Methods of treating spinal muscular atrophy

Abstract

Featured are biornarkers for, e.g., diagnosis and prognosis of spinal muscular atrophy (SMA) as well as identification of responders to treatment of SMA. Also provided are methods of treating subjects with SMA.

1 . A method of treating spinal muscular atrophy (SMA) in a human subject in need thereof, comprising administering to the human subject a therapeutically effective amount of an SMA therapy, wherein the human subject has been previously determined to have, in a biological sample obtained from the human subject, a neurofilament level prior to initiation of the SMA therapy that is higher than a control. 
     
     
         2 . A method of treating spinal muscular atrophy (SMA) in a human subject in need thereof, comprising:
 measuring a neurofilament level in a biological sample obtained from the human subject before initiation of an SMA therapy; and   administering a therapeutically effective amount of the SMA therapy to the human subject.   
     
     
         3 . The method of  claim 1 , wherein the neurofilament level in the biological sample is above 400 pg/mL. 
     
     
         4 . A method of treating spinal muscular atrophy (SMA) in a human subject in need thereof, comprising:
 measuring a neurofilament level in a first biological sample obtained from the human subject before initiation of an SMA therapy;   administering an SMA therapy to the human subject; and   measuring a neurofilament level in a second biological sample obtained from the human subject after initiation of the SMA therapy.   
     
     
         5 - 19 . (canceled) 
     
     
         20 . A method of treating spinal muscular atrophy (SMA) in a human subject in need thereof, comprising:
 measuring a neurofilament level in a first biological sample obtained from the human subject before administration of a candidate amount of an SMA therapy;   measuring a neurofilament level in a second biological sample obtained from the human subject after administration of the candidate amount of the SMA therapy, wherein the neurofilament level in the second biological sample is lower than the neurofilament level in the first biological sample, thereby indicating that the candidate amount of the SMA therapy is a therapeutically effective amount;   administering the therapeutically effective amount of the SMA therapy to the human subject after having measured the lowered neurofilament level in the second biological sample.   
     
     
         21 . A method of predicting the prognosis of spinal muscular atrophy (SMA), comprising:
 measuring a neurofilament level in a biological sample obtained from a human subject having mutations in both copies of the SMN1 gene that lead to functional SMN protein deficiency; and   comparing the neurofilament level measured in the biological sample to a control,   wherein the neurofilament level measured in the biological sample, as compared to the control, is predictive of the severity or type of SMA that the subject will develop.   
     
     
         22 - 25 . (canceled) 
     
     
         26 . A method of predicting the prognosis of spinal muscular atrophy (SMA), comprising:
 measuring, before initiation of an SMA therapy, a neurofilament level in a first biological sample obtained from a human subject having mutations in both copies of the SMN1 gene that lead to functional SMN protein deficiency;   measuring a neurofilament level in a second biological sample obtained from the human subject after initiation of the SMA therapy; and   comparing the neurofilament level measured in the second biological sample to the neurofilament level measured in the first biological sample,   wherein the neurofilament level measured in the second biological sample, as compared to the neurofilament level measured in the first biological sample, is predictive of the severity or type of SMA that the subject will develop.   
     
     
         27 . The method of  claim 26 , wherein the second biological sample is obtained from the human subject 40-90 days after initiation of the SMA therapy. 
     
     
         28 - 35 . (canceled) 
     
     
         36 . The method of  claim 1 , wherein the SMA therapy is nusinersen or a nusinersen salt. 
     
     
         37 . The method of  claim 1 , wherein the SMA therapy is nusinersen sodium. 
     
     
         38 . The method of  claim 1 , wherein the SMA therapy is olesoxime, AVX-101, CK-2127107, RG7916, RG7800, R07034067, LMI070, or SRK-015. 
     
     
         39 . The method of  claim 1 , wherein the control is a pre-established neurofilament cut-off value. 
     
     
         40 . The method of  claim 1 , wherein the control is the neurofilament level in a biological sample or biological samples obtained from one or more human subjects that do not have SMA. 
     
     
         41 . A method for measuring a neurofilament level, comprising:
 providing a biological sample obtained from a human subject having mutations in both copies of the SMN1 gene that lead to functional SMN protein deficiency; and   measuring a neurofilament level in the biological sample.   
     
     
         42 . The method of  claim 1 , wherein the neurofilament is a neurofilament heavy chain. 
     
     
         43 . The method of  claim 1 , wherein the neurofilament is a phosphorylated neurofilament heavy chain. 
     
     
         44 . The method of  claim 1 , wherein the neurofilament is a neurofilament medium/intermediate chain. 
     
     
         45 . The method of  claim 1 , wherein the neurofilament is a neurofilament light chain. 
     
     
         46 . The method of  claim 1 , wherein the biological sample is blood, serum, plasma, or cerebrospinal fluid.