METHODS AND COMPOSITIONS FOR TREATING LEUKODYSTROPHIES

1 - 10 . (canceled)

11 . A method of treating Canavan disease in a subject in need thereof, comprising: administering to the subject a therapeutically effective amount of a recombinant adeno-associated virus (rAAV) vector, wherein the rAAV vector comprises:

(i) a nucleic acid molecule comprising at least one AAV inverted terminal repeat (ITR) and

(ii) a non-AAV nucleotide sequence encoding aspartoacylase (ASPA), wherein the non-AAV nucleotide sequence is operably linked to a promoter; and

wherein the therapeutically effective amount is in the range of about 10 13 vg/kg to about 10 15 vg/kg,

thereby treating Canavan disease in the subject.

12 . (canceled)

13 . The method of claim 11 , wherein administration of the rAAV vector results in expression of ASPA in a peripheral tissue and/or central nervous system (CNS) tissue of the subject.

14 . (canceled)

15 . The method of claim 11 , wherein the subject has it a metabolic imbalance comprising a shift from glycolysis to beta-oxidation, wherein the metabolic imbalance comprises an imbalance in a level of glucose, glucose-6-phosphate, 3-phosphoglycerate, pyruvate, lactate, phosphoenolpyruvate, carnitine, malonylcarnitine, myristoylcarnitine, palmitoylcarnitine, malonylcarnitine, beta-hydroxybutyrate, or a combination thereof.

16 - 24 . (canceled)

25 . The method of claim 11 , wherein the therapeutically effective amount is in the range of about 1×10 14 vg/kg to about 5×10 14 vg/kg.

26 . The method of claim 25 , wherein the therapeutically effective amount is about 1.32 X_10 14 vg/kg or about 3×10 14 vg/kg.

27 . (canceled)

28 . The method of claim 11 , wherein the rAAV vector is administered via intravenous infusion, intravenous injection, intravascular injection, or intraventricular injection.

29 - 31 . (canceled)

32 . The method of claim 11 , wherein the subject is less than, or equal to, 30 months of age.

33 . The method of claim 11 , wherein ASPA comprises human ASPA protein.

34 . The method of claim 11 , wherein ASPA comprises an amino acid sequence of SEQ ID NO: 2, or an amino acid sequence with at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 2.

35 . The method of claim 11 , wherein the promoter is an astrocyte-specific promoter, a glial fibrillary acidic protein (GFAP) promoter, an enhanced chicken R-actin promoter, a cytomegalovirus/3-actin hybrid promoter, or a PGK promoter.

36 . (canceled)

37 . The method of claim 35 , wherein the cytomegalovirus/0-actin hybrid promoter is a CAG promoter, a CB6 promoter, or a CBA promoter.

38 . The method of claim 11 , wherein the non-AAV nucleotide sequence encoding ASPA comprises or consists of ii)_the human ASPA cDNA; (ii) a codon-optimized nucleotide sequence; and/or iii) SEQ ID NO: 1.

39 . (canceled)

40 . (canceled)

41 . The method of claim 11 , wherein the non-AAV nucleotide sequence encodes the amino acid sequence of SEQ ID NO: 6, or an amino acid sequence with at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to SEQ ID NO: 6.

42 . The method of claim 11 , wherein the nucleic acid molecule comprises a cytomegalovirus immediate-early enhancer, a rabbit (-globin polyA signal, a Kozak sequence, and/or an miR-122 binding site.

43 - 45 . (canceled)

46 . The method of claim 11 , wherein the ITR is an AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, rh10, or rh74 serotype ITR.

47 . The method of claim 11 , wherein the rAAV is an AAV1, AAV2, AAV3, AAV4, AAV5, AAV6, AAV7, AAV8, AAV9, AAV10, AAV11, AAV12, rh10, or rh74 serotype rAAV.

48 . (canceled)

49 . The method of claim 11 , wherein the rAAV is a self-complementary rAAV (scAAV) and/or a single-stranded rAAV (ssAAV).

50 - 53 . (canceled)

54 . The method of claim 11 , further comprising administering a therapeutically effective amount of a glucocorticoid and/or anti-histamine to the subject.

55 . (canceled)

56 . The method of claim 54 , wherein the glucocorticoid is prednisolone, methylprednisolone, or a combination thereof; and the anti-histamine is diphenhydramine, hydroxyzine, chlorpheniramine, or any combination thereof.

57 - 59 . (canceled)

60 . The method of claim 11 , wherein after administering the rAAV vector, N-acetylaspartate (NAA) levels in urine, cerebrospinal fluid (CSF), and/or brain tissue are decreased.

61 - 70 . (canceled)