Gene therapy for combined methylmalonic acidemia/aciduria and hyperhomocysteinemia/homocystinuria, cobalamin c type, and deficiency of mmachc

Abstract

The present invention provides a synthetic MMACHC polynucleotide comprising a polynucleotide encoding MMACHC that is codon-optimized for expression in a human. Also provided is a polypeptide encoded by a synthetic MMACHC polynucleotide, an expression vector comprising a MMACHC gene sequence under the control of a chicken beta actin (CBA) promoter, and an expression vector comprising a synthetic MMACHC polynucleotide. Methods of treating cobalamin C deficiency and for detecting or tracking exogenous MMACHC are also provided.

1 .- 13 . (canceled) 
     
     
         13 . A polypeptide encoded by a synthetic methylmalonic aciduria cblC type with homocystinuria (MMACHC) polynucleotide comprising a polynucleotide encoding MMACHC that is codon-optimized for expression in a human. 
     
     
         14 . (canceled) 
     
     
         15 . An expression vector comprising a MMACHC gene sequence under the control of a chicken beta actin (CBA) promoter. 
     
     
         16 .- 17 . (canceled) 
     
     
         18 . The expression vector of  claim 15 , wherein the expression vector is a viral vector. 
     
     
         19 . The expression vector of  claim 18 , wherein the viral vector is an adeno-associated viral (AAV) vector. 
     
     
         20 . The expression vector of  claim 19 , wherein the AAV is pseudotyped with at least one of rh10, type 9, type 8, and 7m8 capsid. 
     
     
         21 .- 24 . (canceled) 
     
     
         25 . A method of treating or preventing at least one condition of methylmalonic acidemia, hyperhomocysteinemia, homocystinura, cobalamin C type and deficiency of MMACHC, and low levels of MMACHC in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a synthetic methylmalonic aciduria cblC type with homocystinuria (MMACHC) polynucleotide comprising a polynucleotide encoding MMACHC that is codon-optimized for expression in a human, wherein the administration treats the condition in the subject. 
     
     
         26 .- 29 . (canceled) 
     
     
         30 . The method of  claim 25 , wherein the condition includes vision loss. 
     
     
         31 . A method of treating or preventing at least one condition of congenital heart defects (CHD), neural tube defects (NTD), combined methylmalonic acidemia and homocystinuria X type (cblX), HCFC1 spectrum defects, hyperhomocystinuria, and vitamin B12 deficiency in a subject, the method comprising administering to a subject in need thereof a therapeutically effective amount of a synthetic methylmalonic aciduria cblC type with homocystinuria (MMACHC) polynucleotide comprising a polynucleotide encoding MMACHC that is codon-optimized for expression in a human, wherein the administration treats the condition in the subject. 
     
     
         32 .- 37 . (canceled) 
     
     
         38 . A method of detecting or tracking exogenous MMACHC in a subject comprising (a) administering to the subject exogenous MMACHC in the form of a synthetic methylmalonic aciduria cblC type with homocystinuria (MMACHC) polynucleotide comprising a polynucleotide encoding MMACHC that is codon-optimized for expression in a human; (b) obtaining a sample of tissue, biospecimen, or body fluid from the subject; and (c) determining the expression level of the exogenous MAACHC in the sample. 
     
     
         39 . The method of  claim 38 , wherein the expression vector is Anc80. 
     
     
         40 . The method of  claim 38 , wherein the expression vector is an AAV vector pseudotyped with at least one of rh10, type 9, type 8, and 7m8 capsid.