof wherein said primer dose is continued a period of from about 24 days to about 45 days; and   b) subsequently following said primer dose with said maintenance dose which is from about 30 to 65% of the amount of 7,7,10,10,13,13-D6 arachidonic acid or ester thereof administered in said primer dose.   
     
     
         21 . The method of  claim 20 , which further comprises:
 c) monitoring the concentration of 7,7,10,10,13,13-D6 arachidonic acid in the patient to ensure that the patient maintains a therapeutic concentration of said 7,7,10,10,13,13-D6 arachidonic acid; and   d) increasing the dosing of 7,7,10,10,13,13-D6 arachidonic acid or an ester thereof when said concentrations of 7,7,10,10,13,13-D6 -arachidonic acid are deemed to be less than a therapeutic concentration.   
     
     
         22 . The method of  claim 21 , which further comprises restricting the patient's consumption of excessive dietary polyunsaturated fatty acids during said first and second dosing components. 
     
     
         23 . A kit of parts comprising a multiplicity of containers wherein each container contains a single daily dose of the primer dose totalling about 9 grams of 11,11-D2-linoleic acid or an ester thereof or a single daily dose of the maintenance dose totalling about 5 grams of 11,11-D2-linoleic acid. 
     
     
         24 . The kit of parts of  claim 23 , wherein said primer dose comprises an aggregate of 9 subunits each subunit being about 1 gram. 
     
     
         25 . The kit of parts of  claim 23 , wherein said maintenance dose comprises an aggregate of 5 subunits each subunit being about 1 gram. 
     
     
         26 . A unit dose of 11,11-D2-linoleic acid or an ester thereof comprising either about 9 grams or about 5 grams of 11,11-D2-linoleic acid or as ester thereof. 
     
     
         27 . The method of  claim 11 , wherein said primer dose and/or said maintenance dose is provided in 1, 2 or 3 sittings. 
     
     
         28 . The method of  claim 14 , wherein said primer dose and/or said maintenance dose is provided in 1, 2 or 3 sittings. 
     
     
         29 . The method of  claim 17 , wherein said primer dose and/or said maintenance dose is provided in 1, 2 or 3 sittings. 
     
     
         30 . The method of  claim 20 , wherein said primer dose and/or said maintenance dose is provided in 1, 2 or 3 sittings.