Allele preferential rnai of mutant huntingtin (MTHTT) using allele-specific inhibitory nucleic acid molecules

Abstract

The present disclosure generally relates to the treatment of subjects having Huntington's disease and having mtHTT or at risk of developing Huntington's disease and having mtHTT, by administering allele-specific inhibitory nucleic acid molecules to the subject, and to methods of identifying subjects having an increased risk of developing Huntington's disease.

Description

[0001] DOCKET NO.: 38120-4600 (11607WO-01) PATENT Allele Preferential RNAi Of Mutant Huntingtin (mtHTT) Using Allele-Specific Inhibitory Nucleic Acid Molecules

[0002] Reference To Sequence Listing

[0003] This application includes a Sequence Listing submitted electronically as an XML file named 381204600SEQ, created on March 13, 2026, with a size of 432,946 bytes. The Sequence Listing is incorporated herein by reference.

[0004] Field

[0005] The present disclosure generally relates to the treatment of subjects having Huntington's disease and having mtHTT or at risk of developing Huntington's disease and having mtHTT, by administering allele-specific inhibitory nucleic acid molecules to the subject, and to methods of identifying subjects having an increased risk of developing Huntington's disease.

[0006] Background

[0007] Huntington's disease (HD) is an autosomal dominant progressive neurodegenerative disorder characterized by loss of striatal neurons. HD affects areas of the brain that help to control voluntary (intentional) movement, as well as other areas. People living with HD develop involuntary jerking or twitching movements known as chorea and abnormal body postures, as well as problems with behavior, emotion, thinking, and / or personality. Adult-onset HD, the most common form of this disorder, usually appears in a person's thirties or forties. Early signs of HD can vary, but often include mild clumsiness or problems with balance or movement, cognitive or psychiatric symptoms (problems with thinking or emotion), and changes in behavior. As the disease progresses, involuntary movements become more pronounced and affected individuals may have trouble walking, speaking, and swallowing. In addition, affected individuals may also experience changes in personality and a decline in thinking and reasoning abilities. Therapeutics can help manage some of the symptoms but cannot slow down or stop the disease as there is no cure for HD.

[0008] - 1 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT Huntington (HTT) protein is encoded by a 202 kb gene located at the 4pl6.3 chromosomal locus. HTT is 3142 amino acids long and is a 347 KDa protein thought to be involved in axonal transport. Mutant Huntingtin (mtHTT) is characterized by an unstable trinucleotide repeat expansion in the HTT gene. Specifically, a polyglutamine encoding CAG repeat in the HTT gene (4:3074877:CAG:(CAG)n) with excessive (more than 36) CAG repeats results in an unstable mutant Huntingtin protein and is the cause of Huntington's Disease (HD).

[0009] Summary

[0010] The present disclosure provides methods of treating a subject having Huntington's disease or at risk of developing Huntington's disease, wherein the subject has a pathogenic mutant huntingtin (mtHTT) allele, the methods comprising: a) performing or having performed a sequence analysis on a biological sample obtained from the subject; b) determining from the sequence analysis or having determined from the sequence analysis whether the subject is heterozygous for a first mtHTT variant, wherein a first mtHTT variant targeted allele is in phase with the pathogenic mtHTT allele, wherein the first mtHTT variant targeted allele is the alternate allele of the first mtHTT variant and is in phase with the pathogenic mtHTT allele more often than any other allele in a population of subjects; and i) administering or continuing to administer a first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule to the subject that is heterozygous for the first mtHTT variant targeted allele in phase with the pathogenic mtHTT allele; or ii) performing step c) for the subject that is homozygous for the first mtHTT variant or heterozygous for the first mtHTT variant but the targeted allele is not in phase with the pathogenic mtHTT allele; c) determining from the sequence analysis or having determined from the sequence analysis whether the subject is heterozygous for a subsequent mtHTT variant in which the alternate allele or reference allele is in phase with the pathogenic mtHTT allele; and i) administering or continuing to administer a subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule or a subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, whichever is in phase with the pathogenic mtHTT allele, to the subject that is heterozygous for the subsequent mtHTT variant; or ii) repeating step c) for - 2 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT the subject that is homozygous for the subsequent mtHTT variant until a further subsequent mtHTT variant that is heterozygous is identified for the subject, and administering to the subject or continuing to administer to the subject a further subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule or a further subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, whichever is in phase with the pathogenic mtHTT allele.

[0011] The present disclosure also provides methods of treating a subject having Huntington's disease or at risk of developing Huntington's disease, wherein the subject has a pathogenic mutant huntingtin (mtHTT) allele, the methods comprising: a) performing or having performed a sequence analysis on a biological sample obtained from the subject; b) determining from the sequence analysis or having determined from the sequence analysis whether the subject is heterozygous for a first mtHTT variant, wherein the first mtHTT variant targeted allele is in phase with the pathogenic mtHTT allele, wherein the first mtHTT variant targeted allele is the alternate allele of the first mtHTT variant and is in phase with the pathogenic mtHTT allele more often than any other allele in a population of subjects; and i) administering or continuing to administer a first mtHTT variant alternate allelespecific inhibitory nucleic acid molecule to the subject that is heterozygous for the first mtHTT variant targeted allele in phase with the pathogenic mtHTT allele; or ii) performing step c) for the subject that is homozygous for the first mtHTT variant or heterozygous for the first mtHTT variant but the targeted allele is not in phase with the pathogenic mtHTT allele; c) determining from the sequence analysis or having determined from the sequence analysis whether the subject is heterozygous for a first subsequent mtHTT variant and heterozygous for a second subsequent mtHTT variant; and i) administering or continuing to administer a first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule to the subject that has both the first subsequent mtHTT variant alternate allele and the second subsequent mtHTT variant alternate allele in phase with the pathogenic mtHTT allele; or ii) administering or continuing to administer a first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule to the subject that has both the first subsequent mtHTT variant reference allele - 3 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT and the second subsequent mtHTT variant reference allele in phase with the pathogenic mtHTT allele; or iii) administering or continuin to administer a first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule to the subject that has both the first subsequent mtHTT variant alternate allele and the second subsequent mtHTT variant reference allele in phase with the pathogenic mtHTT allele; or iv) administering or continuing to administer a first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule to the subject that has both the first subsequent mtHTT variant reference allele and the second subsequent mtHTT variant alternate allele in phase with the pathogenic mtHTT allele; or ii) repeating step c) for the subject that is homozygous for either the first subsequent mtHTT variant or the second subsequent mtHTT variant until a first further subsequent mtHTT variant or a second further subsequent mtHTT variant that are heterozygous is identified for the subject, and administering to the subject or continuing to administer to the subject: a first further subsequent mtHTT variant alternate allele-specific / second further subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule to the subject that has both the first further subsequent mtHTT variant alternate allele and the second further subsequent mtHTT variant alternate allele in phase with the pathogenic mtHTT allele; or a first further subsequent mtHTT variant reference allele-specific / second further subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule to the subject that has both the first further subsequent mtHTT variant reference allele and the second further subsequent mtHTT variant reference allele in phase with the pathogenic mtHTT allele; or a first further subsequent mtHTT variant alternate allele-specific / second further subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule to the subject that has both the first further subsequent mtHTT variant alternate allele and the second further subsequent mtHTT variant reference allele in phase with the pathogenic mtHTT allele; or a first further subsequent mtHTT variant reference allele-specific / second further subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule to the subject that has both the first further subsequent mtHTT variant reference allele and the second further subsequent mtHTT variant alternate allele in phase with the pathogenic mtHTT allele.

[0012] - 4 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT The present disclosure also provides methods of treating a subject having Huntington's disease or at risk of developing Huntington's disease, wherein the subject has a pathogenic mutant huntingtin (mtHTT) allele, the methos comprising: i) administering a first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule to the subject that is heterozygous for a first mtHTT variant targeted allele in phase with the pathogenic mtHTT allele, wherein the first mtHTT variant targeted allele is the alternate allele of the first mtHTT variant and is in phase with the pathogenic mtHTT allele more often than any other allele in a population of subjects; and ii) for the subject that is homozygous for the first mtHTT variant or heterozygous for the first mtHTT variant but the targeted allele is not in phase with the pathogenic mtHTT allele, administering a subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule or a subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, whichever is in phase with the pathogenic mtHTT allele.

[0013] The present disclosure also provides methods of treating a subject having Huntington's disease or at risk of developing Huntington's disease, wherein the subject has a pathogenic mutant huntingtin (mtHTT) allele, the methods comprising: i) administering a first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule to the subject that is heterozygous for a first mtHTT variant targeted allele in phase with the pathogenic mtHTT allele, wherein the first mtHTT variant targeted allele is the alternate allele of the first mtHTT variant and is in phase with the pathogenic mtHTT allele more often than any other allele in a population of subjects; and ii) for the subject that is homozygous for the first mtHTT variant or heterozygous for the first mtHTT variant but the targeted allele is not in phase with the pathogenic mtHTT allele: a) administering or continuing to administer a first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule to the subject that has both the first subsequent mtHTT variant alternate allele and the second subsequent mtHTT variant alternate allele in phase with the pathogenic mtHTT allele; or b) administering or continuing to administer a first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule to the subject that has both the first subsequent mtHTT variant reference allele and the second subsequent - 5 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT mtHTT variant reference allele in phase with the pathogenic mtHTT allele; or c) administering or continuing to administer a first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule to the subject that has both the first subsequent mtHTT variant alternate allele and the second subsequent mtHTT variant reference allele in phase with the pathogenic mtHTT allele; or d) administering or continuing to administer a first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule to the subject that has both the first subsequent mtHTT variant reference allele and the second subsequent mtHTT variant alternate allele in phase with the pathogenic mtHTT allele.

[0014] The present disclosure also provides methods of identifying a subject having Huntington's disease or at risk of developing Huntington's disease that is a candidate for treatment with an inhibitory nucleic acid molecule, wherein the subject has a pathogenic mutant huntingtin (mtHTT) allele, the methods comprising: a) performing or having performed a sequence analysis on a biological sample obtained from the subject; and i) determining from the sequence analysis or having determined from the sequence analysis whether the subject is heterozygous for a first mtHTT variant, wherein a first mtHTT variant targeted allele is in phase with the pathogenic mtHTT allele, wherein the first mtHTT variant targeted allele is the alternate allele of the first mtHTT variant and is in phase with the pathogenic mtHTT allele more often than any other allele in a population of subjects, wherein the subject is a candidate for treatment with a first mtHTT variant alternate allelespecific inhibitory nucleic acid molecule when the subject is heterozygous for the first mtHTT variant targeted allele in phase with the pathogenic mtHTT allele; or ii) for the subject that is homozygous for the first mtHTT variant, or heterozygous for the first mtHTT variant but the targeted allele is not in phase with the pathogenic mtHTT allele, determining from the sequence analysis or having determined from the sequence analysis whetherthe subject is heterozygous for a subsequent mtHTT variant in which the alternate allele or reference allele is in phase with the pathogenic mtHTT allele, wherein the subject is a candidate for treatment with a subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule or a subsequent mtHTT variant alternate allele-specific - 6 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT inhibitory nucleic acid molecule, whichever is in phase with the pathogenic mtHTT allele, when the subject is heterozygous for the subsequent mtHTT variant.

[0015] The present disclosure also provides methods of identifying a subject having Huntington's disease or at risk of developing Huntington's disease that is a candidate for treatment with an inhibitory nucleic acid molecule, wherein the subject has a pathogenic mutant huntingtin (mtHTT) allele, the methods comprising: performing or having performed a sequence analysis on a biological sample obtained from the subject; and i) determining from the sequence analysis or having determined from the sequence analysis whetherthe subject is heterozygous for a first mtHTT variant, wherein a first mtHTT variant targeted allele is in phase with the pathogenic mtHTT allele, wherein the first mtHTT variant targeted allele is the alternate allele of the first mtHTT variant and is in phase with the pathogenic mtHTT allele more often than any other allele in a population of subjects, wherein the subject is a candidate fortreatment with a first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule when the subject is heterozygous for the first mtHTT variant targeted allele in phase with the pathogenic mtHTT allele; or ii) for the subject that is homozygous for the first mtHTT variant, or heterozygous for the first mtHTT variant but the targeted allele is not in phase with the pathogenic mtHTT allele, determining from the sequence analysis or having determined from the sequence analysis whether the subject is heterozygous for a first subsequent mtHTT variant and heterozygous for a second subsequent mtHTT variant, wherein the subject is a candidate fortreatment with: a) a first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule to the subject that has both the first subsequent mtHTT variant alternate allele and the second subsequent mtHTT variant alternate allele in phase with the pathogenic mtHTT allele; b) a first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule to the subject that has both the first subsequent mtHTT variant reference allele and the second subsequent mtHTT variant reference allele in phase with the pathogenic mtHTT allele; c) a first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule to the subject that has both the first subsequent mtHTT variant alternate allele - 7 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT and the second subsequent mtHTT variant reference allele in phase with the pathogenic mtHTT allele; or d) a first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule to the subject that has both the first subsequent mtHTT variant reference allele and the second subsequent mtHTT variant alternate allele in phase with the pathogenic mtHTT allele.

[0016] Brief Description Of The Drawings

[0017] The patent or application file contains at least one drawing executed in color. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.

[0018] Figure 1 shows association data for 23 HTT coding variants with MAF>1% (population) and >2% proportion of patientstreatable.

[0019] Description

[0020] Various terms relating to aspects of the present disclosure are used throughout the specification and claims. Such terms are to be given their ordinary meaning in the art, unless otherwise indicated. Other specifically defined terms are to be construed in a manner consistent with the definitions provided herein.

[0021] Unless otherwise expressly stated, it is in no way intended that any method or aspect set forth herein be construed as requiring that its steps be performed in a specific order. Accordingly, where a method claim does not specifically state in the claims or descriptions that the steps are to be limited to a specific order, it is in no way intended that an order be inferred, in any respect. This holds for any possible non-expressed basis for interpretation, including matters of logic with respect to arrangement of steps or operational flow, plain meaning derived from grammatical organization or punctuation, or the number or type of aspects described in the specification.

[0022] As used herein, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise.

[0023] As used herein, the term "about" means that the recited numerical value is approximate and small variations would not significantly affect the practice of the disclosed - 8 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT embodiments. Where a numerical value is used, unless indicated otherwise by the context, the term "about" means the numerical value can vary by ±10% and remain within the scope ofthe disclosed embodiments.

[0024] As used herein, the term "comprising" may be replaced with "consisting" or "consisting essentially of' in particular embodiments as desired.

[0025] As used herein, the terms "nucleic acid", "nucleic acid molecule", "nucleic acid sequence", "polynucleotide", or "oligonucleotide" can comprise a polymeric form of nucleotides of any length, can comprise DNA and / or RNA, and can be single-stranded, double-stranded, or multiple stranded, or can be conjugated to another molecule, such as an antibody. One strand of a nucleic acid also refers to its complement.

[0026] As used herein, the term "subject" includes any animal, including mammals.

[0027] Mammals include, but are not limited to, farm animals (such as, for example, horses, cows, and pigs), companion animals (such as, for example, dogs and cats), laboratory animals (such as, for example, mice, rats, and rabbits), and non-human primates. In some embodiments, the subject is a human. In some embodiments, the human is a patient under the care of a physician.

[0028] As used herein, the term "mtHTT variant" means any HTT gene that has an alteration in its genetic sequence, thus producing a reference allele (i.e., wild type) and an alternate allele. In some embodiments, the reference allele is in phase with the pathogenic mtHTT allele. In some embodiments, the alternate allele is in phase with the pathogenic mtHTT allele.

[0029] The huntingtin (HTT) gene is large, spanning 180 kb and consisting of 67 exons. The HTT gene comprises a trinucleotide (CAG) repeat (4:3074877:CAG:(CAG)n), which translates as a polyglutamine repeat in the protein product. A range of trinucleotide repeats (i.e., n = 9-35) has been identified in normal controls. The HTT gene is located at chromosome 4 (i.e., positions 3,074,681-3,243,957) using the nucleotide sequence ofthe HTT reference genomic nucleic acid molecule in the GRCh38 / hg38 human genome assembly (see, ENSG00000197386.14, ENST00000355072.il annotated in the Ensembl database (URL: world wide web at "https: / / www.ncbi.nlm.nih.gOv / nuccore / NM_002111.8.")) as a reference sequence. The sequence provided in this transcript for the HTT genomic nucleic - 9 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT acid molecule is only an exemplary sequence. Other sequences for the HTT genomic nucleic acid molecule are also possible (URL: world wide web at "useast.ensembl.org / Homo_ sapiens / Gene / Summary?g=ENSG00000197386;r=4:3041363-3243957; transcript=ENST00000355072.11").

[0030] In the embodiments described herein, the subject has a pathogenic mtHTT allele, which is expanded and unstable. The CAG repeat number is 37 or more, up to 120 repeats or more (i.e., 4:3074877:CAG:(CAG)n>36). One skilled in the art can determine whether a particular subject has a pathogenic mtHTT allele by obtaining a biological sample from the subject and examining the HTT nucleotide sequence by, for example, sequencing.

[0031] In any of the embodiments described herein, the subject can have Huntington's disease. In any of the embodiments described herein, the subject can be at risk of developing Huntington's disease.

[0032] The present disclosure provides methods of treating a subject having Huntington's disease or at risk of developing Huntington's disease. The subject has a pathogenic mutant huntingtin (mtHTT) allele. The methods comprise performing or having performed a sequence analysis on a biological sample obtained from the subject. The methods also comprise determining from the sequence analysis or having determined from the sequence analysis whether the subject is heterozygous for a first mtHTT variant, wherein a first mtHTT variant targeted allele is in phase with the pathogenic mtHTT allele. The first mtHTT variant targeted allele is the alternate allele of the first mtHTT variant and is in phase with the pathogenic mtHTT allele more often than any other allele in a population of subjects. For a subject that is heterozygous for the first mtHTT variant targeted allele in phase with the pathogenic mtHTT allele, the methods comprise administering or continuing to administer a first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule to the subject. For a subject that is homozygous for the first mtHTT variant or heterozygous for the first mtHTT variant but the targeted allele is not in phase with the pathogenic mtHTT allele, the methods comprise determining from the sequence analysis or having determined from the sequence analysis whether the subject is heterozygous for a subsequent mtHTT variant in which the alternate allele or reference allele is in phase with the pathogenic mtHTT allele. For a subject that is heterozygous for the subsequent mtHTT variant, the methods comprise - 10 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT administering or continuing to administer a subsequent mtHTT variant reference allelespecific inhibitory nucleic acid molecule or a subsequent mtHTT variant alternate allelespecific inhibitory nucleic acid molecule, whichever is in phase with the pathogenic mtHTT allele. Fora subject that is homozygous for the subsequent mtHTT variant, the methods comprise determining from the sequence analysis or having determined from the sequence analysis whether the subject is heterozygous for a further subsequent mtHTT variant in which the alternate allele or reference allele is in phase with the pathogenic mtHTT allele until a further subsequent mtHTT variant that is heterozygous is identified for the subject, at which time the methods comprise administering to the subject or continuing to administer to the subject a further subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule or a further subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, whichever is in phase with the pathogenic mtHTT allele.

[0033] The present disclosure also provides methods of treating a subject having Huntington's disease or at risk of developing Huntington's disease. The subject has a pathogenic mutant huntingtin (mtHTT) allele. For a subject that is heterozygous for a first mtHTT variant targeted allele in phase with the pathogenic mtHTT allele, wherein the first mtHTT variant targeted allele is the alternate allele of the first mtHTT variant and is in phase with the pathogenic mtHTT allele more often than any other allele in a population of subjects, the methods comprise administering a first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule to the subject. For a subject that is homozygous for the first mtHTT variant or heterozygous forthe first mtHTT variant but the targeted allele is not in phase with the pathogenic mtHTT allele, the methods comprise administering a subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule or a subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, whichever is in phase with the pathogenic mtHTT allele.

[0034] Table 1 shows variants in the HTT mRNA and the proportion of patients with the indicated target allele on the same chromosome as the pathogenic triplet repeat expansion.

[0035] Table 1

[0036] Variant name Target allele Proportion Prop. Het Proportion of Hets in Cases Cases In Patients

[0037]

[0038] - 11 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT Phase Targeted

[0039] 4:3074723:C:T ALT 0.035398 0 0 4:3074723:C:T REF 0.035398 1 0.035398 4:3115441:C:G ALT 0.044248 0 0 4:3115441:C:G REF 0.044248 1 0.044248 4:3121347:C:T ALT 0.088496 0.7 0.061947 4:3121347:C:T REF 0.088496 0.3 0.026549 4:3135947:G:A ALT 0.141593 0.625 0.088496 4:3135947:G:A REF 0.141593 0.375 0.053097 4:3146926:T:G ALT 0.017699 0.5 0.00885 4:3146926:T:G REF 0.017699 0.5 0.00885 4:3160329:C:T ALT 0.389381 0.181818 0.070796 4:3160329:C:T REF 0.389381 0.818182 0.318584 4:3178294:T:C ALT 0.486726 0.290909 0.141593 4:3178294:T:C REF 0.486726 0.709091 0.345133 4:3187820:C:A ALT 0.150442 0.352941 0.053097 4:3187820:C:A REF 0.150442 0.647059 0.097345 4:3212105:G:A ALT 0.39823 0.2 0.079646 4:3212105:G:A REF 0.39823 0.8 0.318584 4:3212148:T:C ALT 0.141593 0.375 0.053097 4:3212148:T:C REF 0.141593 0.625 0.088496 4:3212714:G:A ALT 0.017699 0 0 4:3212714:G:A REF 0.017699 1 0.017699 4:3214108:T:C ALT 0.460177 0.192308 0.088496 4:3214108:T:C REF 0.460177 0.807692 0.371681 4:3225692:A:G ALT 0.389381 0.181818 0.070796 4:3225692:A:G REF 0.389381 0.818182 0.318584 4:3228683:AGAG:A ALT 0.442478 0.82 0.362832

[0040]

[0041] - 12 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT 4:3228683:AGAG:A REF 0.442478 0.18 0.079646 4:3229934:G:A ALT 0.115044 0.307692 0.035398 4:3229934:G:A REF 0.115044 0.692308 0.079646 4:3233253:G:A ALT 0.40708 0.173913 0.070797 4:3233253:G:A REF 0.40708 0.826087 0.336283 4:3240118:C:T ALT 0.442478 0.82 0.362832 4:3240118:C:T REF 0.442478 0.18 0.079646 4:3240373:G:A ALT 0.40708 0.173913 0.070797 4:3240373:G:A REF 0.40708 0.826087 0.336283 4:3240421:C:G ALT 0.39823 0.155556 0.061947 4:3240421:C:G REF 0.39823 0.844444 0.336283 4:3240433:C:G ALT 0.141593 0.4375 0.061947 4:3240433:C:G REF 0.141593 0.5625 0.079646 4:3240545:C:A ALT 0.141593 0.4375 0.061947 4:3240545:C:A REF 0.141593 0.5625 0.079646 4:3240580:C:T ALT 0.150442 0.470588 0.070796 4:3240580:C:T REF 0.150442 0.529412 0.079646 4:3241211:G:T ALT 0.017699 0.5 0.00885 4:3241211:G:T REF 0.017699 0.5 0.00885 4:3241491:C:T ALT 0.40708 0.173913 0.070797 4:3241491:C:T REF 0.40708 0.826087 0.336283 4:3241563:G:A ALT 0.106195 0.833333 0.088496 4:3241563:G:A REF 0.106195 0.166667 0.017699 4:3242045:TG:T ALT 0.150442 0.411765 0.061947 4:3242045:TG:T REF 0.150442 0.588235 0.088496 4:3243330:C:T ALT 0.318584 0.555556 0.176991 4:3243330:C:T REF 0.318584 0.444444 0.141593

[0042]

[0043] In any of the methods of treatment described herein, the first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, subsequent mtHTT variant

[0044] - 13 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT reference allele-specific inhibitory nucleic acid molecule, subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, further subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, and further subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule comprise an antisense nucleic acid molecule, a small interfering RNA (siRNA), or a short hairpin RNA (shRNA).

[0045] In any of the methods of treatment described herein, the first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, further subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, and further subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule comprise an siRNA.

[0046] In any of the methods of treatment described herein, the first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, further subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, and further subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule comprise an antisense nucleic acid molecule.

[0047] In any of the methods of treatment described herein, the first mtHTT variant comprises 4:3228683:AGAG:A; and i) the first mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisin the nucleotide sequence of SEQ ID NO:334, SEQ ID NO:335, or SEQ ID NO:336; or ii) the first mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:89 / 334, SE ID NQs:90 / 335, or SEQ ID NOs:91 / 336.

[0048] In any of the methods of treatment described herein, the subsequent mtHTT variant or further subsequent mtHTT variant comprises 4:3240421:C:G; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:380, SEQ - 14 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT ID NO:382, SEQ ID NO:384, SEQ ID NO:387, SEQ ID NO:389, or SEQ ID NO:392; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs: 135 / 380, SEQ ID NOs:137 / 382, SEQ ID NOs:139 / 384, SEQ ID NOs:142 / 387, SEQ ID NOs:144 / 389, or SEQ ID NOs:147 / 392; iii) the subsequent mtHTT variant reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:379, SEQ ID NO:381, SEQ ID NO:383, SEQ ID NO:385, SEQ ID NO:386, SEQ ID NO:388, SEQ ID NQ:390, SEQ ID NO:391, or SEQ ID NO:393; or iv) the subsequent mtHTT variant reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant reference-specific inhibitory nucleic acid molecule comprises an siRNA comprisingthe nucleotide sequences of SEQ ID NOs:134 / 379, SEQ ID NOs:136 / 381, SEQ ID NOs:138 / 383, SEQ ID NOs:140 / 385, SEQ ID NOs:141 / 386, SEQ ID NOs:143 / 388, SEQ ID NQs:145 / 390, SEQ ID NOs:146 / 391, or SEQ ID NOs: 148 / 393.

[0049] In any of the methods of treatment described herein, the subsequent mtHTT variant or further subsequent mtHTT variant comprises 4:3074723:C:T; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:247, SEQ ID NO:249, SEQ ID NO:251, SEQ ID NO:253, SEQ ID NO:255, SEQ ID NO:257, SEQ ID NO:259, SEQ ID NO:261, or SEQ ID NO:263; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprisingthe nucleotide sequences of SEQ ID NOs:2 / 247, SEQ ID NOs:4 / 249, SEQ ID NOs:6 / 251, SEQ ID NOs:8 / 253, SEQ ID NQs:10 / 255, SEQ ID NOs:12 / 257, SEQ ID NOs:14 / 259, SEQ ID NOs:16 / 261, or SEQ ID NOs:18 / 263; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:246, SEQ ID NO:248, SEQ ID NQ:250, SEQ ID NO:252, SEQ ID NO:254, SEQ ID NO:256, SEQ ID NO:258,

[0050] - 15 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT SEQ ID NO:260, or SEQ ID NO:262; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:l / 246, SEQ ID NOs:3 / 248, SEQ ID NOs:5 / 250, SEQ ID NOs:7 / 252, SEQ ID NOs:9 / 254, SEQ ID NOs:ll / 256, SEQ ID NOs:13 / 258, SEQ ID NQs:15 / 260, or SEQ ID NOs:17 / 262.

[0051] In any of the methods of treatment described herein, the subsequent mtHTT variant or further subsequent mtHTT variant comprises 4:3115441:C:G; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:265, SEQ ID NO:266, SEQ ID NO:268, SEQ ID NO:270, SEQ ID NO:272, SEQ ID NO:274, SEQ ID NO:276, or SEQ ID NO:278; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NQs:20 / 265, SEQ ID NOs:21 / 266, SEQ ID NOs:23 / 268, SEQ ID NQs:25 / 270, SEQ ID NOs:27 / 272, SEQ ID NOs:29 / 274, SEQ ID NOs:31 / 276, or SEQ ID NOs:33 / 278; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT referencespecific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:264, SEQ ID NO:267, SEQ ID NO:269, SEQ ID NO:271, SEQ ID NO:273, SEQ ID NO:275, or SEQ ID NO:277; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT referencespecific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:19 / 264, SEQ ID NOs:22 / 267, SEQ ID NOs:24 / 269, SEQ ID NOs:26 / 271, SEQ ID NOs:28 / 273, SEQ ID NOs:30 / 275, or SEQ ID NOs:32 / 277.

[0052] In any of the methods of treatment described herein, the subsequent mtHTT variant or further subsequent mtHTT variant comprises 4:3160329:C:T; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:279, SEQ ID NQ:280, SEQ ID NO:282, SEQ ID NO:284, SEQ ID NO:286, or SEQ ID NO:287; ii) the

[0053] - 16 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:34 / 279, SEQ ID NOs:35 / 280, SEQ ID NOs:37 / 282, SEQ ID NOs:39 / 284, SEQ ID NOs:41 / 286, or SEQ ID NOs:42 / 287; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:281, SEQ ID NO:283, SEQ ID NO:285, or SEQ ID NO:288; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:36 / 281, SEQ ID NOs:38 / 283, SEQ ID NQs:40 / 285, or SEQ ID NOs:43 / 288.

[0054] In any of the methods of treatment described herein, the subsequent mtHTT variant or further subsequent mtHTT variant comprises 4:3187820:C:A; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:289, SEQ ID NO:291, SEQ ID NO:294, SEQ ID NO:296, or SEQ ID NO:297; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:44 / 289, SEQ ID NOs:46 / 291, SEQ ID NOs:49 / 294, SEQ ID NOs:51 / 296, or SEQ ID NOs:52 / 297; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:290, SEQ ID NO:292, SEQ ID NO:293, SEQ ID NO:295, or SEQ ID NO:298; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NQs:45 / 290, SEQ ID NOs:47 / 292, SEQ ID NOs:48 / 293, SEQ ID NQs:50 / 295, or SEQ ID NOs:53 / 298.

[0055] In any of the methods of treatment described herein, the subsequent mtHTT variant or further subsequent mtHTT variant comprises 4:3212105:G:A; and i) the

[0056] - 17 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT subsequent mtHTT variant reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:299, SEQ ID NQ:300, SEQ ID NO:301, SEQ ID NO:302, or SEQ ID NO:303; or ii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT referencespecific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:54 / 299, SEQ ID NQs:55 / 300, SEQ ID NOs:56 / 301, SEQ ID NOs:57 / 302, or SEQ ID NOs:58 / 303.

[0057] In any of the methods of treatment described herein, the subsequent mtHTT variant or further subsequent mtHTT variant comprises 4:3229934:G:A; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:313, SEQ ID NO:315, SEQ ID NO:316, SEQ ID NO:317, SEQ ID NQ:320, SEQ ID NO:322, or SEQ ID NO:325; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:68 / 313, SEQ ID NOs:70 / 315, SEQ ID NOs:71 / 316, SEQ ID NOs:72 / 317, SEQ ID NOs:75 / 320, SEQ ID NOs:77 / 322, or SEQ ID NOs:80 / 325; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:312, SEQ ID NO:314, SEQ ID NO:318, SEQ ID NO:319, SEQ ID NO:321, SEQ ID NO:323, or SEQ ID NO:324; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:67 / 312, SEQ ID NOs:69 / 314, SEQ ID NOs:73 / 318, SEQ ID NOs:74 / 319, SEQ ID NOs:76 / 321, SEQ ID NOs:78 / 323, or SEQ ID NOs:79 / 324.

[0058] In any of the methods of treatment described herein, the subsequent mtHTT variant or further subsequent mtHTT variant comprises 4:3225692:A:G; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further - 18 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:326, SEQ ID NO:328, or SEQ ID NO:330; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:81 / 326, SEQ ID NOs:83 / 328, or SEQ ID NQs:85 / 330; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT referencespecific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:327, SEQ ID NO:329, SEQ ID NO:331, or SEQ ID NO:332; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:82 / 327, SEQ ID NOs:84 / 329, SEQ ID NOs:86 / 331, or SEQ ID NOs:87 / 332.

[0059] In any of the methods of treatment described herein, the subsequent mtHTT variant or further subsequent mtHTT variant comprises 4:3233253:G:A; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:338, SEQ ID NO:339, SEQ ID NO:341, SEQ ID NO:345, SEQ ID NO:346, SEQ ID NO:349, or SEQ ID NO:351; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:93 / 338, SEQ ID NOs:94 / 339, SEQ ID NOs:96 / 341, SEQ ID NQs:100 / 345, SEQ ID NQs:101 / 346, SEQ ID NOs:104 / 349, or SEQ ID NOs:106 / 351; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:337, SEQ ID NO:340, SEQ ID NO:342, SEQ ID NO:343, SEQ ID NO:344, SEQ ID NO:347, SEQ ID NO:348, or SEQ ID NQ:350; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT referencespecific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide - 19 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT sequences of SEQ ID NOs:92 / 337, SEQ ID NOs:95 / 340, SEQ ID NOs:97 / 342, SEQ ID NOs:98 / 343, SEQ ID NOs:99 / 344, SEQ ID NQs:102 / 347, SEQ ID NQs:103 / 348, or SEQ ID NQs:105 / 350.

[0060] In any of the methods of treatment described herein, the subsequent mtHTT variant or further subsequent mtHTT variant comprises 4:3240373:G:A; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NQ:370, SEQ ID NO:372, SEQ ID NO:373, SEQ ID NO:376, SEQ ID NO:377, or SEQ ID NO:378; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs: 125 / 370, SEQ ID NOs:127 / 372, SEQ ID NOs:128 / 373, SEQ ID NOs:131 / 376, SEQ ID NOs:132 / 377, or SEQ ID NO:133 / 378; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:369, SEQ ID NO:371, SEQ ID NO:374, or SEQ ID NO:375; or iv) the subsequent mtHTT referencespecific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprisingthe nucleotide sequences of SEQ ID NOs:124 / 369, SEQ ID NOs:126 / 371, SEQ ID NOs:129 / 374, or SEQ ID NQs:130 / 375.

[0061] In any of the methods of treatment described herein, the subsequent mtHTT variant or further subsequent mtHTT variant comprises 4:3240433:C:G; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NQ:410 or SEQ ID NO:411; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NQs:165 / 410 or SEQ ID NOs:166 / 411; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule - 20 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:409 or SEQ ID NO:412; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NQs:164 / 409 or SEQ ID NOs:167 / 412.

[0062] In any of the methods of treatment described herein, the subsequent mtHTT variant or further subsequent mtHTT variant comprises 4:3240545:C:A; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:413, SEQ ID NO:415, SEQ ID NO:417, SEQ ID NO:419, SEQ ID NO:421, SEQ ID NO:422, or SEQ ID NO:424; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:168 / 413, SEQ ID NQs:170 / 415, SEQ ID NOs:172 / 417, SEQ ID NOs:174 / 419, SEQ ID NOs:176 / 421, SEQ ID NOs:177 / 422, or SEQ ID NOs:179 / 424; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:414, SEQ ID NO:416, SEQ ID NO:418, SEQ ID NQ:420, or SEQ ID NO:423; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:169 / 414, SEQ ID NOs:171 / 416, SEQ ID NOs:173 / 418, SEQ ID NQs:175 / 420, or SEQ ID NOs:178 / 423.

[0063] In any of the methods of treatment described herein, the subsequent mtHTT variant or further subsequent mtHTT variant comprises 4:3240580:C:T; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:426, SEQ ID NQ:430, SEQ ID NO:432, SEQ ID NO:433, SEQ ID NO:436, SEQ ID NO:438, SEQ ID NO:439, or SEQ ID NO:441; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid - 21 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:181 / 426, SEQ ID NOs:185 / 430, SEQ ID NOs:187 / 432, SEQ ID NOs:188 / 433, SEQ ID NOs:191 / 436, SEQ ID NOs:193 / 438, SEQ ID NOs:194 / 439, or SEQ ID NOs:196 / 441; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT referencespecific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:425, SEQ ID NO:427, SEQ ID NO:428, SEQ ID NO:429, SEQ ID NO:431, SEQ ID NO:434, SEQ ID NO:435, SEQ ID NO:437, SEQ ID NQ:440, or SEQ ID NO:442; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NQs:180 / 425, SEQ ID NOs:182 / 427, SEQ ID NOs:183 / 428, SEQ ID NOs:184 / 429, SEQ ID NOs:186 / 431, SEQ ID NOs:189 / 434, SEQ ID NOs:190 / 435, SEQ ID NOs:192 / 437, SEQ ID NOs:195 / 440, or SEQ ID NOs: 197 / 442.

[0064] In any of the methods of treatment described herein, the subsequent mtHTT variant or further subsequent mtHTT variant comprises 4:3241491:C:T; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:443, SEQ ID NO:445, SEQ ID NO:446, SEQ ID NO:449, SEQ ID NQ:450, SEQ ID NO:452, SEQ ID NO:454, SEQ ID NO:456, or SEQ ID NO:458; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprisingthe nucleotide sequences of SEQ ID NOs:198 / 443, SEQ ID NQs:200 / 445, SEQ ID NQs:201 / 446, SEQ ID NOs:204 / 449, SEQ ID NQs:205 / 450, SEQ ID NQs:207 / 452, SEQ ID NOs:209 / 454, SEQ ID NOs:211 / 456, or SEQ ID NOs:213 / 458; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:444, SEQ ID NO:447, SEQ ID NO:448, SEQ ID NO:451, SEQ ID NO:453, SEQ ID NO:455, SEQ ID NO:457, or SEQ ID NO:459; or iv) the subsequent mtHTT reference-specific inhibitory nucleic - 22 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:199 / 444, SEQ ID NQs:202 / 447, SEQ ID NOs:203 / 448, SEQ ID NQs:206 / 451, SEQ ID NQs:208 / 453, SEQ ID NQs:210 / 455, SEQ ID NOs:212 / 457, or SEQ ID NOs:214 / 459.

[0065] In any of the methods of treatment described herein, the subsequent mtHTT variant or further subsequent mtHTT variant comprises 4:3241563:G:A; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:460, SEQ ID NO:463, SEQ ID NO:465, SEQ ID NO:467, SEQ ID NO:468, SEQ ID NO:469, SEQ ID NO:471, SEQ ID NO:473, SEQ ID NO:475, or SEQ ID NO:477; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NQs:215 / 460, SEQ ID NOs:218 / 463, SEQ ID NQs:220 / 465, SEQ ID NOs:222 / 467, SEQ ID NOs:223 / 468, SEQ ID NOs:224 / 469, SEQ ID NOs:226 / 471, SEQ ID NOs:228 / 473, SEQ ID NQs:230 / 475, or SEQ ID NOs:232 / 477; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT referencespecific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:461, SEQ ID NO:462, SEQ ID NO:464, SEQ ID NO:466, SEQ ID NQ:470, SEQ ID NO:472, SEQ ID NO:474, or SEQ ID NO:476; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:216 / 461, SEQ ID NOs:217 / 462, SEQ ID NOs:219 / 464, SEQ ID NOs:221 / 466, SEQ ID NOs:225 / 470, SEQ ID NOs:227 / 472, SEQ ID NOs:229 / 474, or SEQ ID NOs:231 / 476.

[0066] In any of the methods of treatment described herein, the subsequent mtHTT variant or further subsequent mtHTT variant comprises 4:3243330:C:T; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:478, SEQ - 23 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT ID NO:479, SEQ ID NO:482, SEQ ID NO:484, SEQ ID NO:486, or SEQ ID NO:488; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:233 / 478, SEQ ID NOs:234 / 479, SEQ ID NOs:237 / 482, SEQ ID NOs:239 / 484, SEQ ID NOs:241 / 486, or SEQ ID NOs:243 / 488; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NQ:480, SEQ ID NO:481, SEQ ID NO:483, SEQ ID NO:485, SEQ ID NO:487, SEQ ID NO:489, or SEQ ID NO:490; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NQs:235 / 480, SEQ ID NOs:236 / 481, SEQ ID NOs:238 / 483, SEQ ID NOs:240 / 485, SEQ ID NOs:242 / 487, SEQ ID NOs:244 / 489, or SEQ ID NQs:245 / 490.

[0067] The present disclosure also provides methods of treating a subject having Huntington's disease or at risk of developing Huntington's disease. The subject has a pathogenic mutant huntingtin (mtHTT) allele. The methods comprise performing or having performed a sequence analysis on a biological sample obtained from the subject. The methods comprise determining from the sequence analysis or having determined from the sequence analysis whether the subject is heterozygous for a first mtHTT variant, wherein the first mtHTT variant targeted allele is in phase with the pathogenic mtHTT allele. The first mtHTT variant targeted allele is the alternate allele of the first mtHTT variant and is in phase with the pathogenic mtHTT allele more often than any other allele in a population of subjects. For a subject that is heterozygous for the first mtHTT variant targeted allele in phase with the pathogenic mtHTT allele, the methods comprise administering or continuing to administer a first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule to the subject. For a subject that is homozygous for the first mtHTT variant or heterozygous for the first mtHTT variant but the targeted allele is not in phase with the pathogenic mtHTT allele, the methods comprise determining from the sequence analysis or having determined from the sequence analysis whether the subject is heterozygous for a first subsequent - 24 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT mtHTT variant and heterozygous for a second subsequent mtHTT variant. For a subject that has both the first subsequent mtHTT variant alternate allele and the second subsequent mtHTT variant alternate allele in phase with the pathogenic mtHTT allele, the methods comprise administering or continuing to administer a first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule (i.e., a single inhibitory nucleic acid molecule) to the subject. For a subject that has both the first subsequent mtHTT variant reference allele and the second subsequent mtHTT variant reference allele in phase with the pathogenic mtHTT allele, the methods comprise administering or continuing to administer a first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule to the subject. For the subject that has both the first subsequent mtHTT variant alternate allele and the second subsequent mtHTT variant reference allele in phase with the pathogenic mtHTT allele, the methods comprise administering or continuing to administer a first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule to the subject. For the subject that has both the first subsequent mtHTT variant reference allele and the second subsequent mtHTT variant alternate allele in phase with the pathogenic mtHTT allele, the methods comprise administering or continuing to administer a first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule to the subject. For a subject that is homozygous for either the first subsequent mtHTT variant or the second subsequent mtHTT, the methods comprise determining from the sequence analysis or having determined from the sequence analysis whether the subject is heterozygous for a first further subsequent mtHTT variant and a second further subsequent mtHTT variant until a first further subsequent mtHTT variant and a second further subsequent mtHTT variant is identified for the subject, at which time the methods comprise administering to the subject or continuing to administer to the subject: i) a first further subsequent mtHTT variant alternate allele-specific / second further subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule to the subject that has both the first further subsequent mtHTT variant alternate allele and the second further subsequent mtHTT variant alternate - 25 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT allele in phase with the pathogenic mtHTT allele; or ii) a first further subsequent mtHTT variant reference allele-specific / second further subsequent mtHTT variant reference allelespecific inhibitory nucleic acid molecule to the subject that has both the first further subsequent mtHTT variant reference allele and the second further subsequent mtHTT variant reference allele in phase with the pathogenic mtHTT allele; or iii) a first further subsequent mtHTT variant alternate allele-specific / second further subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule to the subject that has both the first further subsequent mtHTT variant alternate allele and the second further subsequent mtHTT variant reference allele in phase with the pathogenic mtHTT allele; or iv) a first further subsequent mtHTT variant reference allele-specific / second further subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule to the subject that has both the first further subsequent mtHTT variant reference allele and the second further subsequent mtHTT variant alternate allele in phase with the pathogenic mtHTT allele.

[0068] The present disclosure also provides methods of treating a subject having Huntington's disease or at risk of developing Huntington's disease. The subject has a pathogenic mutant huntingtin (mtHTT) allele. For a subject that is heterozygous for a first mtHTT variant targeted allele in phase with the pathogenic mtHTT allele, wherein the first mtHTT variant targeted allele is the alternate allele of the first mtHTT variant and is in phase with the pathogenic mtHTT allele more often than any other allele in a population of subjects, the methods comprise administering a first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule to the subject. For a subject that is homozygous for the first mtHTT variant or heterozygous forthe first mtHTT variant but the targeted allele is not in phase with the pathogenic mtHTT allele, the methods comprise: a) administering or continuing to administer a first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule to the subject that has both the first subsequent mtHTT variant alternate allele and the second subsequent mtHTT variant alternate allele in phase with the pathogenic mtHTT allele; or b) administering or continuing to administer a first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid - 26 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT molecule to the subject that has both the first subsequent mtHTT variant reference allele and the second subsequent mtHTT variant reference allele in phase with the pathogenic mtHTT allele; or c) administering or continuing to administer a first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule to the subject that has both the first subsequent mtHTT variant alternate allele and the second subsequent mtHTT variant reference allele in phase with the pathogenic mtHTT allele; or d) administering or continuing to administer a first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule to the subject that has both the first subsequent mtHTT variant reference allele and the second subsequent mtHTT variant alternate allele in phase with the pathogenic mtHTT allele.

[0069] In any of the methods of treatment described herein, the first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, first further subsequent mtHTT variant alternate allele-specific / second further subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, first further subsequent mtHTT variant reference allele-specific / second further subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, first further subsequent mtHTT variant alternate allele-specific / second further subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, and first further subsequent mtHTT variant reference allele-specific / second further subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule comprise an antisense nucleic acid molecule, a small interfering RNA (siRNA), or a short hairpin RNA (shRNA).

[0070] In any of the methods of treatment described herein, the first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant - 27 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT alternate allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, first further subsequent mtHTT variant alternate allele-specific / second further subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, first further subsequent mtHTT variant reference allele-specific / second further subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, first further subsequent mtHTT variant alternate allele-specific / second further subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, and first further subsequent mtHTT variant reference allele-specific / second further subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule comprise an siRNA.

[0071] In any of the methods of treatment described herein, the first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, first further subsequent mtHTT variant alternate allele-specific / second further subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, first further subsequent mtHTT variant reference allele-specific / second further subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, first further subsequent mtHTT variant alternate allele-specific / second further subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, and first further subsequent mtHTT variant reference allele-specific / second further subsequent mtHTT

[0072] - 28 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT variant alternate allele-specific inhibitory nucleic acid molecule comprise an antisense nucleic acid molecule.

[0073] In any of the methods of treatment described herein, the first mtHTT variant comprises 4:3228683:AGAG:A; and i) the first mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:334, SEQ ID NO:335, or SEQ ID NO:336; or ii) the first mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:89 / 334, SEQ ID NQs:90 / 335, or SEQ ID NOs:91 / 336.

[0074] In any of the methods of treatment described herein, the first subsequent mtHTT variant comprises 4:3240433:C:G and the second subsequent mtHTT variant comprises 4:3240421:C:G, and: i) the first subsequent mtHTT variant alternate-specific / second subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or the first further subsequent mtHTT variant alternate-specific / second further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises: a) an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:394, SEQ ID NO:396, SEQ ID NO:397, SEQ ID NQ:402, SEQ ID NQ:404, or SEQ ID NQ:408; or b) an siRNA comprising the nucleotide sequences of SEQ ID NOs:149 / 394, SEQ ID NOs:151 / 396, SEQ ID NOs:152 / 397, SEQ ID NOs:157 / 402, SEQ ID NOs:159 / 404, or SEQ ID NOs:163 / 408; ii) the first subsequent mtHTT variant reference-specific / second subsequent mtHTT reference-specific inhibitory nucleic acid molecule or the first further subsequent mtHTT variant reference-specific / second further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises: a) an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:398 or SEQ ID NO:405; or b) an siRNA comprisingthe nucleotide sequences of SEQ ID NOs:153 / 398 or SEQ ID NQs:160 / 405; iii) the first subsequent mtHTT variant alternate-specific / second subsequent mtHTT variant reference-specific inhibitory nucleic acid molecule or the first further subsequent mtHTT variant alternate-specific / second further subsequent mtHTT variant reference-specific inhibitory nucleic acid molecule comprises: a) an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:395, SEQ ID NO:399, SEQ ID NQ:401, SEQ ID NQ:403, or SEQ ID - 29 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT NO:407; or b) an siRNA comprisingthe nucleotide sequences of SEQ ID NOs:150 / 395, SEQ ID NOs:154 / 399, SEQ. ID NQs:156 / 401, SEQ ID NQs:158 / 403, or SEQ ID NQs:162 / 407; and iv) the first subsequent mtHTT variant reference-specific / second subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or first further subsequent mtHTT variant reference-specific / second further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises: a) an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NQ:400 or SEQ ID NQ:406; or b) an siRNA comprisingthe nucleotide sequences of SEQ ID NQs:155 / 400 or SEQ ID NQs:161 / 406.

[0075] In some embodiments, the antisense nucleic acid molecule and siRNA hybridize to a sequence within the mtHTT genomic nucleic acid molecule or mRNA molecule and decreases expression of the mtHTT polypeptide in a cell in the subject.

[0076] In some embodiments, the antisense nucleic acid molecules comprise or consist of any of the nucleotide sequences represented by SEQ ID NQs:246-490. In some embodiments, the siRNA molecules comprise or consist of any of the nucleotide sequences represented by SEQ ID NQs:l-490 (e.g., the sense strand is, for example, SEQ ID NO:1 and the corresponding antisense strand is SEQ ID NO:246; the sense strand is, for example, SEQ ID NO:2 and the corresponding antisense strand is SEQ ID NO:247; the sense strand is, for example, SEQ ID NO:245 and the corresponding antisense strand is SEQ ID NQ:490; etc.). Exemplary antisense nucleic acid molecules and siRNA molecules are shown in Table 2.

[0077] Table 2

[0078] SEQ ID Sense Sequence SEQ ID Target Antisense Target SNP Target NO: NO: Sequence Allele 1 GACGGCCGCTCAGG 246 AGCAGAACCUGAGCGGC 3074723 :C>T REF TTCTGCT CGUC

[0079] 2 GACGGCCGCTCAGG 247 AACAG AACC UGAGCGGC 3074723 :C>T ALT TTCTGTT CGUC

[0080] 3 ACGGCCGCTCAGGTT 248 AAGCAGAACCUGAGCGG 3074723 :C>T REF CTGCTT CCGU

[0081] 4 ACGGCCGCTCAGGTT 249 AAACAGAACCUGAGCGG 3074723 :C>T ALT CTGTTT CCGU

[0082] 5 CGGCCGCTCAGGTTC 250 AAAG CAG AACC U G AG CG 3074723 :C>T REF

[0083]

[0084] - 30 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT TGCTTT GCCG

[0085] 6 CGGCCGCTCAGGTTC 251 AAAACAGAACCUGAGCG 3074723 :C>T ALT TGTTTT GCCG

[0086] 7 GGCCGCTCAGGTTCT 252 AAAAG CAG AACC U G AG C 3074723 :C>T REF GCTTTT GGCC

[0087] 8 GGCCGCTCAGGTTCT 253 AAAAACAGAACCUGAGC 3074723 :C>T ALT G l 1 1 1 1 GGCC

[0088] 9 GCCGCTCAGGTTCTG 254 UAAAAGCAGAACCUGAG 3074723 :C>T REF CTTTTA CGGC

[0089] 10 GCCGCTCAGGTTCTG 255 UAAAAACAGAACCUGAG 3074723 :C>T ALT 1 1 1 1 IA CGGC

[0090] 11 CCGCTCAGGTTCTGC 256 GUAAAAGCAGAACCUGA 3074723 :C>T REF TTTTAC GCGG

[0091] 12 CCGCTCAGGTTCTGT 257 G U AAA AACAG AACC U G A 3074723 :C>T ALT TTTTAC GCGG

[0092] 13 CGCTCAGGTTCTGCT 258 G G U AAAAG CAG AACC UG 3074723 :C>T REF TTTACC AGCG

[0093] 14 CGCTCAGGTTCTGTT 259 GG UAAAAACAGAACCUG 3074723 :C>T ALT TTTACC AGCG

[0094] 15 GCTCAGGTTCTGCTT 260 AGGUAAAAGCAGAACCU 3074723 :C>T REF TTACCT GAGC

[0095] 16 GCTCAGGTTCTGTTT 261 AG G U AAAAACAG AACCU 3074723 :C>T ALT TTACCT GAGC

[0096] 17 CTCAGGTTCTGCTTTT 262 CAGGUAAAAGCAGAACC 3074723 :C>T REF ACCTG UGAG

[0097] 18 CTCAGGTTCTG 1 1 1 1 1 263 CAGG U AAAAACAGAACC 3074723 :C>T ALT ACCTG UGAG

[0098] 19 TGGCTACTAAATGTG 264 UAAGAGCACAUUUAGU 3115441:C>G REF CTCTTA AGCCA

[0099] 20 TGGCTACTAAATGTG 265 UAACAGCACAUUUAGU 3115441:C>G ALT CTGTTA AGCCA

[0100] 21 GGCTACTAAATGTGC 266 C U AACAG CACA U U U AG U 3115441:C>G ALT

[0101]

[0102] - 31 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT TGTTAG AGCC

[0103] 22 GCTACTAAATGTGCT 267 CCUAAGAGCACAUUUAG 3115441:C>G REF CTTAGG UAGC

[0104] 23 GCTACTAAATGTGCT 268 CCUAACAGCACAU U U AG 3115441:C>G ALT GTTAGG UAGC

[0105] 24 CTACTAAATGTGCTC 269 GCCUAAGAGCACAUUUA 3115441:C>G REF TTAGGC GUAG

[0106] 25 CTACTAAATGTGCTG 270 GCCUAACAGCACAUUUA 3115441:C>G ALT TTAGGC GUAG

[0107] 26 TACTAAATGTGCTCT 271 AG CC U AAG AG CACA U U U 3115441:C>G REF TAG G CT AGUA

[0108] 27 TACTAAATGTGCTGT m AG CC U AACAG CACA U U U 3115441:C>G ALT TAGGCT AGUA

[0109] 28 ACTAAATGTGCTCTT 273 AAGCCUAAGAGCACAUU 3115441:C>G REF AGGCTT UAGU

[0110] 29 ACTAAATGTGCTGTT 274 AAGCCUAACAGCACAUU 3115441:C>G ALT AGGCTT UAGU

[0111] 30 CTAAATGTGCTCTTA 275 UAAGCCUAAGAGCACAU 3115441:C>G REF GGCTTA UUAG

[0112] 31 CTAAATGTGCTGTTA 276 U AAG CC U AACAG CACAU 3115441:C>G ALT GGCTTA UUAG

[0113] 32 TAAATGTGCTCTTAG TH G UAAGCCU AAGAGCACA 3115441:C>G REF GCTTAC UUUA

[0114] 33 TAAATGTGCTGTTAG 278 GUAAGCCUAACAGCACA 3115441:C>G ALT GCTTAC UUUA

[0115] 34 AAAAGTTTGGAGGG 279 G AAG AAACCCU CCAAAC 3160329:C>T ALT TTTCTTC UUUU

[0116] 35 AGTTTGGAGGGTTTC 280 AGCGAAGAAACCCUCCA 3160329:C>T ALT TTCGCT AACU

[0117] 36 GTTTGGAGGGTTTCT 281 GAGCGGAGAAACCCUCC 3160329:C>T REF CCGCTC AAAC

[0118] 37 GTTTGGAGGGTTTCT 282 GAGCGAAGAAACCCUCC 3160329:C>T ALT

[0119]

[0120] - 32 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT TCGCTC AAAC

[0121] 38 TTTGGAGGGTTTCTC 283 UGAGCGGAGAAACCCUC 3160329:C>T REF CGCTCA CAAA

[0122] 39 TTTGGAGGGTTTCTT 284 U G AG CG AAG AAACCC U C 3160329:C>T ALT CGCTCA CAAA

[0123] 40 TTGGAGGGTTTCTCC 285 CUGAGCGGAGAAACCCU 3160329:C>T REF GCTCAG CCAA

[0124] 41 TTGGAGGGTTTCTTC 286 CUGAGCGAAGAAACCCU 3160329:C>T ALT GCTCAG CCAA

[0125] 42 TGGAGGGTTTCTTCG 287 GCUGAGCGAAGAAACCC 3160329:C>T ALT CTCAGC UCCA

[0126] 43 TGGAGGGTTTCTCCG 288 GCUGAGCGGAGAAACCC 3160329:C>T REF CTCAGC UCCA

[0127] 44 AGATGGGGACAGTA 289 GUUGAAUUACUGUCCC 3187820:C>A ALT ATTCAAC CAUCU

[0128] 45 AGATGGGGACAGTA 290 GUUGAAGUACUGUCCC 3187820:C>A REF CTTCAAC CAUCU

[0129] 46 GATGGGGACAGTAA 291 CGUUGAAUUACUGUCC 3187820:C>A ALT TTCAACG CCAUC

[0130] 47 GATGGGGACAGTAC 292 CGUUGAAGUACUGUCC 3187820:C>A REF TTCAACG CCAUC

[0131] 48 ATGGGGACAGTACTT 293 GCGUUGAAGUACUGUC 3187820:C>A REF CAACGC CCCAU

[0132] 49 ATGGGGACAGTAATT 294 GCGUUGAAUUACUGUC 3187820:C>A ALT CAACGC CCCAU

[0133] 50 TGGGGACAGTACTTC 295 AGCGUUGAAGUACUGU 3187820:C>A REF AACGCT CCCCA

[0134] 51 TGGGGACAGTAATTC 296 AGCGUUGAAUUACUGU 3187820:C>A ALT AACGCT CCCCA

[0135] 52 GGGGACAGTAATTC 297 UAGCGUUGAAUUACUG 3187820:C>A ALT AACGCTA UCCCC

[0136] 53 GGGGACAGTACTTCA 298 UAGCGUUGAAGUACUG 3187820:C>A REF

[0137]

[0138] - 33 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT ACGCTA UCCCC

[0139] 54 CGAGCTGCCTGCAGA 299 GCCGGCUCUGCAGGCAG 3212105:G>A REF GCCGGC CUCG

[0140] 55 GAGCTGCCTGCAGA 300 CGCCGGCUCUGCAGGCA 3212105:G>A REF GCCGGCG GCUC

[0141] 56 AGCTGCCTGCAGAGC 301 CCGCCGGCUCUGCAGGC 3212105:G>A REF CGGCGG AGCU

[0142] 57 GCTGCCTGCAGAGCC 302 GCCGCCGGCUCUGCAGG 3212105:G>A REF GGCGGC CAGC

[0143] 58 TGCCTGCAGAGCCG 303 AGGCCGCCGGCUCUGCA 3212105:G>A REF GCGGCCT GGCA

[0144] 59 CCACGCCTGCTCCCT 304 UAGAUGAGGGAGCAGG 3214108:T>C REF CATCTA CGUGG

[0145] 60 CACGCCTGCTCCCTC 305 GUGGAUGAGGGAGCAG 3214108:T>C ALT ATCCAC GCGUG

[0146] 61 CACGCCTGCTCCCTC 306 GUAGAUGAGGGAGCAG 3214108:T>C REF ATCTAC GCGUG

[0147] 62 ACGCCTGCTCCCTCA 307 AGUGGAUGAGGGAGCA 3214108:T>C ALT TCCACT GGCGU

[0148] 63 CGCCTGCTCCCTCAT 308 CAGUGGAUGAGGGAGC 3214108:T>C ALT CCACTG AGGCG

[0149] 64 GCTCCCTCATCTACT 309 GCACACAGUAGAUGAG 3214108:T>C REF GTGTGC GGAGC

[0150] 65 GCTCCCTCATCCACT 310 GCACACAGUGGAUGAG 3214108:T>C ALT GTGTGC GGAGC

[0151] 66 CTCCCTCATCTACTGT 311 UGCACACAG UAGAUGA 3214108:T>C REF GTGCA GGGAG

[0152] 67 AGCGCAACCAGTTTG 312 UCAGCUCAAACUGGUU 3229934:G>A REF AGCTGA GCGCU

[0153] 68 AGCGCAACCAGTTTG 313 UUAGCUCAAACUGGUU 3229934:G>A ALT AGCTAA GCGCU

[0154] 69 GCGCAACCAGTTTGA 314 AUCAGCUCAAACUGGU 3229934:G>A REF

[0155]

[0156] - 34 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT GCTGAT UGCGC

[0157] 70 GCGCAACCAGTTTGA 315 AUUAGCUCAAACUGGU 3229934:G>A ALT GCTAAT UGCGC

[0158] 71 CGCAACCAGTTTGAG 316 CAUUAGCUCAAACUGG 3229934:G>A ALT CTAATG UUGCG

[0159] 72 GCAACCAGTTTGAGC 317 ACAUUAGCUCAAACUGG 3229934:G>A ALT TAATGT UUGC

[0160] 73 AACCAGTTTGAGCTG 318 AUACAUCAGCUCAAACU 3229934:G>A REF ATGTAT GGUU

[0161] 74 ACCAGTTTGAGCTGA 319 CAUACAUCAGCUCAAAC 3229934:G>A REF TGTATG UGGU

[0162] 75 ACCAGTTTGAGCTAA 320 CAUACAUUAGCUCAAAC 3229934:G>A ALT TGTATG UGGU

[0163] 76 CCAGTTTGAGCTGAT 321 ACAU ACA U CAG C U CAAA 3229934:G>A REF GTATGT CUGG

[0164] 77 CCAGTTTGAGCTAAT 322 ACAUACAUUAGCU CAAA 3229934:G>A ALT GTATGT CUGG

[0165] 78 CAGTTTGAGCTGATG 323 CACAUACAUCAGCUCAA 3229934:G>A REF TATGTG ACUG

[0166] 79 AGTTTGAGCTGATGT 324 UCACAUACAUCAGCUCA 3229934:G>A REF ATGTGA AACU

[0167] 80 AGTTTGAGCTAATGT 325 UCACAUACAUUAGCUCA 3229934:G>A ALT ATGTGA AACU

[0168] 81 AGAAGCTGCTGCTGC 326 UGAUCUGCAGCAGCAGC 3225692:A>G ALT AGATCA UUCU

[0169] 82 AGAAGCTGCTGCTAC 327 UGAUCUGUAGCAGCAG 3225692:A>G REF AGATCA CUUCU

[0170] 83 GAAGCTGCTGCTGCA 328 UUGAUCUGCAGCAGCA 3225692:A>G ALT GATCAA GCUUC

[0171] 84 GAAGCTGCTGCTACA 329 UUGAUCUGUAGCAGCA 3225692:A>G REF GATCAA GCUUC

[0172] 85 AAGCTGCTGCTGCAG 330 GUUGAUCUGCAGCAGC 3225692:A>G ALT

[0173]

[0174] - 35 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT ATCAAC AGCUU

[0175] 86 AAGCTGCTGCTACAG 331 GUUGAUCUGUAGCAGC 3225692:A>G REF ATCAAC AGCUU

[0176] 87 AGCTGCTGCTACAGA 332 GGUUGAUCUGUAGCAG 3225692:A>G REF TCAACC CAGCU

[0177] 88 GAGGAATGGGACGA 333 CUCUUCCUCGUCCCAUU 3228683:AGAG> REF GGAAGAG CCUC A

[0178] 89 AGGAAGAGGAGGAG 334 CGUCGGCCUCCUCCUCU 3228683:AGAG> ALT GCCGACG UCCU A

[0179] 90 GGAAGAGGAGGAG 335 GCGUCGGCCUCCUCCUC 3228683:AGAG> ALT GCCGACGC UUCC A

[0180] 91 GAAGAGGAGGAGGC 336 GGCGUCGGCCUCCUCCU 3228683:AGAG> ALT CGACGCC CUUC A

[0181] 92 GGTTGGAGCCCTGCA 337 ACGCCGUGCAGGGCUCC 3233253:G>A REF CGGCGT AACC

[0182] 93 GGTTGGAGCCCTGCA 338 AUGCCGUGCAGGGCUCC 3233253:G>A ALT CGGCAT AACC

[0183] 94 GTTGGAGCCCTGCAC 339 GAUGCCGUGCAGGGCU 3233253:G>A ALT GGCATC CCAAC

[0184] 95 GTTGGAGCCCTGCAC 340 GACGCCGUGCAGGGCUC 3233253:G>A REF GGCGTC CAAC

[0185] 96 TTGGAGCCCTGCACG 341 GGAUGCCGUGCAGGGC 3233253:G>A ALT GCATCC UCCAA

[0186] 97 TTGGAGCCCTGCACG 342 GGACGCCGUGCAGGGC 3233253:G>A REF GCGTCC UCCAA

[0187] 98 TGGAGCCCTGCACG 343 AGGACGCCGUGCAGGGC 3233253:G>A REF GCGTCCT UCCA

[0188] 99 GGAGCCCTGCACGG 344 GAGGACGCCGUGCAGG 3233253:G>A REF CGTCCTC GCUCC

[0189] 100 GGAGCCCTGCACGG 345 GAGGAUGCCGUGCAGG 3233253:G>A ALT CATCCTC GCUCC

[0190]

[0191] - 36 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT 101 GAGCCCTGCACGGC 346 AGAGGAUGCCGUGCAG 3233253:G>A ALT ATCCTCT GGCUC

[0192] 102 GAGCCCTGCACGGC 347 AGAGGACGCCGUGCAG 3233253:G>A REF GTCCTCT GGCUC

[0193] 103 AGCCCTGCACGGCGT 348 UAGAGGACGCCGUGCA 3233253:G>A REF CCTCTA GGGCU

[0194] 104 AGCCCTGCACGGCAT 349 UAGAGGAUGCCGUGCA 3233253:G>A ALT CCTCTA GGGCU

[0195] 105 CCTGCACGGCGTCCT 350 ACAUAGAGGACGCCGU 3233253:G>A REF CTATGT GCAGG

[0196] 106 CCTGCACGGCATCCT 351 ACAUAGAGGAUGCCGU 3233253:G>A ALT CTATGT GCAGG

[0197] 107 GGAGCCTTTGGAAGT 352 GCACAGACUUCCAAAGG 3240118:C>T ALT CTGTGC CUCC

[0198] 108 GGAGCCTTTGGAAGT 353 GCGCAGACUUCCAAAGG 3240118:C>T REF CTGCGC CUCC

[0199] 109 GAGCCTTTGGAAGTC 354 GGCACAGACUU CCAAAG 3240118:C>T ALT TGTGCC GCUC

[0200] 110 GAGCCTTTGGAAGTC 355 GGCGCAGACUU CCAAAG 3240118:C>T REF TGCGCC GCUC

[0201] 111 AGCCTTTGGAAGTCT 356 GGGCACAGACUUCCAAA 3240118:C>T ALT GTGCCC GGCU

[0202] 112 AGCCTTTGGAAGTCT 357 GGGCGCAGACUUCCAAA 3240118:C>T REF GCGCCC GGCU

[0203] 113 GCCTTTGGAAGTCTG 358 AGGGCGCAGACUUCCAA 3240118:C>T REF CGCCCT AGGC

[0204] 114 CCTTTGGAAGTCTGC 359 AAGGGCGCAGACUUCCA 3240118:C>T REF GCCCTT AAGG

[0205] 115 CCTTTGGAAGTCTGT 360 AAGGGCACAGACUUCCA 3240118:C>T ALT GCCCTT AAGG

[0206] 116 CTTTGGAAGTCTGTG 361 CAAGGGCACAGACUUCC 3240118:C>T ALT CCCTTG AAAG

[0207]

[0208] - 37 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT 117 CTTTGGAAGTCTGCG 362 CAAGGGCGCAGACUUCC 3240118:C>T REF CCCTTG AAAG

[0209] 118 TTTGGAAGTCTGTGC 363 ACAAGGGCACAGACUUC 3240118:C>T ALT CCTTGT CAAA

[0210] 119 TTTGGAAGTCTGCGC 364 ACAAGGGCGCAGACUUC 3240118:C>T REF CCTTGT CAAA

[0211] 120 TTGGAAGTCTGTGCC 365 CACAAGGGCACAGACUU 3240118:C>T ALT CTTGTG CCAA

[0212] 121 TTGGAAGTCTGCGCC 366 CACAAGGGCGCAGACUU 3240118:C>T REF CTTGTG CCAA

[0213] 122 TGGAAGTCTGCGCCC 367 GCACAAGGGCGCAGACU 3240118:C>T REF TTGTGC UCCA

[0214] 123 TGGAAGTCTGTGCCC 368 GCACAAGGGCACAGACU 3240118:C>T ALT TTGTGC UCCA

[0215] 124 GCTGGTTGTTGCCAG 369 UGCAACCUGGCAACAAC 3240373:G>A REF GTTGCA CAGC

[0216] 125 GCTGGTTGTTGCCAG 370 UGUAACCUGG CAACAAC 3240373:G>A ALT GTTACA CAGC

[0217] 126 CTGGTTGTTGCCAGG 371 C U G CAACC UGG CAACAA 3240373:G>A REF TTGCAG CCAG

[0218] 127 CTGGTTGTTGCCAGG 372 C U G U AACC U GG CAACAA 3240373:G>A ALT TTACAG CCAG

[0219] 128 TGGTTGTTGCCAGGT 373 GCUGUAACCUGGCAACA 3240373:G>A ALT TACAGC ACCA

[0220] 129 TGGTTGTTGCCAGGT 374 G C U G CAACC UGG CAACA 3240373:G>A REF TGCAGC ACCA

[0221] 130 GGTTGTTGCCAGGTT 375 AG C U G CAACC UGG CAAC 3240373:G>A REF GCAGCT AACC

[0222] 131 GGTTGTTGCCAGGTT 376 AGCUGUAACCUGGCAAC 3240373:G>A ALT ACAGCT AACC

[0223] 132 GTTGTTGCCAGGTTA 377 CAGCUGUAACCUGGCAA 3240373:G>A ALT CAGCTG CAAC

[0224]

[0225] - 38 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT 133 TGTTGCCAGGTTACA 378 AGCAGCUGUAACCUGGC 3240373:G>A ALT GCTGCT AACA

[0226] 134 CCTCCCTCCTGCAGG 379 AGCCAGCCUGCAGGAGG 3240421:C>G REF CTGGCT GAGG

[0227] 135 CCTCCCTCCTGCAGG 380 ACCCAGCCUGCAGGAGG 3240421:C>G ALT CTGGGT GAGG

[0228] 136 CTCCCTCCTGCAGGC 381 CAGCCAGCCUGCAGGAG 3240421:C>G REF TGGCTG GGAG

[0229] 137 CTCCCTCCTGCAGGC 382 CACCCAGCCUGCAGGAG 3240421:C>G ALT TGGGTG GGAG

[0230] 138 TCCCTCCTGCAGGCT 383 ACAG CCAGCCUGCAGGA 3240421:C>G REF GGCTGT GGGA

[0231] 139 CCCTCCTGCAGGCTG 384 AACACCCAGCCUGCAGG 3240421:C>G ALT GGTGTT AGGG

[0232] 140 CCCTCCTGCAGGCTG 385 AACAGCCAGCCUGCAGG 3240421:C>G REF GCTGTT AGGG

[0233] 141 CCTCCTGCAGGCTGG 386 CAACAGCCAGCCUGCAG 3240421:C>G REF CTGTTG GAGG

[0234] 142 CCTCCTGCAGGCTGG 387 CAACACCCAG CC U G CAG 3240421:C>G ALT GTGTTG GAGG

[0235] 143 CTCCTGCAGGCTGGC 388 CCAACAGCCAGCCUGCA 3240421:C>G REF TGTTGG GGAG

[0236] 144 CTCCTGCAGGCTGGG 389 CCAACACCCAGCCUGCA 3240421:C>G ALT TGTTGG GGAG

[0237] 145 TCCTGCAGG CTGGCT 390 GCCAACAGCCAGCCUGC 3240421:C>G REF GTTGGC AGGA

[0238] 146 CCTGCAGGCTGGCTG 391 GGCCAACAGCCAGCCUG 3240421:C>G REF TTGGCC CAGG

[0239] 147 TGCAGGCTGGGTGTT 392 GGGGCCAACACCCAGCC 3240421:C>G ALT GGCCCC UGCA

[0240] 148 TGCAGGCTGGCTGTT 393 GGGGCCAACAGCCAGCC 3240421:C>G REF GGCCCC UGCA

[0241]

[0242] - 39 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT 149 AGGCTGGGTGTTGG 394 ACAGGGGCCAACACCCA 3240433:C>G, ALT, ALT CCCCTGT GCCU 3240421:C>G 150 GGCTGGCTGTTGGCC 395 CACAGGGGCCAACAGCC 3240433:C>G, ALT, REF CCTGTG AGCC 3240421:C>G

[0243] 151 GGCTGGGTGTTGGC 396 CACAG G GG CCAACACCC 3240433:C>G, ALT, ALT CCCTGTG AGCC 3240421:C>G 152 GCTGGGTGTTGGCCC 397 G CACAG G G G CCAACACC 3240433:C>G, ALT, ALT CTGTGC CAGC 3240421:C>G

[0244] 153 GCTGGCTGTTGGCCC 398 G CAG AG G G G CCAACAG C 3240433:C>G, REF, REF CTCTGC CAGC 3240421:C>G

[0245] 154 GCTGGCTGTTGGCCC 399 G CACAG G G G CCAACAGC 3240433:C>G, ALT, REF CTGTGC CAGC 3240421:C>G

[0246] 155 GCTGGGTGTTGGCCC 400 GCAGAGGGGCCAACACC 3240433:C>G, REF, ALT CTCTGC CAGC 3240421:C>G

[0247] 156 CTGGCTGTTGGCCCC 401 AG CACAG G G G CCAACAG 3240433:C>G, ALT, REF TGTGCT CCAG 3240421:C>G

[0248] 157 CTGGGTGTTGGCCCC 402 AGCACAGGGGCCAACAC 3240433:C>G, ALT, ALT TGTGCT CCAG 3240421:C>G

[0249] 158 TGGCTGTTGGCCCCT 403 CAG CACAG G GG CCAACA 3240433:C>G, ALT, REF GTGCTG GCCA 3240421:C>G

[0250] 159 TGGGTGTTGGCCCCT 404 CAG CACAG G GG CCAACA 3240433:C>G, ALT, ALT GTGCTG CCCA 3240421:C>G

[0251] 160 CTGTTGGCCCCTCTG 405 GGACAGCAGAGGGGCCA 3240433:C>G, REF, REF CTGTCC ACAG 3240421:C>G

[0252] 161 GTGTTGGCCCCTCTG 406 GGACAGCAGAGGGGCCA 3240433:C>G, REF, ALT CTGTCC ACAC 3240421:C>G

[0253] 162 CTGTTGGCCCCTGTG 407 GGACAGCACAGGGGCCA 3240433:C>G, ALT, REF CTGTCC ACAG 3240421:C>G

[0254] 163 GTGTTGGCCCCTGTG 408 GGACAGCACAGGGGCCA 3240433:C>G, ALT, ALT CTGTCC ACAC 3240421:C>G

[0255] 164 TGTTGGCCCCTCTGC 409 AGGACAGCAGAGGGGCC 3240433:C>G REF TGTCCT AACA

[0256]

[0257] - 40 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT 165 TGTTGGCCCCTGTGC 410 AGGACAGCACAGGGGCC 3240433:C>G ALT TGTCCT AACA

[0258] 166 GTTGGCCCCTGTGCT 411 CAGGACAGCACAGGGGC 3240433:C>G ALT GTCCTG CAAC

[0259] 167 GTTGGCCCCTCTGCT 412 CAGGACAGCAGAGGGGC 3240433:C>G REF GTCCTG CAAC

[0260] 168 GATGCACAGATGCCA 413 AUGCCAUGGCAUCUGU 3240545 :C>A ALT TGGCAT GCAUC

[0261] 169 ATGCACAGATGCCAT 414 CAGGCCAUGGCAUCUG 3240545 :C>A REF GGCCTG UGCAU

[0262] 170 ATGCACAGATGCCAT 415 CAUGCCAUGGCAUCUG 3240545 :C>A ALT GGCATG UGCAU

[0263] 171 TGCACAGATGCCATG 416 ACAGGCCAUGGCAUCUG 3240545 :C>A REF GCCTGT UGCA

[0264] 172 TGCACAGATGCCATG 417 ACAUGCCAUGGCAUCUG 3240545 :C>A ALT GCATGT UGCA

[0265] 173 GCACAGATGCCATG 418 CACAGGCCAUGGCAUCU 3240545 :C>A REF GCCTGTG GUGC

[0266] 174 GCACAGATGCCATG 419 CACAUGCCAUGGCAUCU 3240545 :C>A ALT GCATGTG GUGC

[0267] 175 CACAGATGCCATGGC 420 GCACAGGCCAUGGCAUC 3240545 :C>A REF CTGTGC UGUG

[0268] 176 CACAGATGCCATGGC 421 GCACAUGCCAUGGCAUC 3240545 :C>A ALT ATGTGC UGUG

[0269] 177 ACAGATGCCATGGCA 422 AGCACAUGCCAUGGCAU 3240545 :C>A ALT TGTGCT CUGU

[0270] 178 CAGATGCCATGGCCT 423 CAGCACAG G CCA U G G CA 3240545 :C>A REF GTGCTG UCUG

[0271] 179 CAGATGCCATGGCAT 424 CAGCACAUGCCAUGGCA 3240545 :C>A ALT GTGCTG UCUG

[0272] 180 GCTGGGGGTGCTAG 425 CGGGUGUCUAGCACCCC 3240580:C>T REF ACACCCG CAGC

[0273]

[0274] - 41 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT 181 GCTGGGGGTGCTAG 426 CAGG UG UCU AGCACCCC 3240580:C>T ALT ACACCTG CAGC

[0275] 182 CTGGGGGTGCTAGA 427 CCGGGUGUCUAGCACCC 3240580:C>T REF CACCCGG CCAG

[0276] 183 TGGGGGTGCTAGAC 428 GCCGGGUGUCUAGCACC 3240580:C>T REF ACCCGGC CCCA

[0277] 184 GGGGGTGCTAGACA 429 UGCCGGGUGUCUAGCA 3240580:C>T REF CCCGGCA CCCCC

[0278] 185 GGGGGTGCTAGACA 430 UGCCAGGUGUCUAGCA 3240580:C>T ALT CCTGGCA CCCCC

[0279] 186 GGGGTGCTAGACAC 431 GUGCCGGGUGUCUAGC 3240580:C>T REF CCGGCAC ACCCC

[0280] 187 GGGGTGCTAGACAC 432 GUGCCAGGUGUCUAGC 3240580:C>T ALT CTGGCAC ACCCC

[0281] 188 GGGTGCTAGACACCT 433 GGUGCCAGGUGUCUAG 3240580:C>T ALT GGCACC CACCC

[0282] 189 GGGTGCTAGACACCC 434 GGUGCCGGGUGUCUAG 3240580:C>T REF GGCACC CACCC

[0283] 190 GGTGCTAGACACCCG 435 UGGUGCCGGGUGUCUA 3240580:C>T REF GCACCA GCACC

[0284] 191 GGTGCTAGACACCTG 436 UGGUGCCAGGUGUCUA 3240580:C>T ALT GCACCA GCACC

[0285] 192 GTGCTAGACACCCGG 437 AUGGUGCCGGGUGUCU 3240580:C>T REF CACCAT AGCAC

[0286] 193 GTGCTAGACACCTGG 438 AUGGUGCCAGGUGUCU 3240580:C>T ALT CACCAT AGCAC

[0287] 194 TGCTAGACACCTGGC 439 AAUGGUGCCAGGUGUC 3240580:C>T ALT ACCATT UAGCA

[0288] 195 TGCTAGACACCCGGC 440 AAUGGUGCCGGGUGUC 3240580:C>T REF ACCATT UAGCA

[0289] 196 GCTAGACACCTGGCA 441 GAAUGGUGCCAGGUGU 3240580:C>T ALT CCATTC CUAGC

[0290]

[0291] - 42 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT 197 GCTAGACACCCGGCA 442 GAAUGGUGCCGGGUGU 3240580:C>T REF CCATTC CUAGC

[0292] 198 ATTTGGGAGCTCTGC 443 CAG CAAG CAG AGCU CCC 3241491:C>T ALT TTGCTG AAAU

[0293] 199 TTGGGAGCTCTGCTT 444 GUCGGCAAGCAGAGCUC 3241491:C>T REF GCCGAC CCAA

[0294] 200 TTGGGAGCTCTGCTT 445 G U CAG CAAG C AG AG C U C 3241491:C>T ALT GCTGAC CCAA

[0295] 201 TGGGAGCTCTGCTTG 446 AGUCAGCAAGCAGAGCU 3241491:C>T ALT CTGACT CCCA

[0296] 202 TGGGAGCTCTGCTTG 447 AG U CG G CAAG CAG AG C 3241491:C>T REF CCGACT UCCCA

[0297] 203 GGGAGCTCTGCTTGC 448 CAGUCGGCAAGCAGAGC 3241491:C>T REF CGACTG UCCC

[0298] 204 GGGAGCTCTGCTTGC 449 CAG U CAG CAAG CAG AG C 3241491:C>T ALT TGACTG UCCC

[0299] 205 GGAGCTCTGCTTGCT 450 CCAG U CAG CAAG CAG AG 3241491:C>T ALT GACTGG CUCC

[0300] 206 GGAGCTCTGCTTGCC 451 CCAG U CG G CAAG CAG AG 3241491:C>T REF GACTGG CUCC

[0301] 207 GAGCTCTGCTTGCTG 452 GCCAGUCAGCAAGCAGA 3241491:C>T ALT ACTGGC GCUC

[0302] 208 GAGCTCTGCTTGCCG 453 GCCAGUCGGCAAGCAGA 3241491:C>T REF ACTGGC GCUC

[0303] 209 AGCTCTGCTTGCTGA 454 AG CCAG U CAG CAAG CAG 3241491:C>T ALT CTGGCT AGCU

[0304] 210 AGCTCTGCTTGCCGA 455 AG CCAG U CG GCAAG CAG 3241491:C>T REF CTGGCT AGCU

[0305] 211 GCTCTGCTTGCTGAC 456 CAGCCAGUCAGCAAGCA 3241491:C>T ALT TGGCTG GAGC

[0306] 212 GCTCTGCTTGCCGAC 457 CAGCCAG U CG G CAAG CA 3241491:C>T REF TGGCTG GAGC

[0307]

[0308] - 43 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT 213 CTCTGCTTGCTGACT 458 ACAG CCAG U CAG CAAGC 3241491:C>T ALT GGCTGT AGAG

[0309] 214 CTCTGCTTGCCGACT 459 ACAGCCAGUCGGCAAGC 3241491:C>T REF GGCTGT AGAG

[0310] 215 CCAGGCAAGGTTGG 460 AUAGUCGCCAACCUUGC 3241563:G>A ALT CGACTAT CUGG

[0311] 216 CCAGGCAAGGTTGG 461 ACAGUCGCCAACCUUGC 3241563:G>A REF CGACTGT CUGG

[0312] 217 CAGGCAAGGTTGGC 462 GACAG UCGCCAACCU UG 3241563:G>A REF GACTGTC CCUG

[0313] 218 CAGGCAAGGTTGGC 463 GAUAGUCGCCAACCUUG 3241563:G>A ALT GACTATC CCUG

[0314] 219 AGGCAAGGTTGGCG 464 UG ACAG UCGCCAACCU U 3241563:G>A REF ACTGTCA GCCU

[0315] 220 AGGCAAGGTTGGCG 465 UGAUAGUCGCCAACCUU 3241563:G>A ALT ACTATCA GCCU

[0316] 221 GGCAAGGTTGGCGA 466 AUGACAGUCGCCAACCU 3241563:G>A REF CTGTCAT UGCC

[0317] 222 GGCAAGGTTGGCGA 467 AUGAUAGUCGCCAACCU 3241563:G>A ALT CTATCAT UGCC

[0318] 223 GCAAGGTTGGCGAC 468 CAUGAUAGUCGCCAACC 3241563:G>A ALT TATCATG UUGC

[0319] 224 CAAGGTTGGCGACTA 469 ACAUGAUAGUCGCCAAC 3241563:G>A ALT TCATGT CUUG

[0320] 225 AAGGTTGGCGACTGT 470 CACAU GACAG U CGCCAA 3241563:G>A REF CATGTG CCUU

[0321] 226 AAGGTTGGCGACTAT 471 CACAUGAUAGUCG CCAA 3241563:G>A ALT CATGTG CCUU

[0322] 227 AGGTTGGCGACTGTC 472 CCACAUGACAGUCGCCA 3241563:G>A REF ATGTGG ACCU

[0323] 228 AGGTTGGCGACTATC 473 CCACAUGAUAGUCGCCA 3241563:G>A ALT ATGTGG ACCU

[0324]

[0325] - 44 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT 229 GGTTGGCGACTGTCA 474 GCCACAUGACAGUCGCC 3241563:G>A REF TGTGGC AACC

[0326] 230 GGTTGGCGACTATCA 475 GCCACAUGAUAGUCGCC 3241563:G>A ALT TGTGGC AACC

[0327] 231 GTTGGCGACTGTCAT 476 AGCCACAUGACAGUCGC 3241563:G>A REF GTGGCT CAAC

[0328] 232 GTTGGCGACTATCAT 477 AGCCACAUGAUAGUCGC 3241563:G>A ALT GTGGCT CAAC

[0329] 233 CCCCCGCTTCCTCCCT 478 CACAGAGGGAGGAAGC 3243330:C>T ALT CTGTG GGGGG

[0330] 234 CCCGCTTCCTCCCTCT 479 CCCACAGAGGGAGGAAG 3243330:C>T ALT GTGGG CGGG

[0331] 235 CCCGCTTCCTCCCTCT 480 CCCGCAGAGGGAGGAAG 3243330:C>T REF GCGGG CGGG

[0332] 236 CCGCTTCCTCCCTCTG 481 CCCCGCAGAGGGAGGAA 3243330:C>T REF CGGGG GCGG

[0333] 237 CGCTTCCTCCCTCTGT 482 UCCCCACAGAGGGAGGA 3243330:C>T ALT GGGGA AGCG

[0334] 238 GCTTCCTCCCTCTGC 483 CUCCCCGCAGAGGGAGG 3243330:C>T REF GGGGAG AAGC

[0335] 239 GCTTCCTCCCTCTGTG 484 CUCCCCACAGAGGGAGG 3243330:C>T ALT GGGAG AAGC

[0336] 240 CTTCCTCCCTCTGCG 485 CCUCCCCGCAGAGGGAG 3243330:C>T REF GGGAGG GAAG

[0337] 241 CTTCCTCCCTCTGTGG 486 CCUCCCCACAGAGGGAG 3243330:C>T ALT GGAGG GAAG

[0338] 242 TTCCTCCCTCTGCGG 487 UCCUCCCCGCAGAGGGA 3243330:C>T REF GGAGGA GGAA

[0339] 243 TTCCTCCCTCTGTGG 488 UCCUCCCCACAGAGGGA 3243330:C>T ALT GGAGGA GGAA

[0340] 244 TCCTCCCTCTGCGGG 489 GUCCUCCCCGCAGAGGG 3243330:C>T REF GAGGAC AGGA

[0341]

[0342] - 45 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT 245 CCTCCCTCTGCGGGG 490 GGUCCUCCCCGCAGAGG 3243330:C>T REF AGGACC GAGG

[0343]

[0344] Although the seqences listed in Table 2 are written as DNA sequences, the corresponding sequences can be in the form of RNA as well.

[0345] The inhibitory nucleic acid molecules can comprise RNA, DNA, or both RNA and DNA. The inhibitory nucleic acid molecules can also be linked or fused to a heterologous nucleic acid sequence, such as in a vector, or a heterologous label. For example, the inhibitory nucleic acid molecules can be within a vector or as an exogenous donor sequence comprising the inhibitory nucleic acid molecule and a heterologous nucleic acid sequence. The inhibitory nucleic acid molecules can also be linked or fused to a heterologous label. The label can be directly detectable (such as, for example, fluorophore) or indirectly detectable (such as, for example, hapten, enzyme, or fluorophore quencher). Such labels can be detectable by spectroscopic, photochemical, biochemical, immunochemical, or chemical means. Such labels include, for example, radiolabels, pigments, dyes, chromogens, spin labels, and fluorescent labels. The label can also be, for example, a chemiluminescent substance; a metal-containing substance; or an enzyme, where there occurs an enzymedependent secondary generation of signal. The term "label" can also refer to a "tag" or hapten that can bind selectively to a conjugated molecule such that the conjugated molecule, when added subsequently along with a substrate, is used to generate a detectable signal. For example, biotin can be used as a tag along with an avidin or streptavidin conjugate of horseradish peroxidate (HRP) to bind to the tag, and examined using a calorimetric substrate (such as, for example, tetra methylbenzidine (TMB)) or a fluorogenic substrate to detect the presence of HRP. Exemplary labels that can be used as tags to facilitate purification include, but are not limited to, myc, HA, FLAG or 3XFLAG, 6XHis or polyhistidine, glutathione-S-transferase (GST), maltose binding protein, an epitope tag, or the Fc portion of immunoglobulin. Numerous labels include, for example, particles, fluorophores, haptens, enzymes and their calorimetric, fluorogenic and chemiluminescent substrates and other labels.

[0346] - 46 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT The inhibitory nucleic acid molecules can comprise, for example, nucleotides or non-natural or modified nucleotides, such as nucleotide analogs or nucleotide substitutes. Such nucleotides include a nucleotide that contains a modified base, sugar, or phosphate group, or that incorporates a non-natural moiety in its structure. Examples of non-natural nucleotides include, but are not limited to, dideoxynucleotides, biotinylated, aminated, deaminated, alkylated, benzylated, and fluorophor-labeled nucleotides.

[0347] The inhibitory nucleic acid molecules can also comprise one or more nucleotide analogs or substitutions. A nucleotide analog is a nucleotide which contains a modification to either the base, sugar, or phosphate moieties. Modifications to the base moiety include, but are not limited to, natural and synthetic modifications of A, C, G, and T / U, as well as different purine or pyrimidine bases such as, for example, pseudouridine, u racil-5-y I, hypoxanthin-9-yl (I), and 2-aminoadenin-9-yl. Modified bases include, but are not limited to, 5-methylcytosine (5-me-C), 5-hydroxymethyl cytosine, xanthine, hypoxanthine,

[0348] 2-aminoadenine, 6-methyl and other alkyl derivatives of adenine and guanine, 2-propyl and other alkyl derivatives of adenine and guanine, 2-thiouracil, 2-thiothymine and

[0349] 2-thiocytosine, 5-halouracil and cytosine, 5-propynyl uracil and cytosine, 6-azo uracil, cytosine and thymine, 5-uracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-th iol, 8-thioalkyl, 8-hydroxyl and other 8-substituted adenines and guanines, 5-halo (such as, for example, 5-bromo), 5-trifluoromethyl and other 5-substituted uracils and cytosines, 7-methylguanine, 7-methyladenine, 8-azaguanine, 8-azaadenine, 7-deazaguanine,

[0350] 7-deazaadenine, 3-deazaguanine, and 3-deazaadenine.

[0351] Nucleotide analogs can also include modifications of the sugar moiety.

[0352] Modifications to the sugar moiety include, but are not limited to, natural modifications of the ribose and deoxy ribose as well as synthetic modifications. Sugar modifications include, but are not limited to, the following modifications at the 2' position: OH; F; O-, S-, or N-alkyl; O-, S-, or N-alkenyl; O-, S- or N-alkynyl; or O-a I kyl-O-a I kyl, wherein the alkyl, alkenyl, and alkynyl may be substituted or unsubstituted Ci-ioalkyl or Ci-ioalkenyl, and Cz-ioalkynyl.

[0353] Exemplary 2' sugar modifications also include, but are not limited to, -O[(CH2)nO]mCH3,

[0354] - 47 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT -O(CH2)nOCH3, -O(CH2)nNH2, -O(CH2)nCH3, -O(CH2)n-ONH2, and -O(CH2)nON[(CH2)nCH3)]2, where n and m, independently, are from 1 to about 10. Other modifications at the 2' position include, but are not limited to, Ci-walkyl, substituted lower alkyl, alkaryl, aralkyl, O-alkaryl or O-aralkyl, SH, SCH3, OCN, Cl, Br, CN, CF3, OCF3, SOCH3, SO2CH3, ONO2, NO2, N3, NH2, heterocycloalkyl, heterocycloalkaryl, aminoalkylamino, polyalkylamino, substituted silyl, an RNA cleaving group, a reporter group, an intercalator, a group for improving the pharmacokinetic properties of an oligonucleotide, or a group for improving the pharmacodynamic properties of an oligonucleotide, and other substituents having similar properties. Similar modifications may also be made at other positions on the sugar, particularly the 3' position of the sugar on the 3' terminal nucleotide or in 2'-5' linked oligonucleotides and the 5' position of 5' terminal nucleotide. Modified sugars can also include those that contain modifications at the bridging ring oxygen, such as CH2and S. Nucleotide sugar analogs can also have sugar mimetics, such as cyclobutyl moieties in place ofthe pentofuranosyl sugar.

[0355] Nucleotide analogs can also be modified at the phosphate moiety. Modified phosphate moieties include, but are not limited to, those that can be modified so that the linkage between two nucleotides contains a phosphorothioate, chiral phosphorothioate, phosphorodithioate, phosphotriester, aminoalkylphosphotriester, methyl and other alkyl phosphonates including 3' -alkylene phosphonate and chiral phosphonates, phosphinates, phosphoramidates including 3'-amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters, and boranophosphates. These phosphate or modified phosphate linkage between two nucleotides can be through a 3'-5' linkage or a 2'-5' linkage, and the linkage can contain inverted polarity such as 3'-5' to 5'-3' or 2'-5' to 5'-2'. Various salts, mixed salts, and free acid forms are also included. Nucleotide substitutes also include peptide nucleic acids (PNAs).

[0356] In some embodiments, the antisense nucleic acid molecules are gapmers, whereby the first one to seven nucleotides at the 5' and 3' ends each have 2'-methoxyethyl (2'-MOE) modifications. In some embodiments, the first five nucleotides at the 5' and 3' ends each have 2'-MOE modifications. In some embodiments, the first one to seven nucleotides at the - 48 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT 5' and 3' ends are RNA nucleotides. In some embodiments, the first five nucleotides at the 5' and 3' ends are RNA nucleotides. In some embodiments, each of the backbone linkages between the nucleotides is a phosphorothioate linkage.

[0357] In some embodiments, the siRNA molecules have termini modifications. In some embodiments, the 5' end of the antisense strand is phosphorylated. In some embodiments, 5'-phosphate analogs that cannot be hydrolyzed, such as 5'-(E)-vinyl-phosphonate are used.

[0358] In some embodiments, the siRNA molecules have backbone modifications. In some embodiments, the modified phosphodiester groups that link consecutive ribose nucleosides have been shown to enhance the stability and in vivo bioavailability of siRNAs The non-ester groups (-OH, =0) of the phosphodiester linkage can be replaced with sulfur, boron, or acetate to give phosphorothioate, boranophosphate, and phosphonoacetate linkages. In addition, substituting the phosphodiester group with a phosphotriester can facilitate cellular uptake of siRNAsand retention on serum components by eliminating their negative charge. In some embodiments, the siRNA molecules have sugar modifications. In some embodiments, the sugars are deprotonated (reaction catalyzed by exo- and endonucleases) whereby the 2'-hydroxyl can act as a nucleophile and attack the adjacent phosphorous in the phosphodiester bond. Such alternatives include 2'-O-methyl, 2'-0-methoxyethyl, and 2' -fluoro modifications.

[0359] In some embodiments, the siRNA molecules have base modifications. In some embodiments, the bases can be substituted with modified bases such as pseudouridine, 5'-methylcytidine, N6-methyladenosine, inosine, and N7-methylguanosine.

[0360] In some embodiments, the siRNA molecules are conjugated to lipids. Lipids can be conjugated to the 5' or 3' termini of siRNA to improve their in vivo bioavailability by allowing them to associate with serum lipoproteins. Representative lipids include, but are not limited to, cholesterol and vitamin E, and fatty acids, such as palmitate and tocopherol.

[0361] In some embodiments, a representative siRNA has the following formula:

[0362] Sense: mN*mN Vi2FN / mN / i2FN / mN / i2FN / mN / i2FN / mN / i2FN / mN / i2FN / mN / i2FN / mN / i2FN / *mN* / 32FN /

[0363] Antisense: / 52FN / * / i2FN / *mN / i2FN / mN / i2FN / mN / i2FN / mN / i2FN / mN / i2FN / mN / i2FN / mN / i2FN / mN / i2FN / mN*N*N

[0364] - 49 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT wherein: "N" is the base; "2F" is a 2'-F modification; "m" is a 2'-O-methyl modification, "I" is an internal base; and "*" is a phosphorothioate backbone linkage.

[0365] In any of the embodiments described herein, the inhibitory nucleic acid molecules may be administered, for example, as one- to two-hour i.v. infusions or s.c. injections. In any of the embodiments described herein, the inhibitory nucleic acid molecules may be administered at dose levels that range from about 50 mg to about 900 mg, from about 100 mg to about 800 mg, from about 150 mg to about 700 mg, or from about 175 mg to about 640 mg (2.5 to 9.14 mg / kg; 92.5 to 338 mg / m2- based on an assumption of a body weight of 70 kg and a conversion of mg / kg to mg / m2dose levels based on a mg / kg dose multiplier value of 37 for humans).

[0366] The present disclosure also provides vectors comprising any one or more of the inhibitory nucleic acid molecules. In some embodiments, the vectors comprise any one or more of the inhibitory nucleic acid molecules and a heterologous nucleic acid. The vectors can be viral or nonviral vectors capable of transporting a nucleic acid molecule. In some embodiments, the vector is a plasmid or cosmid (such as, for example, a circular doublestranded DNA into which additional DNA segments can be ligated). In some embodiments, the vector is a viral vector, wherein additional DNA segments can be ligated into the viral genome. Expression vectors include, but are not limited to, plasmids, cosmids, retroviruses, adenoviruses, adeno-associated viruses (AAV), plant viruses such as cauliflower mosaic virus and tobacco mosaic virus, yeast artificial chromosomes (YACs), Epstein-Barr (EBV)-derived episomes, and other expression vectors known in the art.

[0367] The present disclosure also provides compositions comprising any one or more of the inhibitory nucleic acid molecules. In some embodiments, the composition is a pharmaceutical composition. In some embodiments, the compositions comprise a carrier and / or excipient. Examples of carriers include, but are not limited to, poly(lactic acid) (PLA) microspheres, poly(D,L-lactic-coglycolic-acid) (PLGA) microspheres, liposomes, micelles, inverse micelles, lipid cochleates, and lipid microtubules. A carrier may comprise a buffered salt solution such as PBS, HBSS, etc.

[0368] In any of the embodiments described herein, the inhibitory nucleic acid molecules specifically detect and / or identify a target sequence. The inhibitory nucleic acid molecules - 50 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT described herein may have complete nucleotide sequence identity of contiguous nucleotides within the target nucleotide sequence, although inhibitory nucleic acid molecules differing from the target nucleotide sequence and that retain the ability to specifically detect and / or identify a target nucleotide sequence may be designed by conventional methods. The inhibitory nucleic acid molecules described herein may have about 80%, about 85%, about 90%, about 91%, about 92%, about 93%, about 94%, about 95%, about 96%, about 97%, about 98%, about 99%, or 100% sequence identity or complementarity with the nucleotide sequences shown in Table 2.

[0369] Detecting the presence or absence of any of the mtHTT variants described herein in a biological sample from a subject and / or determining whether a subject has an mtHTT variant nucleic acid molecule can be carried out by any of the methods described herein. In some embodiments, these methods can be carried out in vitro. In some embodiments, these methods can be carried out in situ. In some embodiments, these methods can be carried out in vivo. In any of these embodiments, the nucleic acid molecule can be present within a cell obtained from the subject.

[0370] In any of the methods described herein, the subject may also be administered a Huntington's disease therapeutic agent. In some embodiments, the Huntington's disease therapeutic agent comprises an antipsychotic used for movement and other symptoms. In some embodiments, the Huntington's disease therapeutic agent includes, but is not limited to, deutetrabenazine, fluphenazine, haloperidol, tetrabenazine, tiapride, valbenazine, risperidone, olanzapine, cysteamine (such as cysteamine bitartrate), and aripiprazole, or any combination thereof.

[0371] The present disclosure also provides compositions comprising a combination of any ofthe inhibitory nucleic acid molecules described herein and any of the Huntington's disease therapeutic agents described herein.

[0372] Administration ofthe Huntington's disease therapeutic agents and / or inhibitory nucleic acid molecules can be repeated, for example, after one day, two days, three days, five days, one week, two weeks, three weeks, one month, five weeks, six weeks, seven weeks, eight weeks, two months, or three months. The repeated administration can be at the same dose or at a different dose. The administration can be repeated once, twice, three - 51 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT times, four times, five times, six times, seven times, eight times, nine times, ten times, or more. For example, according to certain dosage regimens a subject can receive therapy for a prolonged period of time such as, for example, 6 months, 1 year, or more.

[0373] Administration of the Huntington's disease therapeutic agents and / or inhibitory nucleic acid molecules can occur by any suitable route including, but not limited to, parenteral, intravenous, oral, subcutaneous, intra-arterial, intracranial, intrathecal, intraperitoneal, topical, intranasal, or intramuscular. Pharmaceutical compositions for administration are desirably sterile and substantially isotonic and manufactured under GMP conditions. Pharmaceutical compositions can be provided in unit dosage form (i.e., the dosage for a single administration). Pharmaceutical compositions can be formulated using one or more physiologically and pharmaceutically acceptable carriers, diluents, excipients, or auxiliaries. The formulation depends on the route of administration chosen. The term "pharmaceutically acceptable" means that the carrier, diluent, excipient, or auxiliary is compatible with the other ingredients of the formulation and not substantially deleterious to the recipient thereof.

[0374] The terms "treat", "treating", and "treatment" and "prevent", "preventing", and "prevention" as used herein, refer to eliciting the desired biological response, such as a therapeutic and prophylactic effect, respectively. In some embodiments, a therapeutic effect comprises one or more of a decrease / reduction in Huntington's disease, a decrease / reduction in the severity of Huntington's disease (such as, for example, a reduction or inhibition of development of Huntington's disease), a decrease / reduction in symptoms and disease-related effects, delaying the onset of symptoms and disease-related effects, reducing the severity of symptoms of disease-related effects, reducing the number of symptoms and disease-related effects, reducing the latency of symptoms and disease-related effects, an amelioration of symptomsand disease-related effects, reducing secondary symptoms, reducing secondary infections, preventing relapse to Huntington's disease, decreasing the number or frequency of relapse episodes, increasing latency between symptomatic episodes, increasing time to sustained progression, speeding recovery, or increasing efficacy of or decreasing resistance to alternative therapeutics, and / or an increased survival time of the affected host animal, following administration of - 52 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT the agent or composition comprising the agent. A prophylactic effect may comprise a complete or partial avoidance / inhibition or a delay of Huntington's disease development / progression (such as, for example, a complete or partial avoidance / inhibition or a delay), and an increased survival time of the affected host animal, following administration of a therapeutic protocol. Treatment of Huntington's disease encompasses the treatment of a subject already diagnosed as having any form of Huntington's disease at any clinical stage or manifestation, the delay of the onset or evolution or aggravation or deterioration of the symptoms or signs of Huntington's disease, and / or preventing and / or reducing the severity of Huntington's disease.

[0375] In some embodiments, the inhibitory nucleic acid molecule and the Huntington's disease therapeutic agent are disposed within a pharmaceutical composition. In some embodiments, the inhibitory nucleic acid molecule is disposed within a first pharmaceutical composition and the Huntington's disease therapeutic agent is disposed within a second pharmaceutical composition. In some embodiments, the first pharmaceutical composition and the second pharmaceutical composition are administered simultaneously. In some embodiments, the first pharmaceutical composition is administered before the second pharmaceutical composition. In some embodiments, the first pharmaceutical composition is administered after the second pharmaceutical composition.

[0376] The present disclosure provides methods of identifying a subject having Huntington's disease or at risk of developing Huntington's disease that is a candidate for treatment with an inhibitory nucleic acid molecule. The subject has a pathogenic mutant huntingtin (mtHTT) allele. The methods comprise performing or having performed a sequence analysis on a biological sample obtained from the subject. In some embodiments, the methods comprise determining from the sequence analysis or having determined from the sequence analysis whether the subject is heterozygous for a first mtHTT variant, wherein a first mtHTT variant targeted allele is in phase with the pathogenic mtHTT allele, wherein the first mtHTT variant targeted allele is the alternate allele of the first mtHTT variant and is in phase with the pathogenic mtHTT allele more often than any other allele in a population of subjects. Such a subject is a candidate for treatment with a first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule when the subject is

[0377] - 53 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT heterozygous for the first mtHTT variant targeted allele in phase with the pathogenic mtHTT allele. In some embodiments, for a subject that is homozygous for the first mtHTT variant, or heterozygous for the first mtHTT variant but the targeted allele is not in phase with the pathogenic mtHTT allele, the methods comprise determining from the sequence analysis or having determined from the sequence analysis whetherthe subject is heterozygous for a subsequent mtHTT variant in which the alternate allele or reference allele is in phase with the pathogenic mtHTT allele. Such a subject is a candidate for treatment with a subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule or a subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, whichever is in phase with the pathogenic mtHTT allele, when the subject is heterozygous for the subsequent mtHTT variant.

[0378] The present disclosure also provides methods of identifying a subject having Huntington's disease or at risk of developing Huntington's disease that is a candidate for treatment with an inhibitory nucleic acid molecule. The subject has a pathogenic mutant huntingtin (mtHTT) allele. The methods comprise performing or having performed a sequence analysis on a biological sample obtained from the subject. In some embodiments, the methods comprise determining from the sequence analysis or having determined from the sequence analysis whether the subject is heterozygous for a first mtHTT variant, wherein a first mtHTT variant targeted allele is in phase with the pathogenic mtHTT allele, wherein the first mtHTT variant targeted allele is the alternate allele of the first mtHTT variant and is in phase with the pathogenic mtHTT allele more often than any other allele in a population of subjects. Such a subject is a candidate for treatment with a first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule when the subject is heterozygous for the first mtHTT variant targeted allele in phase with the pathogenic mtHTT allele. In some embodiments, for a subject that is homozygous for the first mtHTT variant, or heterozygous for the first mtHTT variant but the targeted allele is not in phase with the pathogenic mtHTT allele, determining from the sequence analysis or having determined from the sequence analysis whetherthe subject is heterozygous for a first subsequent mtHTT variant and heterozygous for a second subsequent mtHTT variant. Such a subject is a candidate for treatment with: a) a first subsequent mtHTT variant alternate allele- - 54 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule to the subject that has both the first subsequent mtHTT variant alternate allele and the second subsequent mtHTT variant alternate allele in phase with the pathogenic mtHTT allele; b) a first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule to the subject that has both the first subsequent mtHTT variant reference allele and the second subsequent mtHTT variant reference allele in phase with the pathogenic mtHTT allele; c) a first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule to the subject that has both the first subsequent mtHTT variant alternate allele and the second subsequent mtHTT variant reference allele in phase with the pathogenic mtHTT allele; ord) a first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule to the subject that has both the first subsequent mtHTT variant reference allele and the second subsequent mtHTT variant alternate allele in phase with the pathogenic mtHTT allele.

[0379] Determining whether a subject has of any of the mtHTT variants described herein in a biological sample from a subject and / or determining whether a subject has of any of the mtHTT variants described herein can be carried out by any of the methods described herein. In some embodiments, these methods can be carried out in vitro. In some embodiments, these methods can be carried out in situ. In some embodiments, these methods can be carried out in vivo. In any of these embodiments, the nucleic acid molecule can be present within a cell obtained from the subject.

[0380] The present disclosure also provides methods of detecting the presence or absence of any of the mtHTT variants described herein (i.e., a genomic nucleic acid molecule, an mRNA molecule, ora cDNA molecule produced from an mRNA molecule) in a biological sample from a subject. It is understood that gene sequences within a population and mRNA molecules encoded by such genes can vary due to polymorphisms such as single-nucleotide polymorphisms.

[0381] The biological sample can be derived from any cell, tissue, or biological fluid from the subject. The biological sample may comprise any clinically relevant tissue, such as a - 55 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT bone marrow sample, a tumor biopsy, a fine needle aspirate, or a sample of bodily fluid, such as blood, gingival crevicular fluid, plasma, serum, lymph, ascitic fluid, cystic fluid, or urine. In some cases, the sample comprises a buccal swab. The biological sample used in the methods disclosed herein can vary based on the assay format, nature of the detection method, and the tissues, cells, or extracts that are used as the sample. A biological sample can be processed differently depending on the assay being employed. For example, when detecting of any of the mtHTT variants described herein, preliminary processing designed to isolate or enrich the biological sample for the genomic DNA can be employed. A variety of techniques may be used for this purpose.

[0382] In some embodiments, detecting of any of the mtHTT variants described herein in a subject comprises performing a sequence analysis on a biological sample obtained from the subject to determine whether of any of the mtHTT variant genomic nucleic acid molecule in the biological sample, and / or any of the mtHTT variant mRNA molecule in the biological sample, and / or any of the mtHTT variant cDNA molecule produced from an mRNA molecule in the biological sample, is present in the sample.

[0383] In some embodiments, the methods of detecting the presence or absence of any of the mtHTT variants described herein (such as, for example, a genomic nucleic acid molecule, an mRNA molecule, and / or a cDNA molecule produced from an mRNA molecule) in a subject comprise performing an assay on a biological sample obtained from the subject. The assay determines whether a nucleic acid molecule in the biological sample comprises a particular nucleotide sequence.

[0384] In some embodiments, the biological sample comprises a cell or cell lysate. Such methods can further comprise, for example, obtaining a biological sample from the subject comprising of any of the mtHTT variants described herein, and if mRNA, optionally reverse transcribing the mRNA into cDNA. Such assays can comprise, for example determiningthe identity of these positions of the particular mtHTT variant described herein. In some embodiments, the method is an in vitro method.

[0385] In some embodiments, the determining step, detecting step, or sequence analysis comprises sequencing at least a portion of the nucleotide sequence of of any of the mtHTT

[0386] - 56 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT variants described herein in the biological sample that comprises a genetic variation compared to the corresponding HTT reference molecule.

[0387] In some embodiments, the assay comprises sequencing the entire nucleic acid molecule. In some embodiments, only an mtHTT variant genomic nucleic acid molecule is analyzed. In some embodiments, only an mtHTT variant mRNA is analyzed. In some embodiments, only an mtHTT variant cDNA obtained from the mRNA is analyzed.

[0388] Alteration-specific polymerase chain reaction techniques can be used to detect mutations such as SNPs in a nucleic acid sequence. Alteration-specific primers can be used because the DNA polymerase will not extend when a mismatch with the template is present.

[0389] In some embodiments, the nucleic acid molecule in the sample is mRNA and the mRNA is reverse-transcribed into a cDNA prior to the amplifying step. In some embodiments, the nucleic acid molecule is present within a cell obtained from the subject.

[0390] In some embodiments, the assay comprises contacting the biological sample with a primer or probe, such as an alteration-specific primer or alteration-specific probe, that specifically hybridizes to an mtHTT variant genomic sequence, variant mRNA sequence, or variant cDNA sequence and not the corresponding HTT reference sequence under stringent conditions and determining whether hybridization has occurred.

[0391] In some embodiments, the determining step, detecting step, or sequence analysis comprises: a) amplifying at least a portion of the mtHTT variant nucleic acid molecule; b) labeling the amplified nucleic acid molecule with a detectable label; c) contacting the labeled nucleic acid molecule with a support comprising an alteration-specific probe; and d) detecting the detectable label.

[0392] In some embodiments, the assay comprises RNA sequencing (RNA-Seq). In some embodiments, the assays also comprise reverse transcribing mRNA into cDNA, such as by the reverse transcriptase polymerase chain reaction (RT-PCR).

[0393] Illustrative examples of nucleic acid sequencing techniques include, but are not limited to, chain terminator (Sanger) sequencing and dye terminator sequencing. Other methods involve nucleic acid hybridization methods other than sequencing, including using labeled primers or probes directed against purified DNA, amplified DNA, and fixed cell - 57 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT preparations (fluorescence in situ hybridization (FISH)). In some methods, a target nucleic acid molecule may be amplified prior to or simultaneous with detection. Illustrative examples of nucleic acid amplification techniques include, but are not limited to, polymerase chain reaction (PCR), ligase chain reaction (LCR), strand displacement amplification (SDA), and nucleic acid sequence based amplification (NASBA). Other methods include, but are not limited to, ligase chain reaction, strand displacement amplification, and thermophilic SDA (tSDA).

[0394] In hybridization techniques, stringent conditions can be employed such that a probe or primer will specifically hybridize to its target. In some embodiments, a polynucleotide primer or probe under stringent conditions will hybridize to its target sequence to a detectably greater degree than to other non-target sequences, such as, at least 2-fold, at least 3-fold, at least 4-fold, or more over background, including over 10-fold over background. In some embodiments, a polynucleotide primer or probe under stringent conditions will hybridize to its target nucleotide sequence to a detectably greater degree than to other nucleotide sequences by at least 2-fold. In some embodiments, a polynucleotide primer or probe under stringent conditions will hybridize to its target nucleotide sequence to a detectably greater degree than to other nucleotide sequences by at least 3-fold. In some embodiments, a polynucleotide primer or probe under stringent conditions will hybridize to its target nucleotide sequence to a detectably greater degree than to other nucleotide sequences by at least 4-fold. In some embodiments, a polynucleotide primer or probe under stringent conditions will hybridize to its target nucleotide sequence to a detectably greater degree than to other nucleotide sequences by over 10-fold over background. Stringent conditions are sequence-dependent and will be different in different circumstances.

[0395] Appropriate stringency conditions which promote DNA hybridization, for example, 6X sodium chloride / sodium citrate (SSC) at about 45°C., followed by a wash of 2X SSC at 50°C, are known or can be found in Current Protocols in Molecular Biology, John Wiley & Sons, N.Y. (1989), 6.3.1-6.3.6. Typically, stringent conditions for hybridization and detection will be those in which the salt concentration is less than about 1.5 M Na+ion, typically about 0.01 to 1.0 M Na+ion concentration (or other salts) at pH 7.0 to 8.3 and the temperature is - 58 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT at least about 30°C for short probes (such as, for example, 10 to 50 nucleotides) and at least about 60°C for longer probes (such as, for example, greater than 50 nucleotides). Stringent conditions may also be achieved with the addition of destabilizing agents such as formamide. Optionally, wash buffers may comprise about 0.1% to about 1% SDS. Duration of hybridization is generally less than about 24 hours, usually about 4 to about 12 hours. The duration of the wash time will be at least a length of time sufficient to reach equilibrium.

[0396] In some embodiments, primers, including alteration-specific primers, can be used in second generation sequencing or high throughput sequencing. In some instances, the primers, including alteration-specific primers, can be modified. In particular, the primers can comprise various modifications that are used at different steps of, for example, Massively Parallel Signature Sequencing (MPSS), Polony sequencing, and 454 Pyrosequencing.

[0397] Modified primers can be used at several steps of the process, including biotinylated primers in the cloning step and fluorescently labeled primers used at the bead loading step and detection step. Polony sequencing is generally performed using a paired-end tags library wherein each molecule of DNA template is about 135 bp in length. Biotinylated primers are used at the bead loading step and emulsion PCR. Fluorescently labeled degenerate nonamer oligonucleotides are used at the detection step. An adaptor can contain a 5'-biotin tag for immobilization of the DNA library onto streptavidin-coated beads.

[0398] In the context of the disclosure "specifically hybridizes" means that the probe or primer (such as, for example, the alteration-specific probe or alteration-specific primer) does not hybridize to a nucleic acid sequence encoding an HTT reference genomic nucleic acid molecule, an HTT reference mRNA molecule, and / or an HTT reference cDNA molecule.

[0399] The genomic nucleic acid molecules, mRNA molecules, and cDNA molecules can be from any organism. For example, the genomic nucleic acid molecules, mRNA molecules, and cDNA molecules can be human or an ortholog from another organism, such as a non-human mammal, a rodent, a mouse, or a rat. It is understood that gene sequences within a population can vary due to polymorphisms such as single-nucleotide polymorphisms.

[0400] The isolated nucleic acid molecules disclosed herein can comprise RNA, DNA, or both RNA and DNA. The isolated nucleic acid molecules can also be linked or fused to a heterologous nucleic acid sequence, such as in a vector, or a heterologous label. For

[0401] - 59 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT example, the isolated nucleic acid molecules disclosed herein can be within a vector or as an exogenous donor sequence comprising the isolated nucleic acid molecule and a heterologous nucleic acid sequence. The isolated nucleic acid molecules can also be linked or fused to a heterologous label. The label can be directly detectable (such as, for example, fluorophore) or indirectly detectable (such as, for example, hapten, enzyme, or fluorophore quencher). Such labels can be detectable by spectroscopic, photochemical, biochemical, immunochemical, or chemical means. Such labels include, for example, radiolabels, pigments, dyes, chromogens, spin labels, and fluorescent labels. The label can also be, for example, a chemiluminescent substance; a metal-containing substance; or an enzyme, where there occurs an enzyme-dependent secondary generation of signal. The term "label" can also refer to a "tag" or hapten that can bind selectively to a conjugated molecule such that the conjugated molecule, when added subsequently along with a substrate, is used to generate a detectable signal. For example, biotin can be used as a tag along with an avidin or streptavidin conjugate of horseradish peroxidate (HRP) to bind to the tag, and examined using a calorimetric substrate (such as, for example, tetra methylbenzidine (TMB)) or a fluorogenic substrate to detect the presence of HRP. Exemplary labels that can be used as tags to facilitate purification include, but are not limited to, myc, HA, FLAG or 3XFLAG, 6Xhis or polyhistidine, glutathione-S-transferase (GST), maltose binding protein, an epitope tag, or the Fc portion of immunoglobulin. Numerous labels include, for example, particles, fluorophores, haptens, enzymes and their calorimetric, fluorogenic and chemiluminescent substrates and other labels.

[0402] Percent identity (or percent complementarity) between particular stretches of nucleotide sequences within nucleic acid molecules or amino acid sequences within polypeptides can be determined routinely using BLAST programs (basic local alignment search tools) and PowerBLAST programs (Altschul etal., J. Mol. BioL, 1990, 215, 403-410; Zhang and Madden, Genome Res., 1997, 7, 649-656) or by using the Gap program (Wisconsin Sequence Analysis Package, Version 8 for Unix, Genetics Computer Group, University Research Park, Madison Wis.), using default settings, which uses the algorithm of Smith and Waterman (Adv. Appl. Math., 1981, 2, 482-489). Herein, if reference is made to

[0403] - 60 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT percent sequence identity, the higher percentages of sequence identity are preferred over the lower ones.

[0404] The present disclosure also provides inhibitory nucleic acid molecules for use in the treatment or prevention of Huntington's disease in a subject having a pathogenic mtHTT allele. In some embodiments, the subject is heterozygous for a first mtHTT variant, wherein a first mtHTT variant targeted allele is in phase with the pathogenic mtHTT allele, wherein the first mtHTT variant targeted allele is the alternate allele of the first mtHTT variant and is in phase with the pathogenic mtHTT allele more often than any other allele in a population of subjects, and the inhibitory nucleic acid molecule comprises a first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule. Any of the first mtHTT variant alternate allele-specific inhibitory nucleic acid molecules described herein is included herein. Any of the first mtHTT variants described herein is included herein. In some embodiments, the subject is homozygous for the first mtHTT variant or heterozygous for the first mtHTT variant but the targeted allele is not in phase with the pathogenic mtHTT allele, and the subject is heterozygous for a subsequent mtHTT variant in which the alternate allele or reference allele is in phase with the pathogenic mtHTT allele, and the inhibitory nucleic acid molecule comprises a subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule or a subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, whichever is in phase with the pathogenic mtHTT allele. In some embodiments, the subject is homozygous for the subsequent mtHTT variant, and the subject is heterozygous for a further subsequent mtHTT variant in which the alternate allele or reference allele is in phase with the pathogenic mtHTT allele, and the inhibitory nucleic acid molecule comprises a further subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule or a further subsequent mtHTT variant alternate allelespecific inhibitory nucleic acid molecule, whichever is in phase with the pathogenic mtHTT allele. Any of the subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecules, subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecules, further subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecules, or further subsequent mtHTT variant alternate allele-specific inhibitory nucleic

[0405] - 61 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT acid molecules described herein is included herein. Any of the subsequent mtHTT variants or further subsequent mtHTT variants described herein is included herein.

[0406] The present disclosure also provides inhibitory nucleic acid molecules in the preparation of a medicament for treating or preventing Huntington's disease in a subject having a pathogenic mtHTT allele. In some embodiments, the subject is heterozygous for a first mtHTT variant, wherein a first mtHTT variant targeted allele is in phase with the pathogenic mtHTT allele, wherein the first mtHTT variant targeted allele is the alternate allele of the first mtHTT variant and is in phase with the pathogenic mtHTT allele more often than any other allele in a population of subjects, and the inhibitory nucleic acid molecule comprises a first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule. Any of the first mtHTT variant alternate allele-specific inhibitory nucleic acid molecules described herein is included herein. Any of the first mtHTT variants described herein is included herein. In some embodiments, the subject is homozygous for the first mtHTT variant or heterozygous for the first mtHTT variant but the targeted allele is not in phase with the pathogenic mtHTT allele, and the subject is heterozygous for a subsequent mtHTT variant in which the alternate allele or reference allele is in phase with the pathogenic mtHTT allele, and the inhibitory nucleic acid molecule comprises a subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule or a subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, whichever is in phase with the pathogenic mtHTT allele. In some embodiments, the subject is homozygous for the subsequent mtHTT variant, and the subject is heterozygous for a further subsequent mtHTT variant in which the alternate allele or reference allele is in phase with the pathogenic mtHTT allele, and the inhibitory nucleic acid molecule comprises a further subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule or a further subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, whichever is in phase with the pathogenic mtHTT allele. Any of the subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecules, subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecules, further subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecules, or further subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecules described herein is

[0407] - 62 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT included herein. Any of the subsequent mtHTT variants or further subsequent mtHTT variants described herein is included herein.

[0408] The present disclosure also provides inhibitory nucleic acid molecules for use in the treatment or prevention of Huntington's disease in a subject having a pathogenic mtHTT allele. In some embodiments, the subject is heterozygous for a first mtHTT variant, wherein the first mtHTT variant targeted allele is in phase with the pathogenic mtHTT allele, wherein the first mtHTT variant targeted allele is the alternate allele of the first mtHTT variant and is in phase with the pathogenic mtHTT allele more often than any other allele in a population of subjects, and the inhibitory nucleic acid molecule comprises a first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule. Any of the first mtHTT variant alternate allele-specific inhibitory nucleic acid molecules described herein is included herein. Any of the first mtHTT variants described herein is included herein. In some embodiments, the subject is homozygous for the first mtHTT variant or heterozygous for the first mtHTT variant but the targeted allele is not in phase with the pathogenic mtHTT allele, and the subject is heterozygous for a first subsequent mtHTT variant and heterozygous for a second subsequent mtHTT variant, wherein the subject has both the first subsequent mtHTT variant alternate allele and the second subsequent mtHTT variant alternate allele in phase with the pathogenic mtHTT allele, and the inhibitory nucleic acid molecule comprises a first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule. In some embodiments, the subject is homozygous for the first mtHTT variant or heterozygous for the first mtHTT variant but the targeted allele is not in phase with the pathogenic mtHTT allele, and the subject is heterozygous for a first subsequent mtHTT variant and heterozygous for a second subsequent mtHTT variant, wherein the subject has both the first subsequent mtHTT variant reference allele and the second subsequent mtHTT variant reference allele in phase with the pathogenic mtHTT allele, and the inhibitory nucleic acid molecule comprises a first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule. In some embodiments, the subject is homozygous for the first mtHTT variant or heterozygous for the first mtHTT variant but the targeted allele is not in phase with the pathogenic mtHTT allele, and the subject is - 63 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT heterozygous for a first subsequent mtHTT variant and heterozygous for a second subsequent mtHTT variant, wherein the subject has both the first subsequent mtHTT variant alternate allele and the second subsequent mtHTT variant reference allele in phase with the pathogenic mtHTT allele, and the inhibitory nucleic acid molecule comprises a first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule. In some embodiments, the subject is homozygous for the first mtHTT variant or heterozygous for the first mtHTT variant but the targeted allele is not in phase with the pathogenic mtHTT allele, and the subject is heterozygous for a first subsequent mtHTT variant and heterozygous for a second subsequent mtHTT variant, wherein the subject has both the first subsequent mtHTT variant reference allele and the second subsequent mtHTT variant alternate allele in phase with the pathogenic mtHTT allele, and the inhibitory nucleic acid molecule comprises a first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule. Any of the first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecules described herein is included herein. Any of the first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecules described herein is included herein. Any of the first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecules described herein is included herein. Any of the first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecules described herein is included herein. Any of the first subsequent mtHTT variants and second subsequent mtHTT variants described herein are included herein.

[0409] The present disclosure also provides inhibitory nucleic acid molecules in the preparation of a medicament for treating or preventing Huntington's disease in a subject having a pathogenic mtHTT allele. In some embodiments, the subject is heterozygous for a first mtHTT variant, wherein the first mtHTT variant targeted allele is in phase with the pathogenic mtHTT allele, wherein the first mtHTT variant targeted allele is the alternate allele of the first mtHTT variant and is in phase with the pathogenic mtHTT allele more often - 64 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT than any other allele in a population of subjects, and the inhibitory nucleic acid molecule comprises a first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule. Any of the first mtHTT variant alternate allele-specific inhibitory nucleic acid molecules described herein is included herein. Any of the first mtHTT variants described herein is included herein. In some embodiments, the subject is homozygous for the first mtHTT variant or heterozygous for the first mtHTT variant but the targeted allele is not in phase with the pathogenic mtHTT allele, and the subject is heterozygous for a first subsequent mtHTT variant and heterozygous for a second subsequent mtHTT variant, wherein the subject has both the first subsequent mtHTT variant alternate allele and the second subsequent mtHTT variant alternate allele in phase with the pathogenic mtHTT allele, and the inhibitory nucleic acid molecule comprises a first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule. In some embodiments, the subject is homozygous for the first mtHTT variant or heterozygous for the first mtHTT variant but the targeted allele is not in phase with the pathogenic mtHTT allele, and the subject is heterozygous for a first subsequent mtHTT variant and heterozygous for a second subsequent mtHTT variant, wherein the subject has both the first subsequent mtHTT variant reference allele and the second subsequent mtHTT variant reference allele in phase with the pathogenic mtHTT allele, and the inhibitory nucleic acid molecule comprises a first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule. In some embodiments, the subject is homozygous for the first mtHTT variant or heterozygous for the first mtHTT variant but the targeted allele is not in phase with the pathogenic mtHTT allele, and the subject is heterozygous for a first subsequent mtHTT variant and heterozygous for a second subsequent mtHTT variant, wherein the subject has both the first subsequent mtHTT variant alternate allele and the second subsequent mtHTT variant reference allele in phase with the pathogenic mtHTT allele, and the inhibitory nucleic acid molecule comprises a first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule. In some embodiments, the subject is homozygous for the first mtHTT variant or heterozygous for the first mtHTT variant but the targeted allele is not in phase with the - 65 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT pathogenic mtHTT allele, and the subject is heterozygous for a first subsequent mtHTT variant and heterozygous for a second subsequent mtHTT variant, wherein the subject has both the first subsequent mtHTT variant reference allele and the second subsequent mtHTT variant alternate allele in phase with the pathogenic mtHTT allele, and the inhibitory nucleic acid molecule comprises a first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule. Any of the first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecules described herein is included herein. Any of the first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecules described herein is included herein. Any of the first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecules described herein is included herein. Any of the first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecules described herein is included herein. Any of the first subsequent mtHTT variants and second subsequent mtHTT variants described herein are included herein.

[0410] All patent documents, websites, other publications, accession numbers and the like cited above or below are incorporated by reference in their entirety for all purposes to the same extent as if each individual item were specifically and individually indicated to be so incorporated by reference. If different versions of a sequence are associated with an accession number at different times, the version associated with the accession number at the effective filing date of this application is meant. The effective filing date means the earlier of the actual filing date orfiling date of a priority application referring to the accession number if applicable. Likewise, if different versions of a publication, website or the like are published at different times, the version most recently published at the effective filing date of the application is meant unless otherwise indicated. Any feature, step, element, embodiment, or aspect of the present disclosure can be used in combination with any other feature, step, element, embodiment, or aspect unless specifically indicated otherwise. Although the present disclosure has been described in some detail by way of - 66 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT illustration and example for purposes of clarity and understanding, it will be apparent that certain changesand modifications may be practiced within the scope of the appended claims.

[0411] The following examples are provided to describe the embodiments in greater detail. They are intended to illustrate, not to limit, the claimed embodiments. The following examples provide those of ordinary skill in the art with a disclosure and description of how the compounds, compositions, articles, devices and / or methods described herein are made and evaluated and are intended to be purely exemplary and are not intended to limit the scope of any claims. Efforts have been made to ensure accuracy with respect to numbers (such as, for example, amounts, temperature, etc.), but some errors and deviations may be accounted for. Unless indicated otherwise, parts are parts by weight, temperature is in °C or is at ambient temperature, and pressure is at or near atmospheric.

[0412] Examples

[0413] Example 1: Variants Tagging HTT TRE in HD Cases

[0414] Twenty-three (23) HTT coding variants with MAF>1% (population) and >2% proportion of patients treatable were discovered (see, Figure 1). Briefly, all variants identified in exome sequencing at Regeneron Genetics Center (RGC) mapping to human chromosome 4 positions 28-35 Mb were annotated with respect to the Huntingtin gene mRNA (coding exons, and 5' and 3' untranslated regions), and their frequencies in RGC samples were tabulated. In addition, the proportion of patients treatable was calculated for each common coding variant as follows. First an HTT region genotype dataset was constructed including subjects with ICD10 Huntington's disease (HD) diagnosis code G10 (cases) and control subjects without HD diagnosis from the same cohorts, and including (a) pseudo-genotypes for the HD pathogenic triplet repeat variant coded as heterozygous in cases (variant call format (VCF) "0 / 1") and homozygous REF ("0 / 0") in controls, (b) genotypes of HTT coding variants from exome sequencing, and (c) 24,393 variants from chromosome 4 positions 28-35 Mb derived by imputation from the TOPMED reference panel (Taliun et al., Nature, 2019, 590, 290-299; and Das et al., Nat. Genet., 2016, 48, 1284-1287). This HTT region dataset was then phased using the SHAPEIT software (Delaneau et - 67 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT al., Nature Commun., 2014, 5, 3934) to determine which alleles of HTT variants are on the same chromosome as the pathogenic allele in cases. For each HTT coding variant with minor allele frequency (MAF) greater than 0.01, we then calculated the proportion of HD cases that were heterozygous for the variant and the proportions of heterozygous individuals with ALT and REF alleles of the variant on the same chromosome as the HD pathogenic allele. The proportion of patients treatable by an allele-specific nucleic acid sequence for the variant / Alt allele or reference allele was calculated as the product of the proportion of heterozygous cases and the proportion of those with the given allele on the same chromosome as the HD pathogenic allele, respectively (shown in Table 1). Conditional proportions of patients treatable by targeting specific variants (Alt or reference alleles) was further calculated, conditional on first targeting another variant, by focusing the calculations of proportions of heterozygous cases and of specific alleles on the same chromosome as the pathogenic allele on HD cases who were not targetable by the conditioned-upon variant (i.e., HD cases who were not heterozygous forthe conditioned-upon variant or who did not have the conditioned-upon variant's targeted allele on the same chromosome as the HD pathogenic allele). Conditional proportions of patients treated (not shown in Table 1 as they depend on the sequence of conditioned-upon variant(s)) allowed for optimization of the choice of second variants / alleles to target in HD patients.

[0415] Example 2: Design of Candidate Oligonucleotides for HTT

[0416] Targetable variants were cross-referenced with candidate oligos. Candidate oligonucleotides were designed based on the HTT reference sequence. 2,667 candidate oligonucleotides were identified throughout HTT. 14 oligonucleotide cadidates 5' of the pathogenic TRE site were identified. Zero oligonucleotides overlapping the pathogenic TRE site 4:4:3074877:CAG:(CAG)nwere identified. 2,650 additional oligonucleotides in exons 2 to 67, and >600 oligos in the 3' UTR were identified. 48 candidate oligonucleotides that overlap 5 common HTT coding variants were identified. 135 candidate oligonucleotides overlapping HTT variants in the 3' UTR were identified. A list of oligonucleotides is shown in Table 2. A set of 11 preferred oligonucleotides (sense sequence / target antisense sequence)

[0417] - 68 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT includes SEQ ID Nos: 88 / 333, 89 / 334, 90 / 335, 91 / 336, 135 / 380, 137 / 382, 139 / 384, 142 / 387, 144 / 389, 147 / 392, and 149 / 394.

[0418] Various modifications of the described subject matter, in addition to those described herein, will be apparent to those skilled in the art from the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. Each reference (including, but not limited to, journal articles, U.S. and non-U. S. patents, patent application publications, international patent application publications, gene bank accession numbers, and the like) cited in the present application is incorporated herein by reference in its entirety and for all purposes.

[0419] - 69 - 119110564

Claims

DOCKET NO.: 38120-4600 (11607WO-01) PATENT What is Claimed is:

1. A method of treating a subject having Huntington's disease or at risk of developing Huntington's disease, wherein the subject has a pathogenic mutant huntingtin (mtHTT) allele, the method comprising:a) performing or having performed a sequence analysis on a biological sample obtained from the subject;b) determining from the sequence analysis or having determined from the sequence analysis whether the subject is heterozygous for a first mtHTT variant, wherein a first mtHTT variant targeted allele is in phase with the pathogenic mtHTT allele, wherein the first mtHTT variant targeted allele is the alternate allele of the first mtHTT variant and is in phase with the pathogenic mtHTT allele more often than any other allele in a population of subjects; andi) administering or continuing to administer a first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule to the subject that is heterozygous for the first mtHTT variant targeted allele in phase with the pathogenic mtHTT allele; orii) performing step c) for the subject that is homozygous for the first mtHTT variant or heterozygous for the first mtHTT variant but the targeted allele is not in phase with the pathogenic mtHTT allele;c) determining from the sequence analysis or having determined from the sequence analysis whether the subject is heterozygous for a subsequent mtHTT variant in which the alternate allele or reference allele is in phase with the pathogenic mtHTT allele; andi) administering or continuing to administer a subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule or a subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, whichever is in phase with the pathogenic mtHTT allele, to the subject that is heterozygous for the subsequent mtHTT variant; orii) repeating step c) for the subject that is homozygous for the subsequent mtHTT variant until a further subsequent mtHTT variant that is heterozygous is - 70 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT identified for the subject, and administering to the subject or continuing to administer to the subject a further subsequent mtHTT variant reference allelespecific inhibitory nucleic acid molecule or a further subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, whichever is in phase with the pathogenic mtHTT allele.

2. The method of claim 1, wherein the first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, further subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, and further subsequent mtHTT variant alternate allelespecific inhibitory nucleic acid molecule comprise an antisense nucleic acid molecule, a small interfering RNA (siRNA), or a short hairpin RNA (shRNA).

3. The method of claim 2, wherein the first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, further subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, and further subsequent mtHTT variant alternate allelespecific inhibitory nucleic acid molecule comprise an siRNA.

4. The method of claim 2, wherein the first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, further subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, and further subsequent mtHTT variant alternate allelespecific inhibitory nucleic acid molecule comprise an antisense nucleic acid molecule.

5. The method of any one of claims 1 to 4, wherein the first mtHTT variant comprises 4:3228683:AGAG:A; and i) the first mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:334, SEQ ID NO:335, or SEQ ID NO:336; or ii) the first mtHTT variant alternatespecific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:89 / 334, SEQ ID NQs:90 / 335, or SEQ ID NOs:91 / 336.- 71 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT 6. The method of any one of claims 1 to 5, wherein the subsequent mtHTT variant or further subsequent mtHTT variant comprises 4:3240421:C:G; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:380, SEQ ID NO:382, SEQ ID NO:384, SEQ ID NO:387, SEQ ID NO:389, or SEQ ID NO:392; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:135 / 380, SEQ ID NOs:137 / 382, SEQ ID NOs:139 / 384, SEQ ID NOs:142 / 387, SEQ ID NOs:144 / 389, or SEQ ID NOs:147 / 392; iii) the subsequent mtHTT variant reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:379, SEQ ID NO:381, SEQ ID NO:383, SEQ ID NO:385, SEQ ID NO:386, SEQ ID NO:388, SEQ ID NO:390, SEQ ID NO:391, or SEQ ID NO:393; or iv) the subsequent mtHTT variant reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant reference-specific inhibitory nucleic acid molecule comprises an siRNA comprisingthe nucleotide sequences of SEQ ID NOs:134 / 379, SEQ ID NOs:136 / 381, SEQ ID NOs:138 / 383, SEQ ID NQs:140 / 385, SEQ ID NOs:141 / 386, SEQ ID NOs:143 / 388, SEQ ID NQs:145 / 390, SEQ ID NOs:146 / 391, or SEQ ID NOs: 148 / 393.

7. The method of any one of claims 1 to 5, wherein the subsequent mtHTT variant or further subsequent mtHTT variant comprises 4:3074723:C:T; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:247, SEQ ID NO:249, SEQ ID NO:251, SEQ ID NO:253, SEQ ID NO:255, SEQ ID NO:257, SEQ ID NO:259, SEQ ID NO:261, or SEQ ID NO:263; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:2 / 247, SEQ ID NOs:4 / 249, SEQ ID NOs:6 / 251, SEQ ID NOs:8 / 253, SEQ ID NQs:10 / 255, SEQ ID- 72 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT NOs:12 / 257, SEQ ID NOs:14 / 259, SEQ ID NOs:16 / 261, or SEQ ID NOs:18 / 263; ill) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:246, SEQ ID NO:248, SEQ ID NO:250, SEQ ID NO:252, SEQ ID NO:254, SEQ ID NO:256, SEQ ID NO:258, SEQ ID NO:260, or SEQ ID NO:262; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:l / 246, SEQ ID NOs:3 / 248, SEQ ID NOs:5 / 250, SEQ ID NOs:7 / 252, SEQ ID NOs:9 / 254, SEQ ID NOs:ll / 256, SEQ ID NOs:13 / 258, SEQ ID NQs:15 / 260, or SEQ ID NOs:17 / 262.

8. The method of any one of claims 1 to 5, wherein the subsequent mtHTT variant or further subsequent mtHTT variant comprises 4:3115441:C:G; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:265, SEQ ID NO:266, SEQ ID NO:268, SEQ ID NQ:270, SEQ ID NO:272, SEQ ID NO:274, SEQ ID NO:276, or SEQ ID NO:278; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NQs:20 / 265, SEQ ID NOs:21 / 266, SEQ ID NOs:23 / 268, SEQ ID NQs:25 / 270, SEQ ID NOs:27 / 272, SEQ ID NOs:29 / 274, SEQ ID NOs:31 / 276, or SEQ ID NOs:33 / 278; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT referencespecific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:264, SEQ ID NO:267, SEQ ID NO:269, SEQ ID NO:271, SEQ ID NO:273, SEQ ID NO:275, or SEQ ID NO:277; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT referencespecific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:19 / 264, SEQ ID NOs:22 / 267, SEQ ID NOs:24 / 269, SEQ ID NOs:26 / 271, SEQ ID NOs:28 / 273, SEQ ID NQs:30 / 275, or SEQ ID NOs:32 / 277.- 73 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT 9. The method of any one of claims 1 to 5, wherein the subsequent mtHTT variant or further subsequent mtHTT variant comprises 4:3160329:C:T; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:279, SEQ ID NO:280, SEQ ID NO:282, SEQ ID NO:284, SEQ ID NO:286, or SEQ ID NO:287; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:34 / 279, SEQ ID NQs:35 / 280, SEQ ID NOs:37 / 282, SEQ ID NOs:39 / 284, SEQ ID NOs:41 / 286, or SEQ ID NOs:42 / 287; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT referencespecific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:281, SEQ ID NO:283, SEQ ID NO:285, or SEQ ID NO:288; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:36 / 281, SEQ ID NOs:38 / 283, SEQ ID NQs:40 / 285, or SEQ ID NOs:43 / 288.

10. The method of any one of claims 1 to 5, wherein the subsequent mtHTT variant or further subsequent mtHTT variant comprises 4:3187820:C:A; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:289, SEQ ID NO:291, SEQ ID NO:294, SEQ ID NO:296, or SEQ ID NO:297; ii) the subsequent mtHTT variant alternatespecific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternatespecific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:44 / 289, SEQ ID NOs:46 / 291, SEQ ID NOs:49 / 294, SEQ ID NOs:51 / 296, or SEQ ID NOs:52 / 297; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NQ:290, SEQ ID NO:292, SEQ ID NO:293, SEQ ID NO:295, or SEQ ID NO:298; or iv)- 74 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:45 / 290, SEQ ID NOs:47 / 292, SEQ ID NOs:48 / 293, SEQ ID NOs:50 / 295, or SEQ ID NOs:53 / 298.

11. The method of any one of claims 1 to 5, wherein the subsequent mtHTT variant or further subsequent mtHTT variant comprises 4:3212105:G:A; and i) the subsequent mtHTT variant reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:299, SEQ ID NQ:300, SEQ ID NQ:301, SEQ ID NO:302, or SEQ ID NO:303; or ii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:54 / 299, SEQ ID NQs:55 / 300, SEQ ID NOs:56 / 301, SEQ ID NOs:57 / 302, or SEQ ID NOs:58 / 303.

12. The method of any one of claims 1 to 5, wherein the subsequent mtHTT variant or further subsequent mtHTT variant comprises 4:3229934:G:A; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:313, SEQ ID NO:315, SEQ ID NO:316, SEQ ID NO:317, SEQ ID NO:320, SEQ ID NO:322, or SEQ ID NO:325; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:68 / 313, SEQ ID NQs:70 / 315, SEQ ID NOs:71 / 316, SEQ ID NOs:72 / 317, SEQ ID NOs:75 / 320, SEQ ID NOs:77 / 322, or SEQ ID NOs:80 / 325; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:312, SEQ ID NO:314, SEQ ID NO:318, SEQ ID NO:319, SEQ ID NO:321, SEQ ID NO:323, or SEQ ID NO:324; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an - 75 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT siRNA comprising the nucleotide sequences of SEQ ID NOs:67 / 312, SEQ ID NOs:69 / 314, SEQ ID NOs:73 / 318, SEQ. ID NOs:74 / 319, SEQ ID NOs:76 / 321, SEQ ID NOs:78 / 323, or SEQ ID NOs:79 / 324.

13. The method of any one of claims 1 to 5, wherein the subsequent mtHTT variant or further subsequent mtHTT variant comprises 4:3225692:A:G; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:326, SEQ ID NO:328, or SEQ ID NQ:330; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:81 / 326, SEQ ID NOs:83 / 328, or SEQ ID NQs:85 / 330; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:327, SEQ ID NO:329, SEQ ID NO:331, or SEQ ID NO:332; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:82 / 327, SEQ ID NOs:84 / 329, SEQ ID NOs:86 / 331, or SEQ ID NOs:87 / 332.

14. The method of any one of claims 1 to 5, wherein the subsequent mtHTT variant or further subsequent mtHTT variant comprises 4:3233253:G:A; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:338, SEQ ID NO:339, SEQ ID NO:341, SEQ ID NO:345, SEQ ID NO:346, SEQ ID NO:349, or SEQ ID NO:351; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprisingthe nucleotide sequences of SEQ ID NOs:93 / 338, SEQ ID NOs:94 / 339, SEQ ID NOs:96 / 341, SEQ ID NQs:100 / 345, SEQ ID NQs:101 / 346, SEQ ID NQs:104 / 349, or SEQ ID NQs:106 / 351; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule - 76 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:337, SEQ ID NO:340, SEQ ID NO:342, SEQ ID NO:343, SEQ ID NO:344, SEQ ID NO:347, SEQ ID NO:348, or SEQ ID NO:350; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:92 / 337, SEQ ID NOs:95 / 340, SEQ ID NOs:97 / 342, SEQ ID NOs:98 / 343, SEQ ID NOs:99 / 344, SEQ ID NOs:102 / 347, SEQ ID NQs:103 / 348, or SEQ ID NQs:105 / 350.

15. The method of any one of claims 1 to 5, wherein the subsequent mtHTT variant or further subsequent mtHTT variant comprises 4:3240373:G:A; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:370, SEQ ID NO:372, SEQ ID NO:373, SEQ ID NO:376, SEQ ID NO:377, or SEQ ID NO:378; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:125 / 370, SEQ ID NOs:127 / 372, SEQ ID NOs:128 / 373, SEQ ID NOs:131 / 376, SEQ ID NOs:132 / 377, or SEQ ID NOs:133 / 378; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:369, SEQ ID NO:371, SEQ ID NO:374, or SEQ ID NO:375; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:124 / 369, SEQ ID NOs:126 / 371, SEQ ID NOs:129 / 374, or SEQ ID NOs:130 / 375.

16. The method of any one of claims 1 to 5, wherein the subsequent mtHTT variant or further subsequent mtHTT variant comprises 4:3240433:C:G; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NQ:410 or SEQ ID NO:411; ii)- 77 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:165 / 410 or SEQ ID NOs:166 / 411; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:409 or SEQ ID NO:412; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NQs:164 / 409 or SEQ ID NOs:167 / 412.

17. The method of any one of claims 1 to 5, wherein the subsequent mtHTT variant or further subsequent mtHTT variant comprises 4:3240545:C:A; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:413, SEQ ID NO:415, SEQ ID NO:417, SEQ ID NO:419, SEQ ID NO:421, SEQ ID NO:422, or SEQ ID NO:424; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs: 168 / 413, SEQ ID NQs:170 / 415, SEQ ID NOs:172 / 417, SEQ ID NOs:174 / 419, SEQ ID NOs:176 / 421, SEQ ID NOs:177 / 422, or SEQ ID NOs:179 / 424; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:414, SEQ ID NO:416, SEQ ID NO:418, SEQ ID NO:420, or SEQ ID NO:423; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:169 / 414, SEQ ID NOs:171 / 416, SEQ ID NOs:173 / 418, SEQ ID NQs:175 / 420, or SEQ ID NOs:178 / 423.

18. The method of any one of claims 1 to 5, wherein the subsequent mtHTT variant or further subsequent mtHTT variant comprises 4:3240580:C:T; and i) the subsequent mtHTT - 78 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:426, SEQ ID NQ:430, SEQ ID NO:432, SEQ ID NO:433, SEQ ID NO:436, SEQ ID NO:438, SEQ ID NO:439, or SEQ ID NO:441; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:181 / 426, SEQ ID NOs:185 / 430, SEQ ID NOs:187 / 432, SEQ ID NOs:188 / 433, SEQ ID NOs:191 / 436, SEQ ID NOs:193 / 438, SEQ ID NOs:194 / 439, or SEQ ID NOs: 196 / 441; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT referencespecific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:425, SEQ ID NO:427, SEQ ID NO:428, SEQ ID NO:429, SEQ ID NO:431, SEQ ID NO:434, SEQ ID NO:435, SEQ ID NO:437, SEQ ID NO:440, or SEQ ID NO:442; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:180 / 425, SEQ ID NOs:182 / 427, SEQ ID NOs:183 / 428, SEQ ID NOs:184 / 429, SEQ ID NOs:186 / 431, SEQ ID NOs:189 / 434, SEQ ID NQs:190 / 435, SEQ ID NOs:192 / 437, SEQ ID NQs:195 / 440, or SEQ ID NOs: 197 / 442.

19. The method of any one of claims 1 to 5, wherein the subsequent mtHTT variant or further subsequent mtHTT variant comprises 4:3241491:C:T; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:443, SEQ ID NO:445, SEQ ID NO:446, SEQ ID NO:449, SEQ ID NQ:450, SEQ ID NO:452, SEQ ID NO:454, SEQ ID NO:456, or SEQ ID NO:458; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:198 / 443, SEQ ID NQs:200 / 445, SEQ ID NQs:201 / 446, SEQ ID NQs:204 / 449, SEQ ID NQs:205 / 450, SEQ ID NOs:207 / 452, SEQ ID NOs:209 / 454, SEQ ID NOs:211 / 456, or SEQ ID NOs:213 / 458; iii) the - 79 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:444, SEQ ID NO:447, SEQ ID NO:448, SEQ ID NO:451, SEQ ID NO:453, SEQ ID NO:455, SEQ ID NO:457, or SEQ ID NO:459; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:199 / 444, SEQ ID NQs:202 / 447, SEQ ID NOs:203 / 448, SEQ ID NOs:206 / 451, SEQ ID NOs:208 / 453, SEQ ID NOs:210 / 455, SEQ ID NOs:212 / 457, or SEQ ID NOs:214 / 459.

20. The method of any one of claims 1 to 5, wherein the subsequent mtHTT variant or further subsequent mtHTT variant comprises 4:3241563:G:A; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NQ:460, SEQ ID NO:463, SEQ ID NO:465, SEQ ID NO:467, SEQ ID NO:468, SEQ ID NO:469, SEQ ID NO:471, SEQ ID NO:473, SEQ ID NO:475, or SEQ ID NO:477; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprisingthe nucleotide sequences of SEQ ID NOs:215 / 460, SEQ ID NOs:218 / 463, SEQ ID NQs:220 / 465, SEQ ID NOs:222 / 467, SEQ ID NOs:223 / 468, SEQ ID NOs:224 / 469, SEQ ID NOs:226 / 471, SEQ ID NOs:228 / 473, SEQ ID NOs:230 / 475, or SEQ ID NOs:232 / 477; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:461, SEQ ID NO:462, SEQ ID NO:464, SEQ ID NO:466, SEQ ID NQ:470, SEQ ID NO:472, SEQ ID NO:474, or SEQ ID NO:476; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT referencespecific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:216 / 461, SEQ ID NOs:217 / 462, SEQ ID NOs:219 / 464, SEQ ID NOs:221 / 466, SEQ ID NQs:225 / 470, SEQ ID NOs:227 / 472, SEQ ID NOs:229 / 474, or SEQ ID NOs:231 / 476.- 80 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT 21. The method of any one of claims 1 to 5, wherein the subsequent mtHTT variant or further subsequent mtHTT variant comprises 4:3243330:C:T; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:478, SEQ ID NO:479, SEQ ID NO:482, SEQ ID NO:484, SEQ ID NO:486, or SEQ ID NO:488; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or further subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:233 / 478, SEQ ID NOs:234 / 479, SEQ ID NOs:237 / 482, SEQ ID NOs:239 / 484, SEQ ID NOs:241 / 486, or SEQ ID NOs:243 / 488; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NQ:480, SEQ ID NO:481, SEQ ID NO:483, SEQ ID NO:485, SEQ ID NO:487, SEQ ID NO:489, or SEQ ID NO:490; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule or further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NQs:235 / 480, SEQ ID NOs:236 / 481, SEQ ID NOs:238 / 483, SEQ ID NOs:240 / 485, SEQ ID NOs:242 / 487, SEQ ID NOs:244 / 489, or SEQ ID NQs:245 / 490.

22. A method of treating a subject having Huntington's disease or at risk of developing Huntington's disease, wherein the subject has a pathogenic mutant huntingtin (mtHTT) allele, the method comprising:a) performing or having performed a sequence analysis on a biological sample obtained from the subject;b) determining from the sequence analysis or having determined from the sequence analysis whether the subject is heterozygous for a first mtHTT variant, wherein the first mtHTT variant targeted allele is in phase with the pathogenic mtHTT allele, wherein the first mtHTT variant targeted allele is the alternate allele of the first mtHTT variant and is in phase with the pathogenic mtHTT allele more often than any other allele in a population of subjects; and- 81 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT i) administering or continuing to administer a first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule to the subject that is heterozygous for the first mtHTT variant targeted allele in phase with the pathogenic mtHTT allele; orii) performing step c) for the subject that is homozygous for the first mtHTT variant or heterozygous for the first mtHTT variant but the targeted allele is not in phase with the pathogenic mtHTT allele;c) determining from the sequence analysis or having determined from the sequence analysis whether the subject is heterozygous for a first subsequent mtHTT variant and heterozygous for a second subsequent mtHTT variant; andi) administering or continuing to administer a first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule to the subject that has both the first subsequent mtHTT variant alternate allele and the second subsequent mtHTT variant alternate allele in phase with the pathogenic mtHTT allele; orii) administering or continuing to administer a first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule to the subject that has both the first subsequent mtHTT variant reference allele and the second subsequent mtHTT variant reference allele in phase with the pathogenic mtHTT allele; oriii) administering or continuing to administer a first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant reference allelespecific inhibitory nucleic acid molecule to the subject that has both the first subsequent mtHTT variant alternate allele and the second subsequent mtHTT variant reference allele in phase with the pathogenic mtHTT allele; oriv) administering or continuing to administer a first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant alternate allelespecific inhibitory nucleic acid molecule to the subject that has both the first subsequent mtHTT variant reference allele and the second subsequent mtHTT variant alternate allele in phase with the pathogenic mtHTT allele; or- 82 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT ii) repeating step c) for the subject that is homozygous for either the first subsequent mtHTT variant or the second subsequent mtHTT variant until a first further subsequent mtHTT variant a second further subsequent mtHTT variant that are heterozygous is identified for the subject, and administering to the subject or continuing to administer to the subject:a first further subsequent mtHTT variant alternate allele- specific / second further subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule to the subject that has both the first further subsequent mtHTT variant alternate allele and the second further subsequent mtHTT variant alternate allele in phase with the pathogenic mtHTT allele; ora first further subsequent mtHTT variant reference allele- specific / second further subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule to the subject that has both the first further subsequent mtHTT variant reference allele and the second further subsequent mtHTT variant reference allele in phase with the pathogenic mtHTT allele; ora first further subsequent mtHTT variant alternate allele- specific / second further subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule to the subject that has both the first further subsequent mtHTT variant alternate allele and the second further subsequent mtHTT variant reference allele in phase with the pathogenic mtHTT allele; ora first further subsequent mtHTT variant reference allele- specific / second further subsequent mtHTT variant alternate allelespecific inhibitory nucleic acid molecule to the subject that has both the first further subsequent mtHTT variant reference allele and the second further subsequent mtHTT variant alternate allele in phase with the pathogenic mtHTT allele.- 83 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT 23. The method of claim 22, wherein the first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant reference allelespecific inhibitory nucleic acid molecule, first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, first further subsequent mtHTT variant alternate allele-specific / second further subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, first further subsequent mtHTT variant reference allele-specific / second further subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, first further subsequent mtHTT variant alternate allele-specific / second further subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, and first further subsequent mtHTT variant reference allele-specific / second further subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule comprise an antisense nucleic acid molecule, a small interfering RNA (siRNA), or a short hairpin RNA (shRNA).

24. The method of claim 23, wherein the first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant reference allelespecific inhibitory nucleic acid molecule, first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, first further subsequent mtHTT variant alternate allele-specific / second further subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, first further subsequent mtHTT variant reference allele-specific / second further subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, first further subsequent mtHTT variant alternate allele-specific / second further subsequent mtHTT- 84 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT variant reference allele-specific inhibitory nucleic acid molecule, and first further subsequent mtHTT variant reference allele-specific / second further subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule comprise an siRNA.

25. The method of claim 23, wherein the first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant reference allelespecific inhibitory nucleic acid molecule, first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, first further subsequent mtHTT variant alternate allele-specific / second further subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, first further subsequent mtHTT variant reference allele-specific / second further subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, first further subsequent mtHTT variant alternate allele-specific / second further subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, and first further subsequent mtHTT variant reference allele-specific / second further subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule comprise an antisense nucleic acid molecule.

26. The method of any one of claims 22 to 25, wherein the first mtHTT variant comprises 4:3228683:AGAG:A; and i) the first mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:334, SEQ ID NO:335, or SEQ ID NO:336; or ii) the first mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprisin the nucleotide sequences of SEQ ID NOs:89 / 334, SE ID NQs:90 / 335, or SEQ ID NOs:91 / 336.

27. The method of any one of claims 22 to 26, wherein the first subsequent mtHTT variant comprises 4:3240433:C:G and the second subsequent mtHTT variant comprises 4:3240421:C:G, and:- 85 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT i) the first subsequent mtHTT variant alternate-specific / second subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or the first further subsequent mtHTT variant alternate-specific / second further subsequent mtHTT variant alternatespecific inhibitory nucleic acid molecule comprises: a) an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:394, SEQ ID NO:396, SEQ ID NO:397, SEQ ID NO:402, SEQ ID NO:404, or SEQ ID NQ:408; or b) an siRNA comprising the nucleotide sequences of SEQ ID NOs:149 / 394, SEQ ID NOs:151 / 396, SEQ ID NOs:152 / 397, SEQ ID NOs:157 / 402, SEQ ID NQs:159 / 404, or SEQ ID NOs:163 / 408;ii) the first subsequent mtHTT variant reference-specific / second subsequent mtHTT reference-specific inhibitory nucleic acid molecule or the first further subsequent mtHTT variant reference-specific / second further subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises: a) an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:398 or SEQ ID NO:405; or b) an siRNA comprising the nucleotide sequences of SEQ ID NOs:153 / 398 or SEQ ID NQs:160 / 405;iii) the first subsequent mtHTT variant alternate-specific / second subsequent mtHTT variant reference-specific inhibitory nucleic acid molecule or the first further subsequent mtHTT variant alternate-specific / second further subsequent mtHTT variant referencespecific inhibitory nucleic acid molecule comprises: a) an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:395, SEQ ID NO:399, SEQ ID NQ:401, SEQ ID NQ:403, or SEQ ID NQ:407; or b) an siRNA comprising the nucleotide sequences of SEQ ID NOs:150 / 395, SEQ ID NOs:154 / 399, SEQ ID NOs:156 / 401, SEQ ID NOs:158 / 403, or SEQ ID NOs: 162 / 407; andiv) the first subsequent mtHTT variant reference-specific / second subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule or first further subsequent mtHTT variant reference-specific / second further subsequent mtHTT variant alternatespecific inhibitory nucleic acid molecule comprises: a) an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NQ:400 or SEQ ID NO:406; or b) an siRNA comprising the nucleotide sequences of SEQ ID NQs:155 / 400 or SEQ ID NQs:161 / 406.- 86 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT 28. The method of any one of claims 1 to 27, wherein the subject is also administered a Huntington's disease therapeutic agent.

29. The method of claim 28, wherein the Huntington's disease therapeutic agent comprises deutetrabenazine, fluphenazine, haloperidol, tetrabenazine, tiapride, valbenazine, risperidone, olanzapine, or aripiprazole, or any combination thereof.

30. A method of treating a subject having Huntington's disease or at risk of developing Huntington's disease, wherein the subject has a pathogenic mutant huntingtin (mtHTT) allele, the method comprising:i) administering a first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule to the subject that is heterozygous for a first mtHTT variant targeted allele in phase with the pathogenic mtHTT allele, wherein the first mtHTT variant targeted allele isthe alternate allele of the first mtHTT variant and is in phase with the pathogenic mtHTT allele more often than any other allele in a population of subjects; andii) for the subject that is homozygous for the first mtHTT variant or heterozygous for the first mtHTT variant but the targeted allele is not in phase with the pathogenic mtHTT allele, administering a subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule or a subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, whichever allele is in phase with the pathogenic mtHTT allele.

31. The method of claim 30, wherein the first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, or subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule, a small interfering RNA (siRNA), or a short hairpin RNA (shRNA).

32. The method of claim 31, wherein the first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, or subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule comprises an siRNA.- 87 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT 33. The method of claim 31, wherein the first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, or subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule.

34. The method of any one of claims 30 to 33, wherein the first mtHTT variant comprises 4:3228683:AGAG:A; and i) the first mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:334, SEQ ID NO:335, or SEQ ID NO:336; or ii) the first mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprisin the nucleotide sequences of SEQ ID NOs:89 / 334, SE ID NQs:90 / 335, or SEQ ID NOs:91 / 336.

35. The method of any one of claims 30 to 34, wherein the subsequent mtHTT variant comprises 4:3240421:C:G; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:380, SEQ ID NO:382, SEQ ID NO:384, SEQ ID NO:387, SEQ ID NO:389, or SEQ ID NO:392; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:135 / 380, SEQ ID NOs:137 / 382, SEQ ID NOs:139 / 384, SEQ ID NOs:142 / 387, SEQ ID NOs:144 / 389, or SEQ ID NOs:147 / 392; iii) the subsequent mtHTT variant reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:379, SEQ ID NO:381, SEQ ID NO:383, SEQ ID NO:385, SEQ ID NO:386, SEQ ID NO:388, SEQ ID NQ:390, SEQ ID NO:391, or SEQ ID NO:393; or iv) the subsequent mtHTT variant reference-specific inhibitory nucleic acid molecule comprises an siRNA comprisingthe nucleotide sequences of SEQ ID NOs: 134 / 379, SEQ ID NOs:136 / 381, SEQ ID NOs:138 / 383, SEQ ID NOs:140 / 385, SEQ ID NOs:141 / 386, SEQ ID NOs:143 / 388, SEQ ID NQs:145 / 390, SEQ ID NOs:146 / 391, or SEQ ID NOs:148 / 393.

36. The method of any one of claims 30 to 34, wherein the subsequent mtHTT variant comprises 4:3074723:C:T; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:247, SEQ ID NO:249, SEQ ID NO:251, SEQ ID NO:253, SEQ - 88 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT ID NO:255, SEQ ID NO:257, SEQ ID NO:259, SEQ ID NO:261, or SEQ ID NO:263; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:2 / 247, SEQ ID NOs:4 / 249, SEQ ID NOs:6 / 251, SEQ ID NOs:8 / 253, SEQ ID NQs:10 / 255, SEQ ID NOs:12 / 257, SEQ ID NOs:14 / 259, SEQ ID NOs:16 / 261, or SEQ ID NOs:18 / 263; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:246, SEQ ID NO:248, SEQ ID NO:250, SEQ ID NO:252, SEQ ID NO:254, SEQ ID NO:256, SEQ ID NO:258, SEQ ID NQ:260, or SEQ ID NO:262; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:l / 246, SEQ ID NOs:3 / 248, SEQ ID NQs:5 / 250, SEQ ID NOs:7 / 252, SEQ ID NOs:9 / 254, SEQ ID NOs:ll / 256, SEQ ID NOs:13 / 258, SEQ ID NOs:15 / 260, or SEQ ID NOs:17 / 262.

37. The method of any one of claims 30 to 34, wherein the subsequent mtHTT variant comprises 4:3115441:C:G; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:265, SEQ ID NO:266, SEQ ID NO:268, SEQ ID NQ:270, SEQ ID NO:272, SEQ ID NO:274, SEQ ID NO:276, or SEQ ID NO:278; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NQs:20 / 265, SEQ ID NOs:21 / 266, SEQ ID NOs:23 / 268, SEQ ID NQs:25 / 270, SEQ ID NOs:27 / 272, SEQ ID NOs:29 / 274, SEQ ID NOs:31 / 276, or SEQ ID NOs:33 / 278; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:264, SEQ ID NO:267, SEQ ID NO:269, SEQ ID NO:271, SEQ ID NO:273, SEQ ID NO:275, or SEQ ID NO:277; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:19 / 264, SEQ ID NOs:22 / 267, SEQ ID NOs:24 / 269, SEQ ID NOs:26 / 271, SEQ ID NOs:28 / 273, SEQ ID NQs:30 / 275, or SEQ ID NOs:32 / 277.

38. The method of any one of claims 30 to 34, wherein the subsequent mtHTT variant comprises 4:3160329:C:T; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe- 89 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT nucleotide sequence of SEQ ID NO:279, SEQ ID NO:280, SEQ ID NO:282, SEQ ID NO:284, SEQ ID NO:286, or SEQ ID NO:287; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:34 / 279, SEQ ID NQs:35 / 280, SEQ ID NOs:37 / 282, SEQ ID NOs:39 / 284, SEQ ID NOs:41 / 286, or SEQ ID NOs:42 / 287; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:281, SEQ ID NO:283, SEQ ID NO:285, or SEQ ID NO:288; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:36 / 281, SEQ ID NOs:38 / 283, SEQ ID NQs:40 / 285, or SEQ ID NOs:43 / 288.

39. The method of any one of claims 30 to 34, wherein the subsequent mtHTT variant comprises 4:3187820:C:A; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:289, SEQ ID NO:291, SEQ ID NO:294, SEQ ID NO:296, or SEQ ID NO:297; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:44 / 289, SEQ ID NOs:46 / 291, SEQ ID NOs:49 / 294, SEQ ID NOs:51 / 296, or SEQ ID NOs:52 / 297; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:290, SEQ ID NO:292, SEQ ID NO:293, SEQ ID NO:295, or SEQ ID NO:298; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprisin the nucleotide sequences of SEQ ID NQs:45 / 290, SEQ ID NOs:47 / 292, SEQ ID NOs:48 / 293, SEQ ID NQs:50 / 295, or SEQ ID NOs:53 / 298.

40. The method of any one of claims 30 to 34, wherein the subsequent mtHTT variant comprises 4:3212105:G:A; and i) the subsequent mtHTT variant reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:299, SEQ ID NQ:300, SEQ ID NQ:301, SEQ ID NQ:302, or SEQ ID NQ:303; or ii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:54 / 299, SEQ ID NQs:55 / 300, SEQ ID NQs:56 / 301, SEQ ID NQs:57 / 302, or SEQ ID NOs:58 / 303.- 90 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT 41. The method of any one of claims 30 to 34, wherein the subsequent mtHTT variant comprises 4:3229934:G:A; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:313, SEQ ID NO:315, SEQ ID NO:316, SEQ ID NO:317, SEQ ID NO:320, SEQ ID NO:322, or SEQ ID NO:325; ii) the subsequent mtHTT variant alternatespecific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:68 / 313, SEQ ID NQ:70 / 315, SEQ ID NOs:71 / 316, SEQ ID NOs:72 / 317, SEQ ID NOs:75 / 320, SEQ ID NOs:77 / 322, or SEQ ID NQs:80 / 325; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:312, SEQ ID NO:314, SEQ ID NO:318, SEQ ID NO:319, SEQ ID NO:321, SEQ ID NO:323, or SEQ ID NO:324; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:67 / 312, SEQ ID NOs:69 / 314, SEQ ID NOs:73 / 318, SEQ ID NOs:74 / 319, SEQ ID NOs:76 / 321, SEQ ID NOs:78 / 323, or SEQ ID NOs:79 / 324.

42. The method of any one of claims 30 to 34, wherein the subsequent mtHTT variant comprises 4:3225692:A:G; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:326, SEQ ID NO:328, or SEQ ID NQ:330; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprisingthe nucleotide sequences of SEQ ID NOs:81 / 326, SEQ ID NOs:83 / 328, or SEQ ID NOs:85 / 330; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:327, SEQ ID NO:329, SEQ ID NO:331, or SEQ ID NO:332; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:82 / 327, SEQ ID NOs:84 / 329, SEQ ID NOs:86 / 331, or SEQ ID NOs:87 / 332.

43. The method of any one of claims 30 to 34, wherein the subsequent mtHTT variant comprises 4:3233253:G:A; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe- 91 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT nucleotide sequence of SEQ ID NO:338, SEQ ID NO:339, SEQ ID NO:341, SEQ ID NO:345, SEQ ID NO:346, SEQ ID NO:349, or SEQ ID NO:351; ii) the subsequent mtHTT variant alternatespecific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:93 / 338, SEQ ID NOs:94 / 339, SEQ ID NOs:96 / 341, SEQ ID NQs:100 / 345, SEQ ID NQs:101 / 346, SEQ ID NOs:104 / 349, or SEQ ID NOs:106 / 351; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:337, SEQ ID NQ:340, SEQ ID NO:342, SEQ ID NO:343, SEQ ID NO:344, SEQ ID NO:347, SEQ ID NO:348, or SEQ ID NO:350; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:92 / 337, SEQ ID NOs:95 / 340, SEQ ID NOs:97 / 342, SEQ ID NOs:98 / 343, SEQ ID NOs:99 / 344, SEQ ID NQs:102 / 347, SEQ ID NQs:103 / 348, or SEQ ID NQs:105 / 350.

44. The method of any one of claims 30 to 34, wherein the subsequent mtHTT variant comprises 4:3240373:G:A; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NQ:370, SEQ ID NO:372, SEQ ID NO:373, SEQ ID NO:376, SEQ ID NO:377, or SEQ ID NO:378; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:125 / 370, SEQ ID NOs:127 / 372, SEQ ID NOs:128 / 373, SEQ ID NOs:131 / 376, SEQ ID NOs:132 / 377, or SEQ ID NO:133 / 378; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:369, SEQ ID NO:371, SEQ ID NO:374, or SEQ ID NO:375; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:124 / 369, SEQ ID NOs:126 / 371, SEQ ID NOs:129 / 374, or SEQ ID NOs:130 / 375.

45. The method of any one of claims 30 to 34, wherein the subsequent mtHTT variant comprises 4:3240433:C:G; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NQ:410 or SEQ ID NO:411; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the- 92 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT nucleotide sequences of SEQ ID NOs:165 / 410 or SEQ ID NOs:166 / 411; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:409 or SEQ ID NO:412; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NQs:164 / 409 or SEQ ID NOs:167 / 412.

46. The method of any one of claims 30 to 34, wherein the subsequent mtHTT variant comprises 4:3240545:C:A; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:413, SEQ ID NO:415, SEQ ID NO:417, SEQ ID NO:419, SEQ ID NO:421, SEQ ID NO:422, or SEQ ID NO:424; ii) the subsequent mtHTT variant alternatespecific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:168 / 413, SEQ ID NQs:170 / 415, SEQ ID NOs:172 / 417, SEQ ID NOs:174 / 419, SEQ ID NOs:176 / 421, SEQ ID NOs:177 / 422, or SEQ ID NOs:179 / 424; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:414, SEQ ID NO:416, SEQ ID NO:418, SEQ ID NO:420, or SEQ ID NO:423; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprisingthe nucleotide sequences of SEQ ID NOs:169 / 414, SEQ ID NOs:171 / 416, SEQ ID NOs:173 / 418, SEQ ID NQs:175 / 420, or SEQ ID NOs:178 / 423.

47. The method of any one of claims 30 to 34, wherein the subsequent mtHTT variant comprises 4:3240580:C:T; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:426, SEQ ID NQ:430, SEQ ID NO:432, SEQ ID NO:433, SEQ ID NO:436, SEQ ID NO:438, SEQ ID NO:439, or SEQ ID NO:441; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:181 / 426, SEQ ID NQs:185 / 430, SEQ ID NOs:187 / 432, SEQ ID NOs:188 / 433, SEQ ID NOs:191 / 436, SEQ ID NOs:193 / 438, SEQ ID NOs:194 / 439, or SEQ ID NOs:196 / 441; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:425, SEQ ID NO:427, SEQ ID NO:428, SEQ ID NO:429,- 93 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT SEQ ID NO:431, SEQ ID NO:434, SEQ ID NO:435, SEQ ID NO:437, SEQ ID NO:440, or SEQ ID NO:442; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NQs:180 / 425, SEQ ID NOs:182 / 427, SEQ ID NOs:183 / 428, SEQ ID NOs:184 / 429, SEQ ID NOs:186 / 431, SEQ ID NOs:189 / 434, SEQ ID NQs:190 / 435, SEQ ID NOs:192 / 437, SEQ ID NQs:195 / 440, or SEQ ID NOs: 197 / 442.

48. The method of any one of claims 30 to 34, wherein the subsequent mtHTT variant comprises 4:3241491:C:T; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:443, SEQ ID NO:445, SEQ ID NO:446, SEQ ID NO:449, SEQ ID NQ:450, SEQ ID NO:452, SEQ ID NO:454, SEQ ID NO:456, or SEQ ID NO:458; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprisingthe nucleotide sequences of SEQ ID NOs:198 / 443, SEQ ID NQs:200 / 445, SEQ ID NQs:201 / 446, SEQ ID NQs:204 / 449, SEQ ID NQs:205 / 450, SEQ ID NQs:207 / 452, SEQ ID NQs:209 / 454, SEQ ID NOs:211 / 456, or SEQ ID NOs:213 / 458; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:444, SEQ ID NO:447, SEQ ID NO:448, SEQ ID NO:451, SEQ ID NO:453, SEQ ID NO:455, SEQ ID NO:457, or SEQ ID NO:459; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:199 / 444, SEQ ID NQs:202 / 447, SEQ ID NOs:203 / 448, SEQ ID NOs:206 / 451, SEQ ID NQs:208 / 453, SEQ ID NQs:210 / 455, SEQ ID NOs:212 / 457, or SEQ ID NOs:214 / 459.

49. The method of any one of claims 30 to 34, wherein the subsequent mtHTT variant comprises 4:3241563:G:A; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:460, SEQ ID NO:463, SEQ ID NO:465, SEQ ID NO:467, SEQ ID NO:468, SEQ ID NO:469, SEQ ID NO:471, SEQ ID NO:473, SEQ ID NO:475, or SEQ ID NO:477; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:215 / 460, SEQ ID NOs:218 / 463, SEQ ID NQs:220 / 465, SEQ ID NOs:222 / 467, SEQ ID NOs:223 / 468, SEQ ID - 94 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT NOs:224 / 469, SEQ ID NOs:226 / 471, SEQ ID NOs:228 / 473, SEQ ID NOs:230 / 475, or SEQ ID NOs:232 / 477; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:461, SEQ ID NO:462, SEQ ID NO:464, SEQ ID NO:466, SEQ ID NQ:470, SEQ ID NO:472, SEQ ID NO:474, or SEQ ID NO:476; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:216 / 461, SEQ ID NOs:217 / 462, SEQ ID NOs:219 / 464, SEQ ID NOs:221 / 466, SEQ ID NQs:225 / 470, SEQ ID NOs:227 / 472, SEQ ID NOs:229 / 474, or SEQ ID NOs:231 / 476.

50. The method of any one of claims 30 to 34, wherein the subsequent mtHTT variant comprises 4:3243330:C:T; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:478, SEQ ID NO:479, SEQ ID NO:482, SEQ ID NO:484, SEQ ID NO:486, or SEQ ID NO:488; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:233 / 478, SEQ ID NOs:234 / 479, SEQ ID NOs:237 / 482, SEQ ID NOs:239 / 484, SEQ ID NOs:241 / 486, or SEQ ID NOs:243 / 488; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:480, SEQ ID NO:481, SEQ ID NO:483, SEQ ID NO:485, SEQ ID NO:487, SEQ ID NO:489, or SEQ ID NQ:490; or iv) the subsequent mtHTT referencespecific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NQs:235 / 480, SEQ ID NOs:236 / 481, SEQ ID NOs:238 / 483, SEQ ID NQs:240 / 485, SEQ ID NOs:242 / 487, SEQ ID NOs:244 / 489, or SEQ ID NQs:245 / 490.

51. A method of treating a subject having Huntington's disease or at risk of developing Huntington's disease, wherein the subject has a pathogenic mutant huntingtin (mtHTT) allele, the method comprising:i) administering a first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule to the subject that is heterozygous for a first mtHTT variant targeted allele in phase with the pathogenic mtHTT allele, wherein the first mtHTT variant targeted allele is the alternate allele of the first mtHTT variant and is in phase with the pathogenic mtHTT allele more often than any other allele in a population of subjects; and- 95 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT ii) for the subject that is homozygous for the first mtHTT variant or heterozygous for the first mtHTT variant but the targeted allele is not in phase with the pathogenic mtHTT allele:a) administering or continuing to administer a first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule to the subject that has both the first subsequent mtHTT variant alternate allele and the second subsequent mtHTT variant alternate allele in phase with the pathogenic mtHTT allele; orb) administering or continuing to administer a first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule to the subject that has both the first subsequent mtHTT variant reference allele and the second subsequent mtHTT variant reference allele in phase with the pathogenic mtHTT allele; orc) administering or continuing to administer a first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant reference allelespecific inhibitory nucleic acid molecule to the subject that has both the first subsequent mtHTT variant alternate allele and the second subsequent mtHTT variant reference allele in phase with the pathogenic mtHTT allele; ord) administering or continuing to administer a first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant alternate allelespecific inhibitory nucleic acid molecule to the subject that has both the first subsequent mtHTT variant reference allele and the second subsequent mtHTT variant alternate allele in phase with the pathogenic mtHTT allele.

52. The method of claim 51, wherein the first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant reference allelespecific inhibitory nucleic acid molecule, and first subsequent mtHTT variant reference - 96 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule comprise an antisense nucleic acid molecule, a small interfering RNA (siRNA), or a short hairpin RNA (shRNA).

53. The method of claim 52, wherein the first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant reference allelespecific inhibitory nucleic acid molecule, and first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule comprise an siRNA.

54. The method of claim 52, wherein the first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant reference allelespecific inhibitory nucleic acid molecule, and first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule comprise an antisense nucleic acid molecule.

55. The method of any one of claims 51 to 54, wherein the first mtHTT variant comprises 4:3228683:AGAG:A; and i) the first mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisin the nucleotide sequence of SEQ ID NO:334, SEQ ID NO:335, or SEQ ID NO:336; or ii) the first mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:89 / 334, SE ID NQs:90 / 335, or SEQ ID NOs:91 / 336.- 97 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT 56. The method of any one of claims 51 to 55, wherein the first subsequent mtHTT variant comprises 4:3240433:C:G and the second subsequent mtHTT variant comprises 4:3240421:C:G, and:i) the first subsequent mtHTT variant alternate-specific / second subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises: a) an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:394, SEQ ID NO:396, SEQ ID NO:397, SEQ ID NO:402, SEQ ID NQ:404, or SEQ ID NQ:408; or b) an siRNA comprising the nucleotide sequences of SEQ ID NOs:149 / 394, SEQ ID NOs:151 / 396, SEQ ID NOs:152 / 397, SEQ ID NQs:157 / 402, SEQ ID NQs:159 / 404, or SEQ ID NOs:163 / 408;ii) the first subsequent mtHTT variant reference-specific / second subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises: a) an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:398 or SEQ ID NQ:405; or b) an siRNA comprising the nucleotide sequences of SEQ ID NOs:153 / 398 or SEQ ID NQs:160 / 405;iii) the first subsequent mtHTT variant alternate-specific / second subsequent mtHTT variant reference-specific inhibitory nucleic acid molecule comprises: a) an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:395, SEQ ID NO:399, SEQ ID NO:401, SEQ ID NO:403, or SEQ ID NQ:407; or b) an siRNA comprising the nucleotide sequences of SEQ ID NQs:150 / 395, SEQ ID NOs:154 / 399, SEQ ID NQs:156 / 401, SEQ ID NOs:158 / 403, or SEQ ID NOs:162 / 407; andiv) the first subsequent mtHTT variant reference-specific / second subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises: a) an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NQ:400 or SEQ ID NQ:406; or b) an siRNA comprisingthe nucleotide sequences of SEQ ID NQs:155 / 400 or SEQ ID NQs:161 / 406.

57. The method of any one of claims 30 to 56, wherein the subject is also administered a Huntington's disease therapeutic agent.

58. The method of claim 57, wherein the Huntington's disease therapeutic agent comprises deutetrabenazine, fluphenazine, haloperidol, tetrabenazine, tiapride, valbenazine, risperidone, olanzapine, or aripiprazole, or any combination thereof.- 98 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT 59. A method of identifying a subject having Huntington's disease or at risk of developing Huntington's disease that is a candidate for treatment with an inhibitory nucleic acid molecule, wherein the subject has a pathogenic mutant huntingtin (mtHTT) allele, the method comprising:a) performing or having performed a sequence analysis on a biological sample obtained from the subject; andi) determining from the sequence analysis or having determined from the sequence analysis whether the subject is heterozygous for a first mtHTT variant, wherein a first mtHTT variant targeted allele is in phase with the pathogenic mtHTT allele, wherein the first mtHTT variant targeted allele is the alternate allele of the first mtHTT variant and is in phase with the pathogenic mtHTT allele more often than any other allele in a population of subjects, wherein the subject is a candidate for treatment with a first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule when the subject is heterozygous for the first mtHTT variant targeted allele in phase with the pathogenic mtHTT allele; orii) for the subject that is homozygous for the first mtHTT variant, or heterozygous for the first mtHTT variant but the targeted allele is not in phase with the pathogenic mtHTT allele, determining from the sequence analysis or having determined from the sequence analysis whether the subject is heterozygous for a subsequent mtHTT variant in which the alternate allele or reference allele is in phase with the pathogenic mtHTT allele, wherein the subject is a candidate for treatment with a subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule or a subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, whichever is in phase with the pathogenic mtHTT allele, when the subject is heterozygous forthe subsequent mtHTT variant.

60. The method of claim 59, wherein the first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, and subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule comprise an antisense nucleic acid molecule, a small interfering RNA (siRNA), or a short hairpin RNA (shRNA).- 99 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT 61. The method of claim 60, wherein the first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, and subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule comprise an siRNA.

62. The method of claim 60, wherein the first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, and subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule comprise an antisense nucleic acid molecule.

63. The method of any one of claims 59 to 62, wherein the first mtHTT variant comprises 4:3228683:AGAG:A; and i) the first mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:334, SEQ ID NO:335, or SEQ ID NO:336; or ii) the first mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:89 / 334, SEQ ID NQs:90 / 335, or SEQ ID NOs:91 / 336.

64. The method of any one of claims 59 to 63, wherein the subsequent mtHTT variant comprises 4:3240421:C:G; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NQ:380, SEQ ID NO:382, SEQ ID NO:384, SEQ ID NO:387, SEQ ID NO:389, or SEQ ID NO:392; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NQs:135 / 380, SEQ ID NOs:137 / 382, SEQ ID NOs:139 / 384, SEQ ID NOs:142 / 387, SEQ ID NOs:144 / 389, or SEQ ID NOs:147 / 392; iii) the subsequent mtHTT variant reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:379, SEQ ID NO:381, SEQ ID NO:383, SEQ ID NO:385, SEQ ID NO:386, SEQ ID NO:388, SEQ ID NQ:390, SEQ ID NO:391, or SEQ ID NO:393; or iv) the subsequent mtHTT variant reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs: 134 / 379, SEQ ID NOs:136 / 381, SEQ ID NOs:138 / 383, SEQ ID NOs:140 / 385, SEQ ID NOs:141 / 386, SEQ ID NOs:143 / 388, SEQ ID NQs:145 / 390, SEQ ID NOs:146 / 391, or SEQ ID NOs:148 / 393.- 100 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT 65. The method of any one of claims 59 to 63, wherein the subsequent mtHTT variant comprises 4:3074723:C:T; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:247, SEQ ID NO:249, SEQ ID NO:251, SEQ ID NO:253, SEQ ID NO:255, SEQ ID NO:257, SEQ ID NO:259, SEQ ID NO:261, or SEQ ID NO:263; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:2 / 247, SEQ ID NOs:4 / 249, SEQ ID NOs:6 / 251, SEQ ID NOs:8 / 253, SEQ ID NQs:10 / 255, SEQ ID NOs:12 / 257, SEQ ID NOs:14 / 259, SEQ ID NOs:16 / 261, or SEQ ID NOs:18 / 263; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:246, SEQ ID NO:248, SEQ ID NQ:250, SEQ ID NO:252, SEQ ID NO:254, SEQ ID NO:256, SEQ ID NO:258, SEQ ID NO:260, or SEQ ID NO:262; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:l / 246, SEQ ID NOs:3 / 248, SEQ ID NOs:5 / 250, SEQ ID NOs:7 / 252, SEQ ID NOs:9 / 254, SEQ ID NOs:ll / 256, SEQ ID NOs:13 / 258, SEQ ID NQs:15 / 260, or SEQ ID NOs:17 / 262.

66. The method of any one of claims 59 to 63, wherein the subsequent mtHTT variant comprises 4:3115441:C:G; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:265, SEQ ID NO:266, SEQ ID NO:268, SEQ ID NQ:270, SEQ ID NO:272, SEQ ID NO:274, SEQ ID NO:276, or SEQ ID NO:278; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:20 / 265, SEQ ID NOs:21 / 266, SEQ ID NOs:23 / 268, SEQ ID NQs:25 / 270, SEQ ID NOs:27 / 272, SEQ ID NOs:29 / 274, SEQ ID NOs:31 / 276, or SEQ ID NOs:33 / 278; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:264, SEQ ID NO:267, SEQ ID NO:269, SEQ ID NO:271, SEQ ID NO:273, SEQ ID NO:275, or SEQ ID NO:277; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:19 / 264,- 101 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT SEQ ID NOs:22 / 267, SEQ ID NOs:24 / 269, SEQ ID NOs:26 / 271, SEQ ID NOs:28 / 273, SEQ ID NQs:30 / 275, or SEQ. ID NOs:32 / 277.

67. The method of any one of claims 59 to 63, wherein the subsequent mtHTT variant comprises 4:3160329:C:T; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:279, SEQ ID NQ:280, SEQ ID NO:282, SEQ ID NO:284, SEQ ID NO:286, or SEQ ID NO:287; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:34 / 279, SEQ ID NQs:35 / 280, SEQ ID NOs:37 / 282, SEQ ID NOs:39 / 284, SEQ ID NOs:41 / 286, or SEQ ID NOs:42 / 287; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:281, SEQ ID NO:283, SEQ ID NO:285, or SEQ ID NO:288; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:36 / 281, SEQ ID NOs:38 / 283, SEQ ID NOs:40 / 285, or SEQ ID NOs:43 / 288.

68. The method of any one of claims 59 to 63, wherein the subsequent mtHTT variant comprises 4:3187820:C:A; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:289, SEQ ID NO:291, SEQ ID NO:294, SEQ ID NO:296, or SEQ ID NO:297; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:44 / 289, SEQ ID NOs:46 / 291, SEQ ID NOs:49 / 294, SEQ ID NOs:51 / 296, or SEQ ID NOs:52 / 297; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NQ:290, SEQ ID NO:292, SEQ ID NO:293, SEQ ID NO:295, or SEQ ID NO:298; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprisingthe nucleotide sequences of SEQ ID NQs:45 / 290, SEQ ID NOs:47 / 292, SEQ ID NOs:48 / 293, SEQ ID NQs:50 / 295, or SEQ ID NOs:53 / 298.- 102 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT 69. The method of any one of claims 59 to 63, wherein the subsequent mtHTT variant comprises 4:3212105:G:A; and i) the subsequent mtHTT variant reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:299, SEQ ID NO:300, SEQ ID NO:301, SEQ ID NO:302, or SEQ ID NO:303; or ii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:54 / 299, SEQ ID NQs:55 / 300, SEQ ID NQs:56 / 301, SEQ ID NQs:57 / 302, or SEQ ID NOs:58 / 303.

70. The method of any one of claims 59 to 63, wherein the subsequent mtHTT variant comprises 4:3229934:G:A; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:313, SEQ ID NO:315, SEQ ID NO:316, SEQ ID NO:317, SEQ ID NQ:320, SEQ ID NO:322, or SEQ ID NO:325; ii) the subsequent mtHTT variant alternatespecific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:68 / 313, SEQ ID NQ:70 / 315, SEQ ID NOs:71 / 316, SEQ ID NOs:72 / 317, SEQ ID NOs:75 / 320, SEQ ID NOs:77 / 322, or SEQ ID NQs:80 / 325; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:312, SEQ ID NO:314, SEQ ID NO:318, SEQ ID NO:319, SEQ ID NO:321, SEQ ID NO:323, or SEQ ID NO:324; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:67 / 312, SEQ ID NOs:69 / 314, SEQ ID NOs:73 / 318, SEQ ID NOs:74 / 319, SEQ ID NOs:76 / 321, SEQ ID NOs:78 / 323, or SEQ ID NOs:79 / 324.

71. The method of any one of claims 59 to 63, wherein the subsequent mtHTT variant comprises 4:3225692:A:G; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:326, SEQ ID NO:328, or SEQ ID NQ:330; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprisingthe nucleotide sequences of SEQ ID NOs:81 / 326, SEQ ID NOs:83 / 328, or SEQ ID NOs:85 / 330; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence - 103 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT of SEQ ID NO:327, SEQ ID NO:329, SEQ ID NO:331, or SEQ ID NO:332; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:82 / 327, SEQ ID NOs:84 / 329, SEQ ID NOs:86 / 331, or SEQ ID NOs:87 / 332.

72. The method of any one of claims 59 to 63, wherein the subsequent mtHTT variant comprises 4:3233253:G:A; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisin the nucleotide sequence of SEQ ID NO:338, SEQ ID NO:339, SEQ ID NO:341, SEQ ID NO:345, SEQ ID NO:346, SEQ ID NO:349, or SEQ ID NO:351; ii) the subsequent mtHTT variant alternatespecific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:93 / 338, SEQ ID NOs:94 / 339, SEQ ID NOs:96 / 341, SEQ ID NQs:100 / 345, SEQ ID NQs:101 / 346, SEQ ID NQs:104 / 349, or SEQ ID NOs:106 / 351; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:337, SEQ ID NQ:340, SEQ ID NO:342, SEQ ID NO:343, SEQ ID NO:344, SEQ ID NO:347, SEQ ID NO:348, or SEQ ID NO:350; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:92 / 337, SEQ ID NOs:95 / 340, SEQ ID NOs:97 / 342, SEQ ID NOs:98 / 343, SEQ ID NOs:99 / 344, SEQ ID NOs:102 / 347, SEQ ID NQs:103 / 348, or SEQ ID NQs:105 / 350.

73. The method of any one of claims 59 to 63, wherein the subsequent mtHTT variant comprises 4:3240373:G:A; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NQ:370, SEQ ID NO:372, SEQ ID NO:373, SEQ ID NO:376, SEQ ID NO:377, or SEQ ID NO:378; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:125 / 370, SEQ ID NOs:127 / 372, SEQ ID NOs:128 / 373, SEQ ID NOs:131 / 376, SEQ ID NOs:132 / 377, or SEQ ID NO:133 / 378; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:369, SEQ ID NO:371, SEQ ID NO:374, or SEQ ID NO:375; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises - 104 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT an siRNA comprising the nucleotide sequences of SEQ ID NOs:124 / 369, SEQ ID NOs:126 / 371, SEQ. ID NOs:129 / 374, or SEQ ID NQs:130 / 375.

74. The method of any one of claims 59 to 63, wherein the subsequent mtHTT variant comprises 4:3240433:C:G; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisin the nucleotide sequence of SEQ ID NQ:410 or SEQ ID NO:411; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NQs:165 / 410 or SEQ ID NOs:166 / 411; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NQ:409 or SEQ ID NO:412; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprisingthe nucleotide sequences of SEQ ID NQs:164 / 409 or SEQ ID NOs:167 / 412.

75. The method of any one of claims 59 to 63, wherein the subsequent mtHTT variant comprises 4:3240545:C:A; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:413, SEQ ID NO:415, SEQ ID NO:417, SEQ ID NO:419, SEQ ID NO:421, SEQ ID NO:422, or SEQ ID NO:424; ii) the subsequent mtHTT variant alternatespecific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:168 / 413, SEQ ID NQs:170 / 415, SEQ ID NOs:172 / 417, SEQ ID NOs:174 / 419, SEQ ID NOs:176 / 421, SEQ ID NOs:177 / 422, or SEQ ID NOs:179 / 424; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:414, SEQ ID NO:416, SEQ ID NO:418, SEQ ID NQ:420, or SEQ ID NO:423; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprisin the nucleotide sequences of SEQ ID NOs:169 / 414, SEQ ID NOs:171 / 416, SEQ ID NOs:173 / 418, SEQ ID NQs:175 / 420, or SEQ ID NOs:178 / 423.

76. The method of any one of claims 59 to 63, wherein the subsequent mtHTT variant comprises 4:3240580:C:T; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:426, SEQ ID NQ:430, SEQ ID NO:432, SEQ ID NO:433, SEQ - 105 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT ID NO:436, SEQ ID NO:438, SEQ ID NO:439, or SEQ ID NO:441; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:181 / 426, SEQ ID NQs:185 / 430, SEQ ID NOs:187 / 432, SEQ ID NOs:188 / 433, SEQ ID NOs:191 / 436, SEQ ID NOs:193 / 438, SEQ ID NOs:194 / 439, or SEQ ID NOs:196 / 441; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:425, SEQ ID NO:427, SEQ ID NO:428, SEQ ID NO:429, SEQ ID NO:431, SEQ ID NO:434, SEQ ID NO:435, SEQ ID NO:437, SEQ ID NQ:440, or SEQ ID NO:442; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NQs:180 / 425, SEQ ID NOs:182 / 427, SEQ ID NOs:183 / 428, SEQ ID NOs:184 / 429, SEQ ID NOs:186 / 431, SEQ ID NOs:189 / 434, SEQ ID NQs:190 / 435, SEQ ID NOs:192 / 437, SEQ ID NOs:195 / 440, or SEQ ID NOs: 197 / 442.

77. The method of any one of claims 59 to 63, wherein the subsequent mtHTT variant comprises 4:3241491:C:T; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:443, SEQ ID NO:445, SEQ ID NO:446, SEQ ID NO:449, SEQ ID NQ:450, SEQ ID NO:452, SEQ ID NO:454, SEQ ID NO:456, or SEQ ID NO:458; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:198 / 443, SEQ ID NQs:200 / 445, SEQ ID NOs:201 / 446, SEQ ID NOs:204 / 449, SEQ ID NQs:205 / 450, SEQ ID NOs:207 / 452, SEQ ID NQs:209 / 454, SEQ ID NOs:211 / 456, or SEQ ID NOs:213 / 458; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:444, SEQ ID NO:447, SEQ ID NO:448, SEQ ID NO:451, SEQ ID NO:453, SEQ ID NO:455, SEQ ID NO:457, or SEQ ID NO:459; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:199 / 444, SEQ ID NOs:202 / 447, SEQ ID NQs:203 / 448, SEQ ID NQs:206 / 451, SEQ ID NOs:208 / 453, SEQ ID NOs:210 / 455, SEQ ID NOs:212 / 457, or SEQ ID NOs:214 / 459.- 106 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT 78. The method of any one of claims 59 to 63, wherein the subsequent mtHTT variant comprises 4:3241563:G:A; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:460, SEQ ID NO:463, SEQ ID NO:465, SEQ ID NO:467, SEQ ID NO:468, SEQ ID NO:469, SEQ ID NO:471, SEQ ID NO:473, SEQ ID NO:475, or SEQ ID NO:477; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NQs:215 / 460, SEQ ID NOs:218 / 463, SEQ ID NQs:220 / 465, SEQ ID NOs:222 / 467, SEQ ID NOs:223 / 468, SEQ ID NOs:224 / 469, SEQ ID NOs:226 / 471, SEQ ID NOs:228 / 473, SEQ ID NOs:230 / 475, or SEQ ID NOs:232 / 477; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:461, SEQ ID NO:462, SEQ ID NO:464, SEQ ID NO:466, SEQ ID NQ:470, SEQ ID NO:472, SEQ ID NO:474, or SEQ ID NO:476; or iv) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:216 / 461, SEQ ID NOs:217 / 462, SEQ ID NOs:219 / 464, SEQ ID NOs:221 / 466, SEQ ID NQs:225 / 470, SEQ ID NOs:227 / 472, SEQ ID NOs:229 / 474, or SEQ ID NOs:231 / 476.

79. The method of any one of claims 59 to 63, wherein the subsequent mtHTT variant comprises 4:3243330:C:T; and i) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:478, SEQ ID NO:479, SEQ ID NO:482, SEQ ID NO:484, SEQ ID NO:486, or SEQ ID NO:488; ii) the subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:233 / 478, SEQ ID NOs:234 / 479, SEQ ID NOs:237 / 482, SEQ ID NOs:239 / 484, SEQ ID NOs:241 / 486, or SEQ ID NOs:243 / 488; iii) the subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NQ:480, SEQ ID NO:481, SEQ ID NO:483, SEQ ID NO:485, SEQ ID NO:487, SEQ ID NO:489, or SEQ ID NQ:490; or iv) the subsequent mtHTT referencespecific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:235 / 480, SEQ ID NOs:236 / 481, SEQ ID NOs:238 / 483, SEQ ID NQs:240 / 485, SEQ ID NOs:242 / 487, SEQ ID NOs:244 / 489, or SEQ ID NQs:245 / 490.- 107 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT 80. A method of identifying a subject having Huntington's disease or at risk of developing Huntington's disease that is a candidate for treatment with an inhibitory nucleic acid molecule, wherein the subject has a pathogenic mutant huntingtin (mtHTT) allele, the method comprising:performing or having performed a sequence analysis on a biological sample obtained from the subject; andi) determining from the sequence analysis or having determined from the sequence analysis whether the subject is heterozygous for a first mtHTT variant, wherein a first mtHTT variant targeted allele is in phase with the pathogenic mtHTT allele, wherein the first mtHTT variant targeted allele is the alternate allele of the first mtHTT variant and is in phase with the pathogenic mtHTT allele more often than any other allele in a population of subjects, wherein the subject is a candidate for treatment with a first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule when the subject is heterozygous for the first mtHTT variant targeted allele in phase with the pathogenic mtHTT allele; orii) for the subject that is homozygous for the first mtHTT variant, or heterozygous for the first mtHTT variant but the targeted allele is not in phase with the pathogenic mtHTT allele, determining from the sequence analysis or having determined from the sequence analysis whether the subject is heterozygous for a first subsequent mtHTT variant and heterozygous for a second subsequent mtHTT variant, wherein the subject is a candidate for treatment with:a) a first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule to the subject that has both the first subsequent mtHTT variant alternate allele and the second subsequent mtHTT variant alternate allele in phase with the pathogenic mtHTT allele;b) a first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule to the subject that has both the first subsequent mtHTT variant- 108 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT reference allele and the second subsequent mtHTT variant reference allele in phase with the pathogenic mtHTT allele;c) a first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule to the subject that has both the first subsequent mtHTT variant alternate allele and the second subsequent mtHTT variant reference allele in phase with the pathogenic mtHTT allele; ord) a first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule to the subject that has both the first subsequent mtHTT variant reference allele and the second subsequent mtHTT variant alternate allele in phase with the pathogenic mtHTT allele.

81. The method of claim 80, wherein the first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant reference allelespecific inhibitory nucleic acid molecule, and first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule comprise an antisense nucleic acid molecule, a small interfering RNA (siRNA), or a short hairpin RNA (shRNA).

82. The method of claim 81, wherein the first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant reference allelespecific inhibitory nucleic acid molecule, and first subsequent mtHTT variant reference- 109 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule comprise an siRNA.

83. The method of claim 81, wherein the first mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant reference allele-specific inhibitory nucleic acid molecule, first subsequent mtHTT variant alternate allele-specific / second subsequent mtHTT variant reference allelespecific inhibitory nucleic acid molecule, and first subsequent mtHTT variant reference allele-specific / second subsequent mtHTT variant alternate allele-specific inhibitory nucleic acid molecule comprise an antisense nucleic acid molecule.

84. The method of any one of claims 80 to 83, wherein the first mtHTT variant comprises 4:3228683:AGAG:A; and i) the first mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule comprisingthe nucleotide sequence of SEQ ID NO:334, SEQ ID NO:335, or SEQ ID NO:336; or ii) the first mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises an siRNA comprising the nucleotide sequences of SEQ ID NOs:89 / 334, SEQ ID NQs:90 / 335, or SEQ ID NOs:91 / 336.

85. The method of any one of claims 80 to 84, wherein the first subsequent mtHTT variant comprises 4:3240433:C:G and the second subsequent mtHTT variant comprises 4:3240421:C:G, and:i) the first subsequent mtHTT variant alternate-specific / second subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises: a) an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:394, SEQ ID NO:396, SEQ ID NO:397, SEQ ID NQ:402, SEQ ID NQ:404, or SEQ ID NQ:408; or b) an siRNA comprising the nucleotide sequences of SEQ ID NOs:149 / 394, SEQ ID NOs:151 / 396, SEQ ID NOs:152 / 397, SEQ ID NOs:157 / 402, SEQ ID NOs:159 / 404, or SEQ ID NOs:163 / 408;ii) the first subsequent mtHTT variant reference-specific / second subsequent mtHTT reference-specific inhibitory nucleic acid molecule comprises: a) an antisense nucleic acid- 110 - 119110564DOCKET NO.: 38120-4600 (11607WO-01) PATENT molecule comprising the nucleotide sequence of SEQ ID NO:398 or SEQ ID NO:405; or b) an siRNA comprising the nucleotide sequences of SEQ ID NOs:153 / 398 or SEQ ID NQs:160 / 405;iii) the first subsequent mtHTT variant alternate-specific / second subsequent mtHTT variant reference-specific inhibitory nucleic acid molecule comprises: a) an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NO:395, SEQ ID NO:399, SEQ ID NO:401, SEQ ID NO:403, or SEQ ID NQ:407; or b) an siRNA comprising the nucleotide sequences of SEQ ID NQs:150 / 395, SEQ ID NOs:154 / 399, SEQ ID NQs:156 / 401, SEQ ID NOs:158 / 403, or SEQ ID NOs:162 / 407; andiv) the first subsequent mtHTT variant reference-specific / second subsequent mtHTT variant alternate-specific inhibitory nucleic acid molecule comprises: a) an antisense nucleic acid molecule comprising the nucleotide sequence of SEQ ID NQ:400 or SEQ ID NQ:406; or b) an siRNA comprisingthe nucleotide sequences of SEQ ID NQs:155 / 400 or SEQ ID NQs:161 / 406.- 111 - 119110564

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