Treatment and prevention of muscle atrophy and type 2 diabetes with hexakisphosphate kinase 3 (IP6k3) inhibitors

Abstract

The present disclosure generally relates to the treatment of subjects having muscle atrophy or type 2 diabetes or at risk of developing muscle atrophy or type 2 diabetes by administering an Inositol Hexakisphosphate Kinase 3 (IP6K3) inhibitor to the subject.

Description

[0001] DOCKET NO.: 38120-4404 (12031W001)

[0002] - 1 - Treatment And Prevention Of Muscle Atrophy And Type 2 Diabetes With Hexakisphosphate Kinase 3 (IP6K3) Inhibitors

[0003] Reference to Sequence Listing

[0004] This application includes a Sequence Listing filed electronically as an XML file named 381204404SEQ, created on April 14, 2025, with a size of 1,390,132 bytes. The Sequence Listing is incorporated herein by reference.

[0005] Field

[0006] The present disclosure generally relates to the treatment of subjects having muscle atrophy or type 2 diabetes or at risk of developing muscle atrophy or type 2 diabetes, by administering an IP6K3 inhibitor to the subject, and to methods of identifying subjects having an increased risk of developing muscle atrophy or type 2 diabetes.

[0007] Background

[0008] Skeletal muscular atrophy, also known as muscle wasting, has symptoms including muscle weakness, myokymia, and muscularfasciculation. Skeletal muscle atrophy occurs in response to a variety of pathophysiological stimuli and contributes to profound losses of muscle mass and whole body strength. Examples of settings characterized by muscle atrophy include rare genetic diseases affecting skeletal muscle (including but not limited to muscular dystrophies, myotonic dystrophies, and mitochondrial myopathies), inflammatory muscle diseases (including but not limited to polymyositis and dermatomyositits), sarcopenia (including but not limited to age-related sarcopenia), myopathy arising secondary to environmental influences (e.g., drug-induced, alcohol-induced, among others), myopathy arising secondary to systemic diseases (e.g., thyroid-associated myopathy), and other neuromuscular conditions leading to muscle atrophy (e.g., amyotrophic lateral sclerosis, myasthenia gravis, among others). Weight loss via various mechanisms (e.g., bariatric surgery, or pharmacologically-induced) may also produce substantial loss of skeletal muscle mass and lead to muscle atrophy. Furthermore, skeletal muscle plays a crucial role in metabolic homeostasis. It is the primary site of glucose disposal, helping to regulate blood sugar levels by taking up glucose from the bloodstream during periods of high blood sugar. Additionally, muscle plays a significant role in the regulation of adipose tissue, primarily through the process of lipid oxidation.

[0009] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0010] - 2 - Inositol Hexakisphosphate Kinase 3 (IP6K3) is encoded by a 40 kb gene located at 6p21.31. IP6K3 encodes a 410 amino acid long, 46 kDa protein that belongs to the inositol phosphokinase (IPK) family. Specifically, IP6K3 is likely responsible for the conversion of inositol hexakisphosphate (InsP6) to diphosphoinositol pentakisphosphate (InsP7 / PP-InsP5) and may also convert 1,3,4,5,6-pentakisphosphate (InsP5) to PP-InsP4. Related pathways to IP6K3 are Inositol phosphate metabolism and nuclear receptors meta-pathway.

[0011] Summary

[0012] The present disclosure provides methods of treating a subject having muscle atrophy, or at risk of developing muscle atrophy, the methods comprising administering an IP6K3 inhibitor to the subject.

[0013] The present disclosure provides methods of treating a subject having type 2 diabetes, or at risk of developing type 2 diabetes, the methods comprising administering an IP6K3 inhibitor to the subject.

[0014] The present disclosure also provides methods of treating a subject having muscle atrophy or at risk of developing muscle atrophy by administering a muscle atrophy therapeutic agent or muscle atrophy therapy, the methods comprising: determining or having determined whether the subject has an IP6K3 variant nucleic acid molecule, by: obtaining or having obtained a biological sample from the subject; and performing or having performed a sequence analysis on the biological sample to determine if the subject has a genotype comprisingthe IP6K3 variant nucleic acid molecule; and administering or continuing to administer the muscle atrophy therapeutic agent in an amount that is the same as or less than a standard dosage amount or muscle atrophy therapy, and / or administering an IP6K3 inhibitor to a subject that is IP6K3 reference or to a subject that is heterozygous for the IP6K3 variant nucleic acid molecule; or administering or continuing to administer the muscle atrophy therapeutic agent or muscle atrophy therapy in a standard dosage amount to a subject that is homozygous for the IP6K3 variant nucleic acid molecule; wherein the presence the IP6K3 variant nucleic acid molecule indicates the subject has a decreased risk of developing muscle atrophy.

[0015] The present disclosure also provides methods of treating a subject having type 2 diabetes or at risk of developing type 2 diabetes by administering a type 2 diabetes therapeutic agent, the methods comprising: determining or having determined whether the subject has an IP6K3 variant nucleic acid molecule, by: obtaining or having obtained a biological sample from

[0016] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0017] - 3 -the subject; and performing or having performed a sequence analysis on the biological sample to determine if the subject has a genotype comprising the IP6K3 variant nucleic acid molecule; and administering or continuing to administer the type 2 diabetes therapeutic agent in an amount that is the same as or less than a standard dosage amount, and / or administering an IP6K3 inhibitor to a subject that is IP6K3 reference or to a subject that is heterozygous for the IP6K3 variant nucleic acid molecule; or administering or continuing to administer the type 2 diabetes therapeutic agent in a standard dosage amount to a subject that is homozygous for the IP6K3 variant nucleic acid molecule; wherein the presence the IP6K3 variant nucleic acid molecule indicates the subject has a decreased risk of developing type 2 diabetes.

[0018] The present disclosure also provides methods of identifying a subject having an increased risk of developing muscle atrophy, the methods comprising: determining or having determined the presence or absence of an IP6K3 variant nucleic acid molecule in a biological sample obtained from the subject; wherein: when the subject is IP6K3 reference, then the subject has an increased risk of developing muscle atrophy; and when the subject is heterozygous or homozygous for the IP6K3 variant nucleic acid molecule, then the subject has a decreased risk of developing muscle atrophy.

[0019] The present disclosure also provides methods of identifying a subject having an increased risk of developing type 2 diabetes, the methods comprising: determining or having determined the presence or absence of an IP6K3 variant nucleic acid molecule in a biological sample obtained from the subject; wherein: when the subject is IP6K3 reference, then the subject has an increased risk of developing type 2 diabetes; and when the subject is heterozygous or homozygous for the IP6K3 variant nucleic acid molecule, then the subject has a decreased risk of developing type 2 diabetes.

[0020] The present disclosure also provides muscle atrophy therapeutic agents for use in the treatment or prevention of muscle atrophy in a subject having an IP6K3 variant nucleic acid molecule.

[0021] The present disclosure also provides type 2 diabetes therapeutic agents for use in the treatment or prevention of type 2 diabetes in a subject having an IP6K3 variant nucleic acid molecule.

[0022] The present disclosure also provides IP6K3 inhibitors for use in the treatment or prevention of muscle atrophy in a subject that is IP6K3 reference or in a subject that is heterozygous for an IP6K3 variant nucleic acid molecule.

[0023] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0024] - 4- The present disclosure also provides IP6K3 inhibitors for use in the treatment or prevention of type 2 diabetes in a subject that is IP6K3 reference or in a subject that is heterozygous for an IP6K3 variant nucleic acid molecule.

[0025] Brief Description Of The Drawings

[0026] 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.

[0027] Figure 1 shows loss of function of IP6K3 associates with increased markers of muscle mass, increased BIA- and DXA-derived lean body lean mass, numerical decreases in BIA- and DXA-derived fat mass, increased BIA-derived body lean composition and decreased BIA-derived body fat composition, and increased MRI-derived markers of muscle mass.

[0028] Figure 2 (Panel A and Panel B) shows that the strongest associated trait (creatininexystatin C ratio) for IP6K3 is primarily driven by variant carriers of EUR ancestry in the UKB (Panel A). The association for creatininexystatin C ratio remains robust in the EUR UKB subset of individuals when adjusting for all independent genome-wide significiant common variants (N=13) in the HLA locus near IP6K3 (Panel B).

[0029] Description

[0030] 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.

[0031] 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.

[0032] 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.

[0033] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0034] - 5 - As used herein, the singular forms "a," "an" and "the" include plural referents unless the context clearly dictates otherwise.

[0035] 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 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 of the disclosed embodiments.

[0036] As used herein, the term "comprising" may be replaced with "consisting" or "consisting essentially of" in particular embodiments as desired.

[0037] 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, doublestranded, or multiple stranded. One strand of a nucleic acid also refers to its complement.

[0038] As used herein, the term "subject" includes any animal, including mammals. 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.

[0039] It has been observed in accordance with the present disclosure that rare IP6K3 variant nucleic acid molecules (whether these variants are homozygous or heterozygous in a particular subject) associate with a greater muscle mass and strength and associate with a lower risk of type 2 diabetes. It is believed that IP6K3 variant nucleic acid molecules have not been associated with increased muscle mass or decreased atrophy or decreased risk of type 2 diabetes in humans. In particular, it has been observed that pLoF and missense variants (AAF<1%) in IP6K3 associate with increased creatininexystatin C ratio. Therefore, subjects that are IP6K3 reference or heterozygous for an IP6K3 variant nucleic acid molecule may be treated with an IP6K3 inhibitor such that muscle mass is increased and / or muscle atrophy is inhibited or prevented, the symptoms thereof are reduced or prevented and / or muscle mass is increased to prevent and / or treat obesity or cardiometabolic disease (e.g. diabetes), and / or development of symptoms is repressed or prevented. It is also believed that such subjects having muscle atrophy may further be treated with one or more muscle atrophy therapeutic agents or muscle atrophy therapy that promotes skeletal muscle hypertrophy and / or treats or inhibits muscle

[0040] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0041] - 6 -atrophy. It is also believed that such subjects having type 2 diabetes may further be treated with one or more type 2 diabetes therapeutic agents. In addition, the present disclosure provides methods of leveraging the presence or absence of IP6K3 variant nucleic acid molecules in subjects to identify or stratify risk is such subjects of developing muscle atrophy or type 2 diabetes, or to diagnose subjects as having an increased risk of developing muscle atrophy or type 2 diabetes.

[0042] For purposes of the present disclosure, any particular subject, such as a human, can be categorized as having one of three IP6K3 genotypes: i) IP6K3 reference; ii) heterozygous for an IP6K3 variant nucleic acid molecule; or iii) homozygous for an IP6K3 variant nucleic acid molecule. A subject is IP6K3 reference when the subject does not have a copy of an IP6K3 variant nucleic acid molecule. A subject is heterozygous for an IP6K3 variant nucleic acid molecule when the subject has a single copy of an IP6K3 variant nucleic acid molecule. A subject is homozygous for an IP6K3 variant nucleic acid molecule when the subject has two copies of an IP6K3 variant nucleic acid molecule.

[0043] In any of the embodiments described herein, the IP6K3 variant nucleic acid molecule can be any nucleic acid molecule (such as, a genomic nucleic acid molecule, an mRNA molecule, or a cDNA molecule produced from an mRNA molecule) encoding an IP6K3 variant polypeptide having a partial loss-of -function, a complete loss-of-function, a predicted partial loss-of-function, or a predicted complete loss-of-function. A subject who has an IP6K3 polypeptide having a partial loss-of-function (or predicted partial loss-of-function) is hypomorphic for IP6K3. In some embodiments, the IP6K3 variant nucleic acid molecule may result in decreased or aberrant expression or activity of IP6K3 mRNA or polypeptide. In some embodiments, the IP6K3 variant nucleic acid molecule may be associated with a reduced in vitro response to IP6K3 ligands compared to reference IP6K3. In some embodiments, the IP6K3 variant nucleic acid molecule is a splice-site variant, a stop-gain variant, a start-loss variant, a stop-loss variant, a frameshift variant, an in-frame indel variant, or a variant that encodes a truncated IP6K3 variant polypeptide. In some embodiments, the IP6K3 variant nucleic acid molecule is a missense variant nucleic acid molecule. In some embodiments, the IP6K3 variant nucleic acid molecule comprises a single nucleotide polymorphism (SNP). In some embodiments, the IP6K3 variant nucleic acid molecule comprises a variation in a coding region. In some embodiments, the IP6K3 variant nucleic acid molecule does not comprise a variation in a non-coding region, except for a splice acceptor region (two bases before the start of any exon except the first). In some

[0044] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0045] - 7 -embodiments, the IP6K3 variant nucleic acid molecule results or is predicted to result in a premature truncation of an IP6K3 polypeptide compared to the reference IP6K3. In some embodiments, the IP6K3 variant nucleic acid molecule is a variant that is predicted to be damaging to the protein function (and hence, in this case, protective to the human) by in vitro prediction algorithms such as Polyphen, SIFT, or similar algorithms. In some embodiments, the IP6K3 variant nucleic acid molecule is a variant that causes or is predicted to cause a nonsynonymous amino acid substitution in an IP6K3 nucleic acid molecule and whose allele frequency is less than 1 / 100 alleles in the population from which the subject is selected. In some embodiments, the IP6K3 variant nucleic acid molecule is a rare missense variant (allele frequency < 0.1%; or 1 in 1,000 alleles), or a splice-site, stop-gain, start-loss, stop-loss, frameshift, or in-frame indel, or other frameshift IP6K3 variant.

[0046] In any of the embodiments described herein, the IP6K3 variant genomic nucleic acid molecule may include one or more variations at any of the positions of chromosome 6 (i.e., positions 33,721,662-33,746,905) using the nucleotide sequence of the IP6K3 reference genomic nucleic acid molecule in the GRCh38 / hg38 human genome assembly (see, ENSG00000161896.12, ENST00000293756.5 annotated in the in the Ensembl database (URL: world wide web at "useast.ensembl.org / Homo_sapiens / Gene / Summary? g=ENSG00000161896;r=6:33721662-33746905;transcript=ENST00000293756.5")) as a reference sequence. The sequences provided in this transcript for the IP6K3 genomic nucleic acid molecule is only an exemplary sequence. Other sequences for the IP6K3 genomic nucleic acid molecule are also possible.

[0047] In any of the embodiments described herein, the IP6K3 variant nucleic acid molecule may comprise any one or more of the following genetic variations in the genomic nucleic acid molecule (referring to the chromosome:positions set forth in the GRCh38 / hg38 human genome assembly) listed in Table 1, or a cDNA molecule produced from the mRNA molecule.

[0048] Table 1

[0049]

[0050] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0051] - 8 -

[0052]

[0053] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0054] - 9 -

[0055]

[0056] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0057] - 10-

[0058]

[0059] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0060] - 11-

[0061]

[0062] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0063] - 12-

[0064]

[0065] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0066] - 13-

[0067]

[0068] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0069] - 14-

[0070]

[0071] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0072] - 15-

[0073]

[0074] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0075] - 16-

[0076]

[0077] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0078] - 17-

[0079]

[0080] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0081] - 18-

[0082]

[0083] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0084] - 19-

[0085]

[0086] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0087] - 20-

[0088]

[0089] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0090] - 21-

[0091]

[0092] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0093] - 22-

[0094]

[0095] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0096] - 23-

[0097]

[0098] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0099] - 24-

[0100]

[0101] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0102] - 25-

[0103]

[0104] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0105] - 26-

[0106]

[0107] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0108] - 27-

[0109]

[0110] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0111] - 28-

[0112]

[0113] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0114] - 29-

[0115]

[0116] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0117] - 30-

[0118]

[0119] For subjects that are genotyped or determined to be IP6K3 reference, such subjects have an increased risk of developing muscle atrophy or type 2 diabetes compared to subjects that are heterozygous or homozygous for an IP6K3 variant nucleic acid molecule. For subjects that are genotyped or determined to be either IP6K3 reference or heterozygous for an IP6K3 variant nucleic acid molecule, such subjects can be treated with an IP6K3 inhibitor.

[0120] In any of the embodiments described herein, the subject in whom muscle atrophy is prevented by administering an IP6K3 inhibitor may be anyone at risk for developing muscle atrophy including, but not limited to, subjects with a genetic predisposition for developing muscle atrophy. Additional risk factors for muscle atrophy include, but are not limited to, age, inactivity or disuse, malnutrition, chronic diseases, neurological conditions, endocrine disorders, medications, alcohol and other substances, among others. Furthermore, general weight loss arising from a variety of mechanisms (e.g., bariatric surgery, medication-induced, etc.) may predispose to substantial loss of muscle loss. In some embodiments, administering an IP6K3 inhibitor to a subject having muscle atrophy may be carried out to prevent development of another occurrence of muscle atrophy in a subject who has already had muscle atrophy. In any of the embodiments described herein, the methods can be used to improve muscle atrophy.

[0121] In any of the embodiments described herein, the subject in whom type 2 diabetes is prevented by administering an IP6K3 inhibitor may be anyone at risk for developing type 2 diabetes including, but not limited to, subjects with a genetic predisposition for developing type 2 diabetes. Additional risk factors for type 2 diabetes include, but are not limited to, age

[0122] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0123] -31- (pa rticu larly after the age of 45), overweight, fat distribution, inactivity, race and ethnicity, prediabetes, and gestational diabetes. In any of the embodiments described herein, the methods can be used to improve type 2 diabetes.

[0124] In any of the embodiments described herein, the IP6K3 predicted loss-of-function polypeptide can be any IP6K3 polypeptide having a partial loss-of-function, a complete loss-of-function, a predicted partial loss-of-function, ora predicted complete loss-of-function.

[0125] Any one or more (i.e., any combination) of the IP6K3 variant nucleic acid molecules described herein can be used within any of the methods described herein to determine whether a subject has an increased or decreased risk of developing muscle atrophy or type 2 diabetes. The combinations of particular variants can form a mask used for statistical analysis of the particular association of IP6K3 and an increased or decreased risk of developing muscle atrophy or type 2 diabetes. In some embodiments, the mask used for statistical analysis of the particular association of IP6K3 and an increased or decreased risk of developing muscle atrophy or type 2 diabetes can exclude any one or more of these IP6K3 variant nucleic acid molecules described herein.

[0126] In any of the embodiments described herein, the subject can have muscle atrophy. In any of the embodiments described herein, the subject can be at risk of developing muscle atrophy. In any of the embodiments described herein, the muscle atrophy is skeletal muscle atrophy. In any of the embodiments described herein, the muscle atrophy is cardiac muscle atrophy. In some embodiments, muscle atrophy may be due to: 1) a rare genetic disease affecting skeletal muscle including, but not limited to muscular dystrophies, myotonic dystrophies, and mitochondrial myopathies; 2) inflammatory muscle diseases including, but not limited to, polymyositis and dermatomyositits; 3) sarcopenia including, but not limited to, age-related sarcopenia; 4) myopathy arising secondary to environmental influences (e.g., drug-induced, alcohol-induced, among others); 5) myopathy arising secondary to systemic diseases (e.g., thyroid-associated myopathy); and 6) other neuromuscular conditions leading to muscle atrophy (e.g., amyotrophic lateral sclerosis, myasthenia gravis, among others). Weight loss via various mechanisms (e.g., bariatric surgery, or pharmacologically-induced) may also produce substantial loss of skeletal muscle mass and lead to muscle atrophy. In some embodiments, the muscle atrophy may be due to type 2 diabetes.

[0127] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0128] - 32- In any of the embodiments described herein, the subject can have type 2 diabetes. In any of the embodiments described herein, the subject can be at risk of developing type 2 diabetes.

[0129] Muscle mass and strength can be measured by, for example: i) handgrip strength, ii) MRI-derived thigh muscle volume / perimeter, iii) DXA-derived lean / muscle mass, iv) bioimpedance-derived lean / muscle mass, v) creatinine levels, and vi) creatinine / cystatin C ratio ("sarcopenia index").

[0130] The present disclosure provides methods of treating a subject having muscle atrophy or type 2 diabetes or at risk of developing muscle atrophy or type 2 diabetes, the methods comprising administering an IP6K3 inhibitor to the subject.

[0131] In some embodiments, the IP6K3 inhibitor comprises an inhibitory nucleic acid molecule. Examples of inhibitory nucleic acid molecules include, but are not limited to, antisense nucleic acid molecules, small interfering RNAs (siRNAs), and short hairpin RNAs (shRNAs). Such inhibitory nucleic acid molecules can be designed to target any region of an IP6K3 nucleic acid molecule. In some embodiments, the antisense RNA, siRNA, or shRNA hybridizes to a sequence within an IP6K3 genomic nucleic acid molecule or mRNA molecule and decreases expression of the IP6K3 polypeptide in a cell in the subject. In some embodiments, the IP6K3 inhibitor comprises an antisense molecule that hybridizes to an IP6K3 genomic nucleic acid molecule or mRNA molecule and decreases expression of the IP6K3 polypeptide in a cell in the subject. In some embodiments, the IP6K3 inhibitor comprises an siRNA that hybridizes to an IP6K3 genomic nucleic acid molecule or mRNA molecule and decreases expression of the IP6K3 polypeptide in a cell in the subject. In some embodiments, the IP6K3 inhibitor comprises an shRNA that hybridizes to an IP6K3 genomic nucleic acid molecule or mRNA molecule and decreases expression of the IP6K3 polypeptide in a cell in the subject.

[0132] In some embodiments, the IP6K3 antisense nucleic acid molecules comprise or consist of any of the nucleotide sequences represented by SEQ ID NOs: 1-397. In some embodiments, the IP6K3 siRNA molecules comprise or consist of any of the nucleotide sequences (sense and antisense strands presented one after the other) represented by SEQ ID NOs: 398-1099 (e.g., the sense strand is, for example, SEQ ID NO: 398 and the corresponding antisense strand is SEQ ID NO: 399; the sense strand is, for example, SEQ ID NO: 1098 and the corresponding antisense strand is SEQ ID NO: 1099; etc.).

[0133] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0134] - 33 - Table 2: IP6K3 antisense

[0135]

[0136]

[0137] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0138] - 34 -

[0139]

[0140]

[0141] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0142] - 35 -

[0143]

[0144]

[0145] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0146] - 36 -

[0147]

[0148]

[0149] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0150] - 37-

[0151]

[0152] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0153] - 38- Table 3: IP6K3 siRNA

[0154]

[0155] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0156] - 39-

[0157]

[0158] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0159] - 40-

[0160]

[0161] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0162] - 41-

[0163]

[0164] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0165] - 42-

[0166]

[0167] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0168] - 43-

[0169]

[0170] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0171] - 44-

[0172]

[0173] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0174] - 45-

[0175]

[0176] 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

[0177] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0178] - 46-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, tetramethylbenzidine (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.

[0179] The inhibitory nucleic acid molecules can comprise, for example, nucleotides or nonnatural 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.

[0180] 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, uracil-5-yl, 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, 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 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-thiol, 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,

[0181] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0182] - 47- 7-deazaguanine, 7-deazaadenine, 3-deazaguanine, and 3-deazaadenine.

[0183] Nucleotide analogs can also include modifications of the sugar moiety. 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-alkyl-O-alkyl, wherein the alkyl, alkenyl, and alkynyl may be substituted or unsubstituted Ci-walkyl or C2-ioalkenyl, and C2-ioalkynyl. Exemplary 2' sugar modifications also include, but are not limited to, -O[(CH2)nO]mCH3, -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, C1-10alkyl, 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 of the pentofu ranosyl sugar.

[0184] 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).

[0185] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0186] - 48- 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 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.

[0187] 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.

[0188] 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 siRNAs and 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

[0189] 2'-hydroxyl can act as a nucleophile and attack the adjacent phosphorous in the phosphodiester bond. Such alternatives include 2'-O-methyl, 2'-O-methoxyethyl, and 2'-fluoro modifications.

[0190] 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.

[0191] 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.

[0192] In some embodiments, a representative siRNA has the following formula:

[0193] Sense: mN*mN7i2FN / mN / i2FN / mN / i2FN / mN / i2FN / mN / i2FN / mN / i2FN / mN / i2FN / mN / i2FN / *mN* / 32FN /

[0194] Antisense: / 52FN / * / i2FN / *mN / i2FN / mN / i2FN / mN / i2FN / mN / i2FN / mN / i2FN / mN / i2FN / mN /

[0195] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0196] - 49-i2FN / mN / i2FN / mN*N*N

[0197] 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.

[0198] 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

[0199] 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).

[0200] 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 double-stranded 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.

[0201] 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.

[0202] In some embodiments, the IP6K3 inhibitor comprises a nuclease agent that induces one or more nicks or double-strand breaks at a recognition sequence(s) or a DNA-binding protein that binds to a recognition sequence within an IP6K3 genomic nucleic acid molecule.

[0203] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0204] - 50- The recognition sequence can be located within a coding region of the IP6K3 gene, or within regulatory regions that influence the expression of the gene. A recognition sequence of the DNA-binding protein or nuclease agent can be located in an intron, an exon, a promoter, an enhancer, a regulatory region, or any non-protein coding region. The recognition sequence can include or be proximate to the start codon of the IP6K3 gene. For example, the recognition sequence can be located about 10, about 20, about 30, about 40, about 50, about 100, about 200, about 300, about 400, about 500, or about 1,000 nucleotides from the start codon. As another example, two or more nuclease agents can be used, each targeting a nuclease recognition sequence including or proximate to the start codon. As another example, two nuclease agents can be used, one targeting a nuclease recognition sequence including or proximate to the start codon, and one targeting a nuclease recognition sequence including or proximate to the stop codon, wherein cleavage by the nuclease agents can result in deletion of the coding region between the two nuclease recognition sequences. Any nuclease agent that induces a nick or double-strand break into a desired recognition sequence can be used in the methods and compositions disclosed herein. Any DNA-binding protein that binds to a desired recognition sequence can be used in the methods and compositions disclosed herein.

[0205] Suitable nuclease agents and DNA-binding proteins for use herein include, but are not limited to, zinc finger protein or zinc finger nuclease (ZFN) pair, Transcription Activator-Like Effector (TALE) protein or Transcription Activator-Like Effector Nuclease (TALEN), or Clustered Regularly Interspersed Short Palindromic Repeats (CRISPR) / CRISPR-associated (Cas) systems. The length of the recognition sequence can vary, and includes, for example, recognition sequences that are about 30-36 bp for a zinc finger protein or ZFN pair, about 15-18 bp for each ZFN, about 36 bp for a TALE protein or TALEN, and about 20 bp for a CRISPR / Cas guide RNA.

[0206] In some embodiments, CRISPR / Cas systems can be used to modify an IP6K3 genomic nucleic acid molecule within a cell. The methods and compositions disclosed herein can employ CRISPR-Cas systems by utilizing CRISPR complexes (comprising a guide RNA (gRNA) complexed with a Cas protein) for site-directed cleavage of IP6K3 nucleic acid molecules.

[0207] Cas proteins generally comprise at least one RNA recognition or binding domain that can interact with gRNAs. Cas proteins can also comprise nuclease domains (such as, for example, DNase or RNase domains), DNA binding domains, helicase domains, protein-protein interaction domains, dimerization domains, and other domains. Suitable Cas proteins include, for example, a wild type Cas9 protein and a wild type Cpfl protein (such as, for example,

[0208] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0209] - 51- FnCpfl). A Cas protein can have full cleavage activity to create a double-strand break in an IP6K3 genomic nucleic acid molecule or it can be a nickase that creates a single-strand break in an IP6K3 genomic nucleic acid molecule. Additional examples of Cas proteins include, but are not limited to, Casl, CaslB, Cas2, Cas3, Cas4, Cas5, Cas5e (CasD), Cas6, Cas6e, CasGf, Cas7, Cas8al, Cas8a2, Cas8b, Cas8c, Cas9 (Csnl or Csxl2), CaslO, CaslOd, CasF, CasG, CasH, Csyl, Csy2, Csy3, Csel (CasA), Cse2 (CasB), Cse3 (CasE), Cse4 (CasC), Cscl, Csc2, Csa5, Csn2, Csm2, Csm3, Csm4, Csm5, Csm6, Cmrl, Cmr3, Cmr4, Cmr5, Cmr6, Csbl, Csb2, Csb3, Csxl7, Csxl4, CsxlO, Csxl6, CsaX, Csx3, Csxl, Csxl5, Csfl, Csf2, Csf3, Csf4, and Cul966, and homologs or modified versions thereof. In some embodiments, a Cas system, such as Casl2a, can have multiple gRNAs encoded into a single crRNA. Cas proteins can also be operably linked to heterologous polypeptides as fusion proteins. For example, a Cas protein can be fused to a cleavage domain, an epigenetic modification domain, a transcriptional activation domain, or a transcriptional repressor domain. Cas proteins can be provided in any form. For example, a Cas protein can be provided in the form of a protein, such as a Cas protein complexed with a gRNA. Alternately, a Cas protein can be provided in the form of a nucleic acid molecule encoding the Cas protein, such as an RNA or DNA.

[0210] In some embodiments, targeted genetic modifications of IP6K3 genomic nucleic acid molecules can be generated by contacting a cell with a Cas protein and one or more gRNAs that hybridize to one or more gRNA recognition sequences within a target genomic locus in the IP6K3 genomic nucleic acid molecule. The gRNA recognition sequence can include or be proximate to the start codon of an IP6K3 genomic nucleic acid molecule or the stop codon of an IP6K3 genomic nucleic acid molecule. For example, the gRNA recognition sequence can be located from about 10, from about 20, from about 30, from about 40, from about 50, from about 100, from about 200, from about 300, from about 400, from about 500, or from about 1,000 nucleotides of the start codon or the stop codon.

[0211] The gRNA recognition sequences within a target genomic locus in an IP6K3 genomic nucleic acid molecule are located near a Protospacer Adjacent Motif (PAM) sequence, which is a 2-6 base pair DNA sequence immediately following the DNA sequence targeted by the Cas9 nuclease. The canonical PAM is the sequence 5'-NGG-3' where " N" is any nucleobase followed by two guanine (" G") nucleobases. gRNAs can transport Cas9 to anywhere in the genome for gene editing, but no editing can occur at any site other than one at which Cas9 recognizes PAM. In addition, 5'-NGA-3' can be a highly efficient non-canonical PAM for human cells. Generally,

[0212] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0213] - 52-the PAM is about 2-6 nucleotides downstream of the DNA sequence targeted by the gRNA. The PAM can flank the gRNA recognition sequence. In some embodiments, the gRNA recognition sequence can be flanked on the 3' end by the PAM. In some embodiments, the gRNA recognition sequence can be flanked on the 5' end by the PAM. For example, the cleavage site of Cas proteins can be about 1 to about 10, about 2 to about 5 base pairs, or three base pairs upstream or downstream of the PAM sequence. In some embodiments (such as when Cas9 from S. pyogenes or a closely related Cas9 is used), the PAM sequence of the non-complementary strand can be 5'-NGG-3’, where N is any DNA nucleotide and is immediately 3' of the gRNA recognition sequence of the non-complementary strand of the target DNA. As such, the PAM sequence of the complementary strand would be 5'-CCN-3', where N is any DNA nucleotide and is immediately 5' of the gRNA recognition sequence of the complementary strand of the target DNA.

[0214] A gRNA is an RNA molecule that binds to a Cas protein and targets the Cas protein to a specific location within an IP6K3 genomic nucleic acid molecule. An exemplary gRNA is a gRNA effective to direct a Cas enzyme to bind to or cleave an IP6K3 genomic nucleic acid molecule, wherein the gRNA comprises a DNA-targeting segment that hybridizes to a gRNA recognition sequence within the IP6K3 genomic nucleic acid molecule. Exemplary gRNAs comprise a DNA-targeting segment that hybridizes to a gRNA recognition sequence present within an IP6K3 genomic nucleic acid molecule that includes or is proximate to the start codon or the stop codon. For example, a gRNA can be selected such that it hybridizes to a gRNA recognition sequence that is located from about 5, from about 10, from about 15, from about 20, from about 25, from about 30, from about 35, from about 40, from about 45, from about 50, from about 100, from about 200, from about 300, from about 400, from about 500, or from about 1,000 nucleotides of the start codon or located from about 5, from about 10, from about 15, from about 20, from about 25, from about 30, from about 35, from about 40, from about 45, from about 50, from about 100, from about 200, from about 300, from about 400, from about 500, or from about 1,000 nucleotides of the stop codon. Suitable gRNAs can comprise from about 17 to about 25 nucleotides, from about 17 to about 23 nucleotides, from about 18 to about 22 nucleotides, orfrom about 19 to about 21 nucleotides. In some embodiments, the gRNAs can comprise 20 nucleotides.

[0215] The Cas protein and the gRNA form a complex, and the Cas protein cleaves the IP6K3 genomic nucleic acid molecule. The Cas protein can cleave the nucleic acid molecule at a site

[0216] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0217] - 53-within or outside of the nucleic acid sequence present in the IP6K3 genomic nucleic acid molecule to which the DNA-targeting segment of a gRNA will bind. For example, formation of a CRISPR complex (comprising a gRNA hybridized to a gRNA recognition sequence and complexed with a Cas protein) can result in cleavage of one or both strands in or near (such as, for example, within 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 50, or more base pairs from) the nucleic acid sequence present in the IP6K3 genomic nucleic acid molecule to which a DNA-targeting segment of a gRNA will bind.

[0218] Such methods can result, for example, in an IP6K3 genomic nucleic acid molecule in which a region of the IP6K3 genomic nucleic acid molecule is disrupted, the start codon is disrupted, the stop codon is disrupted, or the coding sequence is disrupted or deleted.

[0219] Optionally, the cell can be further contacted with one or more additional gRNAs that hybridize to additional gRNA recognition sequences within the target genomic locus in the IP6K3 genomic nucleic acid molecule. By contacting the cell with one or more additional gRNAs (such as, for example, a second gRNA that hybridizes to a second gRNA recognition sequence), cleavage by the Cas protein can create two or more double-strand breaks or two or more single-strand breaks.

[0220] In any of the methods of treatment or prevention described herein, the subject being treated may comprise a IP6K3 variant nucleic acid molecule. In some embodiments, the subject being treated is heterozygous for the IP6K3 variant nucleic acid molecule. In some embodiments, the subject being treated is homozygous for the IP6K3 variant nucleic acid molecule. In some embodiments, the subject being treated is IP6K3 reference. The IP6K3 variant nucleic acid molecule can be any of the IP6K3 variant nucleic acid molecules disclosed herein. In some embodiments, the IP6K3 variant nucleic acid molecule is a IP6K3 variant genomic nucleic acid molecule that comprises the genetic variation listed in Table 1, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule.

[0221] In some embodiments, the methods of treatment or prevention further comprise detecting the presence or absence of a IP6K3 variant nucleic acid molecule in a biological sample from the subject. In some embodiments, the IP6K3 variant nucleic acid molecule can be any of the IP6K3 variant nucleic acid molecules disclosed herein. In some embodiments, the IP6K3 variant nucleic acid molecule is a IP6K3 variant genomic nucleic acid molecule that

[0222] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0223] - 54-comprises the genetic variation listed in Table 1, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule.

[0224] The present disclosure also provides methods of treating a subject with a muscle atrophy therapeutic agent or muscle atrophy therapy that treats or inhibits muscle atrophy, wherein the subject has muscle atrophy or is at risk of developing muscle atrophy. The methods comprise determining whether the subject has a IP6K3 variant nucleic acid molecule by obtaining or having obtained a biological sample from the subject, and performing or having performed a sequence analysis on the biological sample to determine if the subject has a genotype comprising the IP6K3 variant nucleic acid molecule. In some embodiments, the methods further comprise administering or continuing to administerthe muscle atrophy therapeutic agent in an amount that is the same as or less than a standard dosage amount or muscle atrophy therapy to the subject, and / or administering a IP6K3 inhibitor to a subject that is IP6K3 reference or to a subject that is heterozygous for the IP6K3 variant nucleic acid molecule. In some embodiments, the methods further comprise administering or continuing to administer the muscle atrophy therapeutic agent in a standard dosage amount or muscle atrophy therapy to a subject that is homozygous for the IP6K3 variant nucleic acid molecule. The presence of a IP6K3 variant nucleic acid molecule indicates the subject has a decreased risk of developing muscle atrophy. In some embodiments, the subject is IP6K3 reference. In some embodiments, the subject is heterozygous for a IP6K3 variant nucleic acid molecule. In some embodiments, the subject is homozygous for a IP6K3 variant nucleic acid molecule. In any of the embodiments described herein, the IP6K3 inhibitor is an example of a muscle atrophy therapeutic agent. In some embodiments, the IP6K3 variant nucleic acid molecule is a IP6K3 variant genomic nucleic acid molecule that comprises the genetic variation listed in Table 1, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule.

[0225] The present disclosure also provides methods of treating a subject with a type 2 diabetes therapeutic agent, wherein the subject has type 2 diabetes or is at risk of developing type 2 diabetes. The methods comprise determining whether the subject has a IP6K3 variant nucleic acid molecule by obtaining or having obtained a biological sample from the subject, and performing or having performed a sequence analysis on the biological sample to determine if the subject has a genotype comprising the IP6K3 variant nucleic acid molecule. In some embodiments, the methods further comprise administering or continuing to administer the

[0226] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0227] - 55-type 2 diabetes therapeutic agent in an amount that is the same as or less than a standard dosage amount to the subject, and / or administering a IP6K3 inhibitor to a subject that is IP6K3 reference or to a subject that is heterozygous for the IP6K3 variant nucleic acid molecule. In some embodiments, the methods further comprise administering or continuing to administer the type 2 diabetes therapeutic agent in a standard dosage amount to a subject that is homozygous for the IP6K3 variant nucleic acid molecule. The presence of a IP6K3 variant nucleic acid molecule indicates the subject has a decreased risk of developing type 2 diabetes. In some embodiments, the subject is IP6K3 reference. In some embodiments, the subject is heterozygous for a IP6K3 variant nucleic acid molecule. In some embodiments, the subject is homozygous for a IP6K3 variant nucleic acid molecule. In any of the embodiments described herein, the IP6K3 inhibitor is an example of a type 2 diabetes therapeutic agent. In some embodiments, the IP6K3 variant nucleic acid molecule is a IP6K3 variant genomic nucleic acid molecule that comprises the genetic variation listed in Table 1, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule.

[0228] For subjects that are genotyped or determined to be either IP6K3 reference or heterozygous for a IP6K3 variant nucleic acid molecule, such subjects can be administered a IP6K3 inhibitor, as described herein.

[0229] Detecting the presence or absence of a IP6K3 variant nucleic acid molecule in a biological sample from a subject and / or determining whether a subject has a IP6K3 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.

[0230] In some embodiments, when the subject is IP6K3 reference, the subject is administered a muscle atrophy therapeutic agent in an amount that is the same as or less than a standard dosage amount or muscle atrophy therapy, and / or a IP6K3 inhibitor. In some embodiments, when the subject is heterozygous for a IP6K3 variant nucleic acid molecule, the subject is administered a muscle atrophy therapeutic agent in an amount that is the same as or less than a standard dosage amount or muscle atrophy therapy, and / or a IP6K3 inhibitor.

[0231] In some embodiments, when the subject is IP6K3 reference, the subject is administered a type 2 diabetes therapeutic agent in an amount that is the same as or less than

[0232] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0233] -56-a standard dosage amount, and / or a IP6K3 inhibitor. In some embodiments, when the subject is heterozygous for a IP6K3 variant nucleic acid molecule, the subject is administered a type 2 diabetes therapeutic agent in an amount that is the same as or less than a standard dosage amount, and / or a IP6K3 inhibitor.

[0234] In some embodiments, the treatment or prevention methods comprise detecting the presence or absence of a decrease in the expression of a IP6K3 variant mRNA or polypeptide in a biological sample from the subject. In some embodiments, when the subject does not have a decrease in the expression of a IP6K3 variant mRNA or polypeptide, the subject is administered a muscle atrophy therapeutic agent in an amount that is the same as or less than a standard dosage amount or muscle atrophy therapy, and / or a IP6K3 inhibitor. In some embodiments, when the subject has a decrease in the expression of a IP6K3 variant mRNA or polypeptide, the subject is administered a muscle atrophy therapeutic agent in a standard dosage amount or muscle atrophy therapy.

[0235] In some embodiments, the treatment or prevention methods comprise detecting the presence or absence of a decrease in the expression of a IP6K3 variant mRNA or polypeptide in a biological sample from the subject. In some embodiments, when the subject does not have a decrease in the expression of a IP6K3 variant mRNA or polypeptide, the subject is administered a type 2 diabetes therapeutic agent in an amount that is the same as or less than a standard dosage amount, and / or a IP6K3 inhibitor. In some embodiments, when the subject has a decrease in the expression of a IP6K3 variant mRNA or polypeptide, the subject is administered a type 2 diabetes therapeutic agent in a standard dosage amount.

[0236] The present disclosure also provides methods of treating a subject with a muscle atrophy therapeutic agent or muscle atrophy therapy that treats or inhibits muscle atrophy, wherein the subject has muscle atrophy or is at risk of developing muscle atrophy. The methods comprise determining whether the subject has a decrease in the expression of a IP6K3 variant mRNA or polypeptide by obtaining or having obtained a biological sample from the subject, and performing or having performed an assay on the biological sample to determine if the subject a decrease in the expression of a IP6K3 variant mRNA or polypeptide. In embodiments where the subject does not have a decrease in the expression of a IP6K3 variant mRNA or polypeptide, the methods further comprise administering or continuing to administerthe muscle atrophy therapeutic agent in an amount that is the same as or less than a standard dosage amount or muscle atrophy therapy to the subject, and / or administering a IP6K3 inhibitor to the subject. In

[0237] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0238] - 57-embodiments where the subject has a decrease in the expression of a IP6K3 variant mRNA or polypeptide, the methods further comprise administering or continuing to administer the muscle atrophy therapeutic agent in a standard dosage amount or muscle atrophy therapy to the subject. The presence of a decrease in the expression of a IP6K3 variant mRNA or polypeptide indicates the subject has a decreased risk of developing muscle atrophy. In some embodiments, the subject has a decrease in the expression of a IP6K3 variant mRNA or polypeptide. In some embodiments, the subject does not have a decrease in the expression of a IP6K3 variant mRNA or polypeptide. In any of the embodiments described herein, the IP6K3 inhibitor is an example of a muscle atrophy therapeutic agent. In some embodiments, the IP6K3 variant nucleic acid molecule is a IP6K3 variant genomic nucleic acid molecule that comprises the genetic variation listed in Table 1, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule.

[0239] The present disclosure also provides methods of treating a subject with a type 2 diabetes therapeutic agent, wherein the subject has type 2 diabetes or is at risk of developing type 2 diabetes. The methods comprise determining whether the subject has a decrease in the expression of a IP6K3 variant mRNA or polypeptide by obtaining or having obtained a biological sample from the subject, and performing or having performed an assay on the biological sample to determine if the subject a decrease in the expression of a IP6K3 variant mRNA or polypeptide. In embodiments where the subject does not have a decrease in the expression of a IP6K3 variant mRNA or polypeptide, the methods further comprise administering or continuing to administer the type 2 diabetes therapeutic agent in an amount that is the same as or less than a standard dosage amount to the subject, and / or administering a IP6K3 inhibitor to the subject. In embodiments where the subject has a decrease in the expression of a IP6K3 variant mRNA or polypeptide, the methods further comprise administering or continuing to administer the type 2 diabetes therapeutic agent in a standard dosage amount to the subject. The presence of a decrease in the expression of a IP6K3 variant mRNA or polypeptide indicates the subject has a decreased risk of developing type 2 diabetes. In some embodiments, the subject has a decrease in the expression of a IP6K3 variant mRNA or polypeptide. In some embodiments, the subject does not have a decrease in the expression of a IP6K3 variant mRNA or polypeptide. In any of the embodiments described herein, the IP6K3 inhibitor is an example of a type 2 diabetes therapeutic agent. In some embodiments, the IP6K3 variant nucleic acid molecule is a IP6K3 variant genomic nucleic acid molecule that comprises the genetic variation

[0240] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0241] - 58-listed in Table 1, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule.

[0242] Detecting a decrease in the expression of a IP6K3 variant mRNA or polypeptide can be carried out by a variety of known methods. 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 mRNA or polypeptide can be present within a cell obtained from the subject.

[0243] In some embodiments, the treatment or prevention methods comprise detecting the presence or absence of a IP6K3 variant polypeptide in a biological sample from the subject. In some embodiments, when the subject does not have a IP6K3 variant polypeptide, the subject is administered a muscle atrophy therapeutic agent in an amount that is the same as or less than a standard dosage amount or muscle atrophy therapy, and / or a IP6K3 inhibitor. In some embodiments, when the subject has a IP6K3 variant polypeptide, the subject is administered a muscle atrophy therapeutic agent in standard dosage amount or muscle atrophy therapy.

[0244] In some embodiments, the treatment or prevention methods comprise detecting the presence or absence of a IP6K3 variant polypeptide in a biological sample from the subject. In some embodiments, when the subject does not have a IP6K3 variant polypeptide, the subject is administered a type 2 diabetes therapeutic agent in an amount that is the same as or less than a standard dosage amount, and / or a IP6K3 inhibitor. In some embodiments, when the subject has a IP6K3 variant polypeptide, the subject is administered a type 2 diabetes therapeutic agent in standard dosage amount.

[0245] The present disclosure also provides methods of treating a subject with a muscle atrophy therapeutic agent or muscle atrophy therapy that treats or inhibits muscle atrophy, wherein the subject has muscle atrophy or is at risk of developing muscle atrophy. The methods comprise determining whether the subject has a IP6K3 variant polypeptide by obtaining or having obtained a biological sample from the subject and performing or having performed an assay on the biological sample to determine if the subject has a IP6K3 variant polypeptide. When the subject does not have a IP6K3 variant polypeptide, the subject is administered the muscle atrophy therapeutic agent in an amount that is the same as or less than a standard dosage amount or muscle atrophy therapy, and / or a IP6K3 inhibitor. When the subject has a IP6K3 variant polypeptide, the subject is administered the muscle atrophy therapeutic agent in a standard dosage amount or muscle atrophy therapy. The presence of a IP6K3 variant

[0246] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0247] - 59-polypeptide indicates the subject has a decreased risk of developing muscle atrophy. In some embodiments, the subject has a IP6K3 variant polypeptide. In some embodiments, the subject does not have a IP6K3 variant polypeptide.

[0248] The present disclosure also provides methods of treating a subject with a type 2 diabetes therapeutic agent, wherein the subject has muscle atrophy or is at risk of developing type 2 diabetes. The methods comprise determining whether the subject has a IP6K3 variant polypeptide by obtaining or having obtained a biological sample from the subject and performing or having performed an assay on the biological sample to determine if the subject has a IP6K3 variant polypeptide. When the subject does not have a IP6K3 variant polypeptide, the subject is administered the type 2 diabetes therapeutic agent in an amount that is the same as or less than a standard dosage amount, and / or a IP6K3 inhibitor. When the subject has a IP6K3 variant polypeptide, the subject is administered the type 2 diabetes therapeutic agent in a standard dosage amount. The presence of a IP6K3 variant polypeptide indicates the subject has a decreased risk of developing type 2 diabetes. In some embodiments, the subject has a IP6K3 variant polypeptide. In some embodiments, the subject does not have a IP6K3 variant polypeptide.

[0249] The present disclosure also provides methods of preventing a subject from developing muscle atrophy by administering a muscle atrophy therapeutic agent or muscle atrophy therapy that prevents muscle atrophy. In some embodiments, the method comprises determining whether the subject has a IP6K3 variant polypeptide by obtaining or having obtained a biological sample from the subject and performing or having performed an assay on the biological sample to determine if the subject has a IP6K3 variant polypeptide. When the subject does not have a IP6K3 variant polypeptide, the subject is administered the muscle atrophy therapeutic agent in an amount that is the same as or less than a standard dosage amount or muscle atrophy therapy, and / or a IP6K3 inhibitor. When the subject has a IP6K3 variant polypeptide, the subject is administered the muscle atrophy therapeutic agent in a standard dosage amount or muscle atrophy therapy. The presence of a IP6K3 variant polypeptide indicates the subject has a decreased risk of developing muscle atrophy. In some embodiments, the subject has a IP6K3 variant polypeptide. In some embodiments, the subject does not have a IP6K3 variant polypeptide.

[0250] The present disclosure also provides methods of preventing a subject from developing type 2 diabetes by administering a type 2 diabetes therapeutic agent. In some embodiments,

[0251] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0252] - 60-the method comprises determining whether the subject has a IP6K3 variant polypeptide by obtaining or having obtained a biological sample from the subject and performing or having performed an assay on the biological sample to determine if the subject has a IP6K3 variant polypeptide. When the subject does not have a IP6K3 variant polypeptide, the subject is administered the type 2 diabetes therapeutic agent in an amount that is the same as or less than a standard dosage amount, and / or a IP6K3 inhibitor. When the subject has a IP6K3 variant polypeptide, the subject is administered the type 2 diabetes therapeutic agent in a standard dosage amount. The presence of a IP6K3 variant polypeptide indicates the subject has a decreased risk of developing type 2 diabetes. In some embodiments, the subject has a IP6K3 variant polypeptide. In some embodiments, the subject does not have a IP6K3 variant polypeptide.

[0253] Detecting the presence or absence of a IP6K3 variant polypeptide in a biological sample from a subject and / or determining whether a subject has a IP6K3 variant polypeptide 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 polypeptide can be present within a cell obtained from the subject.

[0254] In some embodiments, the IP6K3 inhibitor is a small molecule. In some embodiments, the small molecule is low molecular weight (< 900 daltons) organic compound. In some embodiments, the IP6K3 inhibitor comprises an antibody. In some embodiments, the IP6K3 inhibitor comprises Anti-IP6K3 antibody (Sigma-Aldrich; catalog# SAB4500277), Anti-lnositol Hexakisphosphate Kinase 3 (IP6K3) (Biomol; catalog# I8449-02B.100), Anti-IP6K3 (Biomol; catalog# 037070-FITC.200), IP6K3 Polyclonal Antibody (Thermo Fisher; catalog# PA5-106525), IP6K3 Polyclonal Antibody (Thermo Fisher; catalog# PA5-143236), IP6K3 Polyclonal Antibody (Thermo Fisher; catalog# PA5-62822), or IP6K3 Polyclonal Antibody (Thermo Fisher; catalog# PA5-140106), or any combination thereof.

[0255] In some embodiments, the IP6K3 inhibitor comprises an antibody, or antigen-binding fragment thereof. In some embodiments, the antibody, or antigen-binding fragment thereof, binds specifically to huma IP6K3. In some embodiments, the antibody is a fully human monoclonal antibody (mAb), or antigen-binding fragment thereof, that specifically binds and neutralizes, inhibits, blocks, abrogates, reduces, or interferes with, at least one activity of IP6K3, in particular, huma IP6K3. In some embodiments, an antibody or fragment thereof can

[0256] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0257] - 61-neutralize, inhibit, block, abrogate, reduce, or interfere with, an activity of IP6K3 by binding to an epitope of IP6K3 that is directly involved in the targeted activity of IP6K3. In some embodiments, an antibody or fragment thereof can neutralize, inhibit, block, abrogate, reduce, or interfere with, an activity of IP6K3 by binding to an epitope of IP6K3 that is not directly involved in the targeted activity of IP6K3, but the antibody or fragment binding thereto sterically or conformationally inhibits, blocks, abrogates, reduces, or interferes with, the targeted activity of IP6K3. In some embodiments, an antibody or fragment thereof binds to an epitope of IP6K3 that is not directly involved in the targeted activity of IP6K3 (i.e., a nonblocking antibody), but the antibody or fragment binding thereto results in the enhancement of the clearance of IP6K3 from the circulation, compared to the clearance of IP6K3 in the absence of the antibody or fragment thereof, thereby indirectly inhibiting, blocking, abrogating, reducing, or interfering with, an activity of IP6K3. Clearance of IP6K3 from the circulation can be particularly enhanced by combining two or more different non-blocking antibodies that do not compete with one another for specific binding to IP6K3. The antibodies can be full-length (for example, an IgGl or lgG4 antibody) or may comprise only an antigen-binding portion (for example, a Fab, F(ab')2 or scFv fragment), and may be modified to affect functionality, e.g., to eliminate residual effector functions (Reddy et al., J. Immunol., 2000, 164, 1925-1933).

[0258] In some embodiments, the antibody or antigen-binding fragment thereof specifically binds to IP6K3 with an equilibrium dissociation constant (KD) of about 7 nM or less, about 6 nM or less, about 5 nM or less, about 4 nM or less, about 3 nM or less, about 2 nM or less, or about 1 nM or less, as measured by surface plasmon resonance assay (for example, BIACORE™). In some embodiments, the antibody exhibits a KD of about 800 pM or less, about 700 pM or less; about 600 pM or less; about 500 pM or less; about 400 pM or less; about 300 pM or less; about 200 pM or less; about 100 pM or less; or about 50 pM or less.

[0259] In some embodiments, the ant i-l P6K3 antibody has a modified glycosylation pattern. In some applications, modification to remove undesirable glycosylation sites may be useful, or e.g., removal of a fucose moiety to increase antibody dependent cellular cytotoxicity (ADCC) function (see, Shield et al., J. Biol. Chem., 2002, 277, 26733). In other applications, removal of N-glycosylation site may reduce undesirable immune reactions against the therapeutic antibodies or increase affinities of the antibodies. In yet other applications, modification of galactosylation can be made to modify complement dependent cytotoxicity (CDC).

[0260] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0261] - 62- In some embodiments, the IP6K3 inhibitor can be delivered to skeletal muscle tissue or cells by using Calcium Voltage-Gated Channel Auxiliary Subunit Gamma 1 (CACNG1) binding protein delivery systems (see, for example, PCT Publications WO 23 / 81850 and WO 23 / 81847).

[0262] The present disclosure also provides compositions comprising a combination of an antibody or antigen-binding fragment thereof and a muscle atrophy therapeutic agent. The present disclosure also provides compositions comprising a combination of an antibody or antigen-binding fragment thereof and a type 2 diabetes therapeutic agent.

[0263] In some embodiments, the muscle atrophy therapeutic agents include, but are not limited to, a corticosteroid, testosterone, a selective androgen receptor modulator, a growth hormone, a growth hormone secretagogue, a myostatin inhibitor (e.g., trevogrumab), an activin type II receptor inhibitor (e.g., bimagrumab), or a modulator of the activin / inhibin family of ligands and receptors. Additional muscle atrophy therapies include any therapy used to reduce or manage muscle atrophy risk factors or causes. Furthermore, IP6K3 inhibitors can be combined with therapeutic agents that induce muscle atrophy (e.g., glucagon-like peptide 1 receptor agonists, such as semaglutide, or combined agonists of glucagon-like peptide 1 receptor and glucose-dependent insulinotropic polypeptide receptor, such as tirzepatide), to mitigate against muscle loss arising from such therapeutic agents. In some embodiments, the muscle atrophy therapeutic agent or muscle atrophy therapy can be combined with a IP6K3 inhibitor. In some embodiments, the treatment therapy for muscle atrophy is exercise therapy and nutrition therapy. These treatment therapies may be delayed or avoided altogether by treatment with a IP6K3 inhibitor as described herein.

[0264] In some embodiments, the Type 2 diabetes therapeutic agents include, but are not limited to, an alpha-glucosidase inhibitor, a biguanide, a bile acid sequestrant (BAS), a dopamine-2 agonist, a dipeptidyl peptidase-4 (DPP-4) inhibitor (i.e., a gliptin), a meglitinide (i.e., a glinide), a sodium-glucose cotransporter-2 (SGLT2) inhibitor, a sulfonylurea, a thiazolidinedione (TZD), a glucagon-like peptide-1 (GLP-1) receptor agonist, and an insulin, or any combination thereof. In some embodiments, the Type 2 diabetes therapeutic agent comprises a proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitor. In some embodiments, the Type 2 diabetes therapeutic agent comprises an insulin sensitizer, such as metformin or a TZD.

[0265] In some embodiments, the Type 2 diabetes therapeutic agents include, but are not limited to: i) an alpha-glucosidase inhibitor (such as, for example, PRECOSE® (acarbose) and

[0266] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0267] - 63- GLYSET® (migl itol )); ii) a biguanide (such as, for example, GLUCOPHAGE®, GLUCOPHAGE XR®, GLUMETZA®, FORTAMET®, and RIOMET® (metformin)); iii) a BAS (such as, for example, WELCHOL® (colesevelam)); iv) a dopamine-2 agonist (such as, for example, CYCLOSET® (bromocriptine)); v) a DPP-4 inhibitor (i.e., a gliptin) (such as, for example, NESINA® (alogliptin), TRADJENTA® (linagliptin), ONGLYZA® (saxagliptin), and JANUVIA® (sitagliptin)); vi) a meglitinide (i.e., a glinide) (such as, for example, STARLIX® (nateglinide) and PRANDIN® (repaglinide)); vii) an SGLT2 inhibitor (such as, for example, INVOKANA® (canagliflozin), FARXIGA® (dapagliflozin), and JARDIANCE® (empagliflozin)); viii) a sulfonylurea (such as, for example, AMARYL® (glimepiride), GLUCOTROL® and GLUCOTROL XL® (glipizide), and MICRONASE®, GLYNASE®, GLYCRON® and DIABETA® (glyburide)); ix) a TZD (such as, for example, AVANDIA® (rosiglitazone) and ACTOS® (pioglitazone)); x) a GLP-1 receptor agonist (such as, for example, BYETTA® (exenatide), VICTOZA® (liraglutide), TRULICITY® (dulaglutide), BYDUREON® (exenatide extended-release), ADLYXIN® (lixisenatide), OZEMPIC® (semaglutide injection), and RYBELSUS® (semaglutide tablet); and xi) an insulin (such as, for example, APIDRA® (insulin glulisine), HUMALOG® (insulin lispro), NOVOLOG® (insulin aspart), LANTUS® (insulin glargine), LEVEMIR® (insulin detemir), and HUMULIN® N and NOVOLIN® N (insulin isophane); or any combination thereof. In some embodiments, the Type 2 diabetes therapeutic agent comprises a PCSK9 inhibitor (such as, for example, PRALUENT® (alirocumab)).

[0268] In some embodiments, the Type 2 diabetes therapeutic agent comprises an alphaglucosidase inhibitor (such as, for example, acarbose and miglitol). In some embodiments, the Type 2 diabetes therapeutic agent comprises a biguanide (such as, for example, metformin). In some embodiments, the Type 2 diabetes therapeutic agent comprises a BAS (such as, for example, colesevelam). In some embodiments, the Type 2 diabetes therapeutic agent comprises a dopamine-2 agonist (such as, for example, bromocriptine). In some embodiments, the Type 2 diabetes therapeutic agent comprises a DPP-4 inhibitor (i.e., a gliptin) (such as, for example, alogliptin, linagliptin, saxagliptin, and sitagliptin). In some embodiments, the Type 2 diabetes therapeutic agent comprises a meglitinide (i.e., a glinide) (such as, for example, nateglinide and repaglinide). In some embodiments, the Type 2 diabetes therapeutic agent comprises an SGLT2 inhibitor (such as, for example, canagliflozin, dapagliflozin, and empagliflozin). In some embodiments, the Type 2 diabetes therapeutic agent comprises a sulfonylurea (such as, for example, glimepiride, glipizide, and glyburide). In some embodiments, the Type 2 diabetes therapeutic agent comprises a TZD (such as, for example, rosiglitazone and

[0269] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0270] - 64-pioglitazone). In some embodiments, the Type 2 diabetes therapeutic agent comprises a GLP-1 receptor agonist (such as, for example, exenatide, liraglutide, dulaglutide, lixisenatide, and semaglutide). In some embodiments, the Type 2 diabetes therapeutic agent comprises an insulin (such as, for example, insulin glulisine, insulin lispro, insulin aspart, insulin glargine, insulin detemir, and insulin isophane. In some embodiments, the Type 2 diabetes therapeutic agent comprises a PCSK9 inhibitor (such as, for example, alirocumab).

[0271] In some embodiments, the Type 2 diabetes therapeutic agent comprises an agent that preserves beta cell function and survival.

[0272] In some embodiments, the dose of the muscle atrophy therapeutic agents that treat, prevent, or inhibit muscle atrophy or the type 2 diabetes therapeutic agents that treat, prevent, or inhibit type 2 diabetes can be decreased by about 10%, by about 20%, by about 30%, by about 40%, by about 50%, by about 60%, by about 70%, by about 80%, or by about 90% for subjects that are heterozygous for a IP6K3 variant nucleic acid molecule or IP6K3 reference (i.e., a less than the standard dosage amount) compared to subjects that are homozygous for a IP6K3 variant nucleic acid molecule (who may receive a standard dosage amount). In some embodiments, the dose of the muscle atrophy therapeutic agents that treat, prevent, or inhibit muscle atrophy or the type 2 diabetes therapeutic agents that treat, prevent, or inhibit type 2 diabetes can be decreased by about 10%, by about 20%, by about 30%, by about 40%, or by about 50%. In some embodiments, the dose of the muscle atrophy therapeutic agents that treat, prevent, or inhibit muscle atrophy or the type 2 diabetes therapeutic agents that treat, prevent, or inhibit type 2 diabetes can be decreased by about 10%, by about 20%, by about 30%, by about 40%, by about 50%, by about 60%, by about 70%, by about 80%, or by about 90% for subjects that are heterozygous for a IP6K3 variant nucleic acid molecule compared to subjects that are IP6K3 reference. In addition, subjects that are heterozygous for a IP6K3 variant nucleic acid molecule can be administered the muscle atrophy therapeutic agents or the type 2 diabetes therapeutic agents less frequently compared to subjects that are IP6K3 reference.

[0273] Administration of the muscle atrophy therapeutic agents that treat, prevent, or inhibit muscle atrophy, the type 2 diabetes therapeutic agents that treat, prevent, or inhibit type 2 diabetes, and / or IP6K3 inhibitors 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

[0274] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0275] - 65-same dose or at a different dose. The administration can be repeated once, twice, three 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.

[0276] Administration of the muscle atrophy therapeutic agents, type 2 diabetes therapeutic agents, and / or IP6K3 inhibitors 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.

[0277] 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 muscle atrophy or type 2 diabetes, a decrease / reduction in the severity of muscle atrophy or type 2 diabetes (such as, for example, a reduction or inhibition of development of muscle atrophy or type 2 diabetes), 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 symptoms and disease-related effects, reducing secondary symptoms, reducing secondary infections, 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 the agent or composition comprising the agent. A prophylactic effect may comprise a complete or partial avoidance / inhibition or a delay of muscle atrophy or type 2 diabetes development / progression (such as, for example, a complete or partial avoidance / inhibition or a delay), and an increased

[0278] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0279] - 66-survival time of the affected host animal, following administration of a therapeutic protocol. Treatment of muscle atrophy or type 2 diabetes encompasses the treatment of a subject already diagnosed as having any form of muscle atrophy or type 2 diabetes at any clinical stage or manifestation, the delay of the onset or evolution or aggravation or deterioration of the symptoms or signs of muscle atrophy or type 2 diabetes, and / or preventing and / or reducing the severity of muscle atrophy or type 2 diabetes.

[0280] In some embodiments, the IP6K3 inhibitor and the muscle atrophy therapeutic agent or the type 2 diabetes therapeutic agent are disposed within a pharmaceutical composition. In some embodiments, the IP6K3 inhibitor is disposed within a first pharmaceutical composition and the muscle atrophy therapeutic agent or type 2 diabetes 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.

[0281] The present disclosure also provides methods of identifying a subject having an increased risk of developing muscle atrophy. In some embodiments, the method comprises determining or having determined in a biological sample obtained from the subject the presence or absence of a IP6K3 variant nucleic acid molecule (such as a genomic nucleic acid molecule, mRNA molecule, and / or cDNA molecule). When the subject lacks a IP6K3 variant nucleic acid molecule (i.e., the subject is genotypically categorized as IP6K3 reference), then the subject has an increased risk of developing muscle atrophy. When the subject has a IP6K3 variant nucleic acid molecule (i.e., the subject is heterozygous or homozygous for a IP6K3 variant nucleic acid molecule), then the subject has a decreased risk of developing muscle atrophy. In some embodiments, the IP6K3 variant nucleic acid molecule is a IP6K3 variant genomic nucleic acid molecule that comprises the genetic variation listed in Table 1, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule.

[0282] The present disclosure also provides methods of identifying a subject having an increased risk of developing type 2 diabetes. In some embodiments, the method comprises determining or having determined in a biological sample obtained from the subject the presence or absence of a IP6K3 variant nucleic acid molecule (such as a genomic nucleic acid

[0283] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0284] - 67-molecule, mRNA molecule, and / or cDNA molecule). When the subject lacks a IP6K3 variant nucleic acid molecule (i.e., the subject is genotypically categorized as IP6K3 reference), then the subject has an increased risk of developing type 2 diabetes. When the subject has a IP6K3 variant nucleic acid molecule (i.e., the subject is heterozygous or homozygous for a IP6K3 variant nucleic acid molecule), then the subject has a decreased risk of developing type 2 diabetes. In some embodiments, the IP6K3 variant nucleic acid molecule is a IP6K3 variant genomic nucleic acid molecule that comprises the genetic variation listed in Table 1, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule.

[0285] Having a single copy of a IP6K3 variant nucleic acid molecule is more protective of a subject from developing muscle atrophy or type 2 diabetes than having no copies of a IP6K3 variant nucleic acid molecule. Without intending to be limited to any particular theory or mechanism of action, it is believed that a single copy of a IP6K3 variant nucleic acid molecule (i.e., heterozygous for a IP6K3 variant nucleic acid molecule) is protective of a subject from developing muscle atrophy or type 2 diabetes and it is also believed that having two copies of a IP6K3 variant nucleic acid molecule (i.e., homozygous for a IP6K3 variant nucleic acid molecule) may be more protective of a subject from developing muscle atrophy or type 2 diabetes, relative to a subject with a single copy. Thus, in some embodiments, a single copy of a IP6K3 variant nucleic acid molecule may not be completely protective, but instead, may be partially or incompletely protective of a subject from developing muscle atrophy or type 2 diabetes. While not desiring to be bound by any particular theory, there may be additional factors or molecules involved in the development of muscle atrophy or type 2 diabetes that are still present in a subject having a single copy of a IP6K3 variant nucleic acid molecule, thus resulting in less than complete protection from the development of muscle atrophy or type 2 diabetes.

[0286] Determining whether a subject has a IP6K3 variant nucleic acid molecule in a biological sample from a subject and / or determining whether a subject has a IP6K3 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.

[0287] In some embodiments, when a subject is identified as having an increased risk of developing muscle atrophy, the subject is administered a muscle atrophy therapeutic agent or

[0288] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0289] - 68-muscle atrophy therapy, and / or a IP6K3 inhibitor, as described herein. For example, when the subject is IP6K3 reference, and therefore has an increased risk of developing muscle atrophy, the subject is administered a muscle atrophy therapeutic agent in an amount that is the same as or less than a standard dosage amount or muscle atrophy therapy, and / or is administered a IP6K3 inhibitor. In some embodiments, when the subject is heterozygous for a IP6K3 variant nucleic acid molecule, the subject is administered the muscle atrophy therapeutic agent in an amount that is the same as or less than a standard dosage amount or muscle atrophy therapy, and / or is administered a IP6K3 inhibitor. In some embodiments, when the subject is homozygous for a IP6K3 variant nucleic acid molecule, the subject is administered a muscle atrophy therapeutic agent in a standard dosage amount or muscle atrophy therapy. In some embodiments, the subject is IP6K3 reference. In some embodiments, the subject is heterozygous for a IP6K3 variant nucleic acid molecule. In some embodiments, the subject is homozygous for a IP6K3 variant nucleic acid molecule.

[0290] In some embodiments, when a subject is identified as having an increased risk of developing type 2 diabetes, the subject is administered a type 2 diabetes therapeutic agent, and / or a IP6K3 inhibitor, as described herein. For example, when the subject is IP6K3 reference, and therefore has an increased risk of developing type 2 diabetes, the subject is administered a type 2 diabetes therapeutic agent in an amount that is the same as or less than a standard dosage amount, and / or is administered a IP6K3 inhibitor. In some embodiments, when the subject is heterozygous for a IP6K3 variant nucleic acid molecule, the subject is administered the type 2 diabetes therapeutic agent in an amount that is the same as or less than a standard dosage amount, and / or is administered a IP6K3 inhibitor. In some embodiments, when the subject is homozygous for a IP6K3 variant nucleic acid molecule, the subject is administered a type 2 diabetes therapeutic agent in a standard dosage amount or muscle atrophy therapy. In some embodiments, the subject is IP6K3 reference. In some embodiments, the subject is heterozygous for a IP6K3 variant nucleic acid molecule. In some embodiments, the subject is homozygous for a IP6K3 variant nucleic acid molecule.

[0291] The present disclosure also provides methods of determining a subject's aggregate burden, or risk score, of having two or more IP6K3 variant nucleic acid molecules, and / or two or more IP6K3 variant polypeptides associated with a decreased risk of developing muscle atrophy or type 2 diabetes. The aggregate burden is the sum of two or more genetic variants that can be carried out in an association analysis with muscle atrophy or type 2 diabetes. In some

[0292] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0293] - 69-embodiments, the subject is homozygous for one or more IP6K3 variant nucleic acid molecules associated with a decreased risk of developing muscle atrophy or type 2 diabetes. In some embodiments, the subject is heterozygous for one or more IP6K3 variant nucleic acid molecules associated with a decreased risk of developing muscle atrophy or type 2 diabetes. When the subject has a lower aggregate burden, the subject has an increased risk of developing muscle atrophy or type 2 diabetes, and the subject is administered or continued to be administered the muscle atrophy therapeutic agent or the type 2 diabetes therapeutic agent in an amount that is the same as or less than the standard dosage amount or muscle atrophy therapy, and / or a IP6K3 inhibitor. When the subject has a higher aggregate burden, the subject has a decreased risk of developing muscle atrophy or type 2 diabetes and the subject is administered or continued to be administered the muscle atrophy therapeutic agent or the type 2 diabetes therapeutic agent in a standard dosage amount or muscle atrophy therapy. The higher the aggregate burden, the lower the risk of developing muscle atrophy or type 2 diabetes.

[0294] In some embodiments, a subject's aggregate burden of having any two or more IP6K3 variant nucleic acid molecules represents a weighted sum of a plurality of any of the IP6K3 variant nucleic acid molecules. In some embodiments, the aggregate burden is calculated using at least about 2, at least about 3, at least about 4, at least about 5, at least about 10, at least about 20, at least about 30, at least about 40, at least about 50, at least about 60, at least about 70, at least about 80, at least about 100, at least about 120, at least about 150, at least about 200, at least about 250, at least about 300, at least about 400, at least about 500, at least about 1,000, at least about 10,000, at least about 100,000, or at least about or more than 1,000,000 genetic variants present in or around (up to 10 Mb) the IP6K3 gene, where the genetic burden is the number of alleles multiplied by the association estimate with muscle atrophy or type 2 diabetes or related outcome for each allele (e.g., a weighted polygenic burden score). In some embodiments, when the subject has an aggregate burden higher than a desired threshold score, the subject has a decreased risk of developing muscle atrophy or type 2 diabetes. In some embodiments, when the subject has an aggregate burden lower than a desired threshold score, the subject has an increased risk of developing muscle atrophy or type 2 diabetes.

[0295] In some embodiments, the aggregate burden may be divided into quintiles, e.g., top quintile, second quintile, intermediate quintile, fourth quintile, and bottom quintile, wherein the top quintile of aggregate burden corresponds to the lowest risk group and the bottom quintile of aggregate burden corresponds to the highest risk group. In some embodiments, a

[0296] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0297] - 70-subject having a higher aggregate burden comprises the highest weighted aggregate burdens, including, but not limited to the top 10%, top 20%, top 30%, top 40%, or top 50% of aggregate burdens from a subject population. In some embodiments, the genetic variants comprise the genetic variants having association with muscle atrophy or type 2 diabetes in the top 10%, top 20%, top 30%, top 40%, or top 50% of p-value range for the association. In some embodiments, each of the identified genetic variants comprise the genetic variants having association with muscle atrophy or type 2 diabetes with p-value of no more than about 10'2, about 10'3, about 10’4, about 10’5, about 10’6, about 10’7, about 10’8, about 10’9, about 1010, about 1011, about 1012, about 1013, about 1014, about or 1015. In some embodiments, the identified genetic variants comprise the genetic variants having association with muscle atrophy or type 2 diabetes with p-value of less than 5 x 10'8. In some embodiments, the identified genetic variants comprise genetic variants having association with muscle atrophy or type 2 diabetes in high-risk subjects as compared to the rest of the reference population with odds ratio (OR) about 1.5 or greater, about 1.75 or greater, about 2.0 or greater, or about 2.25 or greater for the top 20% of the distribution; or about 1.5 or greater, about 1.75 or greater, about 2.0 or greater, about 2.25 or greater, about 2.5 or greater, or about 2.75 or greater. In some embodiments, the odds ratio (OR) may range from about 1.0 to about 1.5, from about 1.5 to about 2.0, from about 2.0 to about 2.5, from about 2.5 to about 3.0, from about 3.0 to about 3.5, from about 3.5 to about 4.0, from about 4.0 to about 4.5, from about 4.5 to about 5.0, from about 5.0 to about 5.5, from about 5.5 to about 6.0, from about 6.0 to about 6.5, from about 6.5 to about 7.0, or greater than 7.0. In some embodiments, high-risk subjects have aggregate burdens in the bottom decile, quintile, or tertile in a reference population. The threshold of the aggregate burden can be determined on the basis of the nature of the intended practical application and the risk difference that would be considered meaningful for that practical application.

[0298] In embodiments where the aggregate burden is determined for genetic variants of any one of IP6K3 associated with muscle atrophy or type 2 diabetes, then the aggregate burden represents a subject's risk score for developing muscle atrophy or type 2 diabetes. In some embodiments, the aggregate burden or risk score includes genetic variants of any two or more of the IP6K3 (or any other gene) associated with muscle atrophy or type 2 diabetes to generate a polygenic risk score (PRS) for developing muscle atrophy or type 2 diabetes. In some embodiments, the PRS includes the IP6K3 variant genomic nucleic acid molecule that comprises

[0299] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0300] - 71-the genetic variation listed in Table 1, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule.

[0301] The present disclosure also provides methods of detecting the presence or absence of a IP6K3 variant nucleic acid molecule (i.e., a genomic nucleic acid molecule, an mRNA molecule, or a 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.

[0302] 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 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 any IP6K3 variant nucleic acid molecule, 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. When detecting the level of any IP6K3 variant nucleic acid molecule, different techniques can be used enrich the biological sample with mRNA molecules. Various methods to detect the presence or level of an mRNA molecule orthe presence of a particular variant genomic DNA locus can be used.

[0303] In some embodiments, detecting a IP6K3 variant nucleic acid molecule in a subject comprises performing a sequence analysis on a biological sample obtained from the subject to determine whether a IP6K3 genomic nucleic acid molecule in the biological sample, and / or a IP6K3 mRNA molecule in the biological sample, and / or a IP6K3 cDNA molecule produced from an mRNA molecule in the biological sample, is present in the sample. In some embodiments, the IP6K3 variant nucleic acid molecule is a IP6K3 variant genomic nucleic acid molecule that comprises the genetic variation listed in Table 1, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule.

[0304] In some embodiments, the methods of detecting the presence or absence of a IP6K3 variant nucleic acid molecule (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

[0305] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0306] - 72-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.

[0307] 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 a IP6K3 genomic nucleic acid molecule or mRNA molecule, and if mRNA, optionally reverse transcribing the mRNA into cDNA. Such assays can comprise, for example determining the identity of these positions of the particular IP6K3 nucleic acid molecule. In some embodiments, the method is an in vitro method.

[0308] In some embodiments, the determining step, detecting step, or sequence analysis comprises sequencing at least a portion of the nucleotide sequence of the IP6K3 genomic nucleic acid molecule, the IP6K3 mRNA molecule, or the IP6K3 cDNA molecule in the biological sample that comprises a genetic variation compared to the corresponding IP6K3 reference molecule. In some embodiments, the sequenced portion comprises one or more variations that cause a loss-of-function (partial or complete) or are predicted to cause a loss-of-function (partial or complete).

[0309] In some embodiments, the assay comprises sequencing the entire nucleic acid molecule. In some embodiments, only a IP6K3 genomic nucleic acid molecule is analyzed. In some embodiments, only a IP6K3 mRNA is analyzed. In some embodiments, only a IP6K3 cDNA obtained from the IP6K3 mRNA is analyzed.

[0310] 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.

[0311] 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.

[0312] 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 a IP6K3 variant genomic sequence, variant mRNA sequence, or variant cDNA sequence and not the corresponding IP6K3 reference sequence under stringent conditions and determining whether hybridization has occurred.

[0313] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0314] - 73- In some embodiments, the determining step, detecting step, or sequence analysis comprises: a) amplifying at least a portion of the IP6K3 nucleic acid molecule that encodes the IP6K3 polypeptide; 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.

[0315] 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).

[0316] In some embodiments, the methods utilize probes and primers of sufficient nucleotide length to bind to the target nucleotide sequence and specifically detect and / or identify a polynucleotide comprising a IP6K3 variant genomic nucleic acid molecule, variant mRNA molecule, or variant cDNA molecule. The hybridization conditions or reaction conditions can be determined by the operator to achieve this result. The nucleotide length may be any length that is sufficient for use in a detection method of choice, including any assay described or exemplified herein. Such probes and primers can hybridize specifically to a target nucleotide sequence under high stringency hybridization conditions. Probes and primers may have complete nucleotide sequence identity of contiguous nucleotides within the target nucleotide sequence, although probes 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. Probes and primers can 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 sequence of the target nucleic acid molecule.

[0317] 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 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

[0318] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0319] - 74-amplification (NASBA). Other methods include, but are not limited to, ligase chain reaction, strand displacement amplification, and thermophilic SDA (tSDA).

[0320] 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.

[0321] 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 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.

[0322] In some embodiments, such isolated nucleic acid molecules comprise or consist of at least about 5, at least about 8, at least about 10, at least about 11, at least about 12, at least

[0323] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0324] - 75-about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, at least about 25, at least about 30, at least about 35, at least about 40, at least about 45, at least about 50, at least about 55, at least about 60, at least about 65, at least about 70, at least about 75, at least about 80, at least about 85, at least about 90, at least about 95, at least about 100, at least about 200, at least about 300, at least about 400, at least about 500, at least about 600, at least about 700, at least about 800, at least about 900, at least about 1000, at least about 2000, at least about 3000, at least about 4000, or at least about 5000 nucleotides. In some embodiments, such isolated nucleic acid molecules comprise or consist of at least about 5, at least about 8, at least about 10, at least about 11, at least about 12, at least about 13, at least about 14, at least about 15, at least about 16, at least about 17, at least about 18, at least about 19, at least about 20, at least about 21, at least about 22, at least about 23, at least about 24, or at least about 25 nucleotides. In some embodiments, the isolated nucleic acid molecules comprise or consist of at least about 18 nucleotides. In some embodiments, the isolated nucleic acid molecules comprise or consists of at least about 15 nucleotides. In some embodiments, the isolated nucleic acid molecules consist of or comprise from about 10 to about 35, from about 10 to about 30, from about 10 to about 25, from about 12 to about 30, from about 12 to about 28, from about 12 to about 24, from about 15 to about 30, from about 15 to about 25, from about 18 to about 30, from about 18 to about 25, from about 18 to about 24, or from about 18 to about 22 nucleotides. In some embodiments, the isolated nucleic acid molecules consist of or comprise from about 18 to about 30 nucleotides. In some embodiments, the isolated nucleic acid molecules comprise or consist of at least about 15 nucleotides to at least about 35 nucleotides.

[0325] In some embodiments, such isolated nucleic acid molecules hybridize to IP6K3 variant nucleic acid molecules (such as genomic nucleic acid molecules, mRNA molecules, and / or cDNA molecules) under stringent conditions. Such nucleic acid molecules can be used, for example, as probes, primers, alteration-specific probes, or alteration-specific primers as described or exemplified herein, and include, without limitation primers, probes, antisense RNAs, shRNAs, and siRNAs, each of which is described in more detail elsewhere herein and can be used in any of the methods described herein.

[0326] In some embodiments, the isolated nucleic acid molecules hybridize to at least about 15 contiguous nucleotides of a nucleic acid molecule that is at least about 70%, at least about

[0327] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0328] - 76- 75%, at least about 80%, at least about 85%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, at least about 99%, or 100% identical to the IP6K3 variant nucleic acid molecule. In some embodiments, the isolated nucleic acid molecules consist of or comprise from about 15 to about 100 nucleotides, or from about 15 to about 35 nucleotides. In some embodiments, the isolated nucleic acid molecules consist of or comprise from about 15 to about 100 nucleotides. In some embodiments, the isolated nucleic acid molecules consist of or comprise from about 15 to about 35 nucleotides.

[0329] In some embodiments, the alteration-specific probes and alteration-specific primers comprise DNA. In some embodiments, the alteration-specific probes and alteration-specific primers comprise RNA.

[0330] In some embodiments, the probes and primers described herein (including alterationspecific probes and alteration-specific primers) have a nucleotide sequence that specifically hybridizes to any of the nucleic acid molecules disclosed herein, or the complement thereof. In some embodiments, the probes and primers specifically hybridize to any of the nucleic acid molecules disclosed herein under stringent conditions.

[0331] In some embodiments, the 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, Massive Parallel Signature Sequencing (MPSS), Polony sequencing, and 454 Pyrosequencing. 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.

[0332] The probes and primers described herein can be used to detect a nucleotide variation within any of the IP6K3 variant nucleic acid molecules disclosed herein. The primers described herein can be used to amplify any IP6K3 variant nucleic acid molecules, or a fragment thereof.

[0333] 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

[0334] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0335] - 77-not hybridize to a nucleic acid sequence encoding a IP6K3 reference genomic nucleic acid molecule, a IP6K3 reference mRNA molecule, and / or a IP6K3 reference cDNA molecule.

[0336] In some embodiments, the probes (such as, for example, an alteration-specific probe) comprise a label. In some embodiments, the label is a fluorescent label, a radiolabel, or biotin.

[0337] The present disclosure also provides supports comprising a substrate to which any one or more of the probes disclosed herein is attached. Solid supports are solid-state substrates or supports with which molecules, such as any of the probes disclosed herein, can be associated. A form of solid support is an array. Another form of solid support is an array detector. An array detector is a solid support to which multiple different probes have been coupled in an array, grid, or other organized pattern. A form for a solid-state substrate is a microtiter dish, such as a standard 96-well type. In some embodiments, a multiwell glass slide can be employed that normally contains one array per well.

[0338] 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.

[0339] Also provided herein are functional polynucleotides that can interact with the disclosed nucleic acid molecules. Examples of functional polynucleotides include, but are not limited to, antisense molecules, aptamers, ribozymes, triplex forming molecules, and external guide sequences. The functional polynucleotides can act as effectors, inhibitors, modulators, and stimulators of a specific activity possessed by a target molecule, or the functional polynucleotides can possess a de novo activity independent of any other molecules.

[0340] 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 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

[0341] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0342] - 78-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, tetramethylbenzidine (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.

[0343] 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 et al., 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 percent sequence identity, the higher percentages of sequence identity are preferred over the lower ones.

[0344] The present disclosure also provides muscle atrophy therapeutic agents that treat, prevent, or inhibit muscle atrophy for use in the treatment or prevention of muscle atrophy in a subject having a IP6K3 variant nucleic acid molecule. Any of the muscle atrophy therapeutic agents that treat, prevent, or inhibit muscle atrophy described herein can be used herein. Any of the IP6K3 variant nucleic acid molecules disclosed herein can be used herein. In some embodiments, the IP6K3 variant nucleic acid molecule is a IP6K3 variant genomic nucleic acid molecule that comprises the genetic variation listed in Table 1, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule.

[0345] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0346] - 79- The present disclosure also provides uses of muscle atrophy therapeutic agents that treat, prevent, or inhibit muscle atrophy for use in the preparation of a medicament for treating or preventing muscle atrophy in a subject having a IP6K3 variant nucleic acid molecule. Any of the muscle atrophy therapeutic agents that treat, prevent, or inhibit muscle atrophy described herein can be used herein. Any of the IP6K3 variant nucleic acid molecules disclosed herein can be used herein. In some embodiments, the IP6K3 variant nucleic acid molecule is a IP6K3 variant genomic nucleic acid molecule that comprises the genetic variation listed in Table 1, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule.

[0347] The present disclosure also provides type 2 diabetes therapeutic agents that treat, prevent, or inhibit type 2 diabetes for use in the treatment or prevention of type 2 diabetes in a subject having a IP6K3 variant nucleic acid molecule. Any of the type 2 diabetes therapeutic agents that treat, prevent, or inhibit type 2 diabetes described herein can be used herein. Any of the IP6K3 variant nucleic acid molecules disclosed herein can be used herein. In some embodiments, the IP6K3 variant nucleic acid molecule is a IP6K3 variant genomic nucleic acid molecule that comprises the genetic variation listed in Table 1, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule.

[0348] The present disclosure also provides uses of type 2 diabetes therapeutic agents that treat, prevent, or inhibit type 2 diabetes for use in the preparation of a medicament for treating or preventing type 2 diabetes in a subject having a IP6K3 variant nucleic acid molecule. Any of the type 2 diabetes therapeutic agents that treat, prevent, or inhibit type 2 diabetes described herein can be used herein. Any of the IP6K3 variant nucleic acid molecules disclosed herein can be used herein. In some embodiments, the IP6K3 variant nucleic acid molecule is a IP6K3 variant genomic nucleic acid molecule that comprises the genetic variation listed in Table 1, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule.

[0349] The present disclosure also provides IP6K3 inhibitors for use in the treatment or prevention of muscle atrophy in a subject that is IP6K3 reference or is heterozygous for a IP6K3 variant nucleic acid molecule. Any of the IP6K3 inhibitors described herein can be used herein. Any of the IP6K3 variant nucleic acid molecules disclosed herein can be used herein. In some embodiments, the IP6K3 variant nucleic acid molecule is a IP6K3 variant genomic nucleic acid

[0350] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0351] - 80-molecule that comprises the genetic variation listed in Table 1, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule.

[0352] The present disclosure also provides IP6K3 inhibitors in the preparation of a medicament for treating or preventing muscle atrophy in a subject that is IP6K3 reference or is heterozygous for a IP6K3 variant nucleic acid molecule. Any of the IP6K3 inhibitors described herein can be used herein. Any of the IP6K3 variant nucleic acid molecules disclosed herein can be used herein. In some embodiments, the IP6K3 variant nucleic acid molecule is a IP6K3 variant genomic nucleic acid molecule that comprises the genetic variation listed in Table 1, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule.

[0353] The present disclosure also provides IP6K3 inhibitors for use in the treatment or prevention of type 2 diabetes in a subject that is IP6K3 reference or is heterozygous for a IP6K3 variant nucleic acid molecule. Any of the IP6K3 inhibitors described herein can be used herein. Any of the IP6K3 variant nucleic acid molecules disclosed herein can be used herein. In some embodiments, the IP6K3 variant nucleic acid molecule is a IP6K3 variant genomic nucleic acid molecule that comprises the genetic variation listed in Table 1, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule.

[0354] The present disclosure also provides IP6K3 inhibitors in the preparation of a medicament for treating or preventing type 2 diabetes in a subject that is IP6K3 reference or is heterozygous for a IP6K3 variant nucleic acid molecule. Any of the IP6K3 inhibitors described herein can be used herein. Any of the IP6K3 variant nucleic acid molecules disclosed herein can be used herein. In some embodiments, the IP6K3 variant nucleic acid molecule is a IP6K3 variant genomic nucleic acid molecule that comprises the genetic variation listed in Table 1, or is an mRNA molecule produced therefrom, or is a cDNA molecule produced from the mRNA molecule.

[0355] 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 or filing date of a priority application referring to the accession number if applicable.

[0356] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0357] - 81- 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 illustration and example for purposes of clarity and understanding, it will be apparent that certain changes and modifications may be practiced within the scope of the appended claims.

[0358] 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.

[0359] Examples

[0360] Example 1: General Methods

[0361] Genetic association studies were performed in the University of Texas Southwestern Dallas Heart Expansion Study - Dallas Biobank (UTSW-COHEN), the United Kingdom Biobank (UKB) cohort, the UCLA Biobank (UCLA), the Colorado Biobanked and Prospective Collection Project (COLORADO), the DiscoverEHR cohort from the Geisinger Health System (GHS) MyCode Community Health Initiative, Mount Sinai BioMe Biobank cohort (SINAI), The University of Pennsylvania Penn Medicine BioBank (UPENN-PMBB), Malmo Diet and Cancer Study (MDCS), the Mayo Clinic Biobank (MAYO-CLINIC), the Mexico City Prospective Study (MCPS), and the Bangladesh Longitudinal Investigation of Emerging Vascular Events Study (CAMBRIDGE-BELIEVE).

[0362] The UTSW-COHEN is a population-based cohort of 13,888 African- and Hispanic-Americans in the city of Dallas. The UKB is a population-based cohort study of people aged between 40 and 69 years recruited through 22 testing centers in the UK between 2006-2010

[0363] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0364] - 82- (Sudlow et al., PLoS Med., 2015, 12, el001779). Over 430,000 European ancestry participants from UKB with available whole-exome sequencing and clinical phenotype data were included. UCLA is a hospital-based electronic health record data that provided genotypic and phenotypic data on 27,932 individuals. COLORADO is a hospital-based electronic health record database with genotypic and phenotypic data on 35,320 individuals. The GHS MyCode study Community Health Initiative is a health system-based cohort of patients from Central and Eastern Pennsylvania (USA) recruited in 2007-2019 (Carey et al., Genet. Med., 2016, 18, 906-13). Over 130,000 European ancestry participants from GHS with available whole-exome sequencing and clinical phenotype data were included. SINAI is a health-system based cohort of patients from the Mount Sinai BioMe Biobank, recruited from the Mount Sinai Health System (Abul-Husn et al., Cell, 2019, 177, 58-69). UPENN-PMBB is a health-system based cohort of patients from the University of Pennsylvania Penn Medicine BioBank (Park et al., Genet. Med., 2020, 22, 102-111). MDCS is a Swedish population-based, prospective, observational cohort recruited between 1991 and 1996 (Berglund et al., J. Intern. Med., 1993, 233, 45-51). The MAYO-CLINIC is a hospital-based electronic health record database with genotypic and phenotypic data on 81,132 individuals (Olson et al., BMJ Open, 2019, 9(11), e032707). The MCPS is a populationbased prospective study that included up to 159,755 individuals with phenotype and exome sequencing data (Tapia-Conyer et al., Int. J. Epidemiol., 2006, 35, 243-9). The CAMBRIDGE-BELIEVE study is a cross-sectional study conducted in Bangladesh (Khan et al., 2019, BMJ Open, 2019, 9:e030886).

[0365] Phenotype definitions

[0366] Baseline values for blood-based biomarkers (including creatinine, cystatin C, and others) were used in population-based cohorts. For health-system based cohorts, biomarker values were extracted from the electronic medical records of participants and median values were derived if two or more measurements were available for an individual.

[0367] For the analysis of serum creatinine concentration, individuals who likely have chronic kidney disease were first excluded (since kidney disease may influence creatinine levels). Such individuals were identified on the basis of various data sources, including: 1) electronic-health record or self-reported diagnoses of chronic kidney disease (including a record of renal replacement therapy), 2) measured estimated glomerular filtration rate (eGFR) less than 60 ml / min, and, if possible, 3) measured urine albumin-creatinine ratio greater than 30 mg / g. The creatinine-to-cystatin C ratio was derived by dividing the serum creatinine concentration by the

[0368] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0369] - 83-serum cystatin C concentration (without excluding individuals with chronic kidney disease from either measurement), and multiplying this ratio by a hundred.

[0370] Thigh muscle water volume was derived from magnetic resonance imaging (MRI) data in UKB. Analysis was performed using a subset of 38,880 participants with exome sequencing data who had undergone two-point Dixon MRI using Siemens MAGNETOM Aera 1.5T clinical MRI scanners, split into six different imaging series. Whole-body Dixon MRI images for 52 subjects were manually annotated, and then used these annotations to train a multi-class segmentation deep neural-net which employed a UNet architecture with a ResNet34 backbone, and a loss function of a sum of the Jaccard Index and categorical focal loss (Akbari et al., Nat. Commun., 2022, 23, 13(1), 4844). Thigh muscle phenotypes were calculated by summing the resulting segmentation maps from the neural net for each corresponding class.

[0371] Bioelectrical impedance was assessed at baseline in UKB using a Tanita BC 418ma Body Fat Analyser device. Bioelectrical impedance-derived measures of fat and fat-free mass and body composition were used as reported by UKB.

[0372] Dual-energy X-ray absorptiometry was assessed with a Lunar iDXA Scanner. Dualenergy X-ray absorptiometry-derived measures of fat and fat-free mass and body composition were used as reported by UKB.

[0373] Hand grip strength was assessed at baseline in UKB using a Jamar J00105 hydraulic hand dynamometer. The maximum value between the right and left hand values was selected, and adjusted the maximum value for body mass index, body mass index squared, and height, with adjustment performed separately in men and women. The unadjusted maximum value between the right and left hand values was also assessed.

[0374] Genotype data

[0375] High coverage whole exome sequencing was performed as previously described (Dewey et al., Science, 2016, 354, aaf6814; Van Hout et al., Nature, 2020, 586, 749-756) and as summarized below. NimbleGen probes (VCRome; for part of the GHS cohort) or a modified version of the xGen design available from Integrated DNA Technologies (IDT; for the rest of GHS and other cohorts) were used for target sequence capture of the exome. A unique 6 base pair (bp) barcode (VCRome) or 10 bp barcode (IDT) was added to each DNA fragment during library preparation to facilitate multiplexed exome capture and sequencing. Equal amounts of sample were pooled prior to exome capture. Sequencing was performed using 75 bp paired-end reads on Illumina v4 HiSeq 2500 (for part of the GHS cohort) or NovaSeq (for the rest of GHS and

[0376] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0377] - 84-other cohorts) instruments. Sequencing had a coverage depth (i.e., number of sequence-reads covering each nucleotide in the target areas of the genome) sufficient to provide greater than 20x coverage over 85% of targeted bases in 96% of VCRome samples and 20x coverage over 90% of targeted bases in 99% of IDT samples. Data processing steps included sample demultiplexing using Illumina software, alignment to the GRCh38 Human Genome reference sequence including generation of binary alignment and mapping files (BAM), processing of BAM files (e.g., marking of duplicate reads and other read mapping evaluations). Variant calling was performed using the GLNexus system (DOI: 10.1101 / 343970). Variant mapping and annotation were based on the GRCh38 Human Genome reference sequence and Ensembl v85 gene definitions using the snpEff software. The snpEff predictions that involve protein-coding transcripts with an annotated start and stop were then combined into a single functional impact prediction by selecting the most deleterious functional effect class for each gene. The hierarchy (from most to least deleterious) for these annotations was frameshift, stop-gain, stop-loss, splice acceptor, splice donor, stop-lost, in-frame indel, missense, other annotations. Predicted LOF genetic variants included: a) insertions or deletions resulting in a frameshift, b) insertions, deletions or single nucleotide variants resulting in the introduction of a premature stop codon or in the loss of the transcription start site or stop site, and c) variants in donor or acceptor splice sites. Missense variants were classified for likely functional impact according to the number of in silico prediction algorithms that predicted deleteriousness using SIFT (Adzhubei et al., Nat. Methods, 2010, 7, 248-9) and Polyphen2_HVAR (Adzhubei et al., Nat. Methods, 2010, 7, 248-9), LRT (Chun et al., Genome Res., 2009, 19, 1553-61) and MutationTaster (Schwarz et al., Nat. Methods, 2010, 7, 575-6).

[0378] Example 2: Association Analysis Results

[0379] Figure 1 shows loss of function of IP6K3 associates with increased markers of muscle mass, increased BIA- and DXA-derived lean body lean mass, numerical decreases in BIA- and DXA-derived fat mass, increased BIA-derived body lean composition and decreased BIA-derived body fat composition, and increased MRI-derived markers of muscle mass.

[0380] Figure 2 (Panel A and Panel B) shows that the strongest associated trait (creatinine:cystatin C ratio) for IP6K3 is primarily driven by variant carriers of EUR ancestry in the UKB (Panel A). The association for creatininexystatin C ratio remains robust in the EUR UKB

[0381] 115923230DOCKET NO.: 38120-4404 (12031W001)

[0382] - 85-subset of individuals when adjusting for all independent genome-wide significiant common variants (N=13) in the HLA locus near IP6K3 (Panel B).

[0383] 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.

[0384] 115923230

Claims

DOCKET NO.: 38120-4404 (12031W001)- 86- What is Claimed is:

1. A method of treating a subject having muscle atrophy or at risk of developing muscle atrophy, the method comprising administering an Inositol Hexakisphosphate Kinase 3 (IP6K3) inhibitor to the subject.

2. The method of claim 1, wherein the muscle atrophy is skeletal muscle atrophy.

3. The method of claim 1, wherein the muscle atrophy is cardiac muscle atrophy.

4. The method of claim 1, wherein the subject has: i) a muscular dystrophy, a myotonic dystrophy, or a mitochondrial myopathy; ii) an inflammatory muscle disease; iii) a sarcopenia; iv) a myopathy arising secondary to an environmental influence; v) a myopathy arising secondary to a systemic disease; vi) a neuromuscular condition leading to muscle atrophy; or vii) a weight loss mechanism.

5. The method of claim 4, wherein:the inflammatory muscle disease comprises polymyositis or dermatomyositits; the sarcopenia comprises age-related sarcopenia;the myopathy arising secondary to an environmental influence comprises drug-induced or alcohol-induced;the myopathy arising secondary to a systemic disease comprises thyroid-associated myopathy;the neuromuscular condition leading to muscle atrophy comprises amyotrophic lateral sclerosis or myasthenia gravis; andthe weight loss mechanism comprises bariatric surgery or pharmacologically-induced.

6. The method of any one of claims 1 to 5, wherein the IP6K3 inhibitor comprises an inhibitory nucleic acid molecule that hybridizes to an IP6K3 nucleic acid molecule.

7. The method of claim 6, wherein the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule, a small interfering RNA (siRNA), and / or a short hairpin RNA (shRNA).

8. The method of claim 7, wherein the inhibitory nucleic acid molecule comprises an siRNA.

9. The method of claim 7, wherein the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule.

10. The method of any one of claims 1 to 9, wherein the subject is also administered a muscle atrophy therapeutic agent or muscle atrophy therapy.115923230DOCKET NO.: 38120-4404 (12031W001)- 87- 11. The method of any one of claims 1 to 10, further comprising detecting the presence or absence of an IP6K3 variant nucleic acid molecule in a biological sample from the subject.

12. The method of claim 11, further comprising administering a muscle atrophy therapeutic agent in an amount that is the same as or less than a standard dosage amount or muscle atrophy therapy to the subject when the IP6K3 variant nucleic acid molecule is absent from the biological sample.

13. The method of claim 11, further comprising administering a muscle atrophy therapeutic agent in an amount that is the same as or less than a standard dosage amount or muscle atrophy therapy to the subject when the subject is heterozygous for the IP6K3 variant nucleic acid molecule.

14. The method of any one of claims 11 to 13, wherein the IP6K3 variant nucleic acid molecule comprises a splice-site variant, a stop-gain variant, a start-loss variant, a stop-loss variant, a frameshift variant, a missense variant, an in-frame indel variant, and / or a variant that encodes a truncated IP6K3 variant polypeptide.

15. The method of any one of claims 11 to 13, wherein the IP6K3 variant nucleic acid molecule comprises the genetic variation listed in Table 1.

16. A method of treating a subject having type 2 diabetes or at risk of developing type 2 diabetes, the method comprising administering an Inositol Hexakisphosphate Kinase 3 (IP6K3) inhibitor to the subject.

17. The method of claim 16, wherein the IP6K3 inhibitor comprises an inhibitory nucleic acid molecule that hybridizes to an IP6K3 nucleic acid molecule.

18. The method of claim 17, wherein the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule, a small interfering RNA (siRNA), and / or a short hairpin RNA (shRNA).

19. The method of claim 18, wherein the inhibitory nucleic acid molecule comprises an siRNA.

20. The method of claim 18, wherein the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule.

21. The method of any one of claims 16 to 20, wherein the subject is also administered a type 2 diabetes therapeutic agent.

22. The method of any one of claims 16 to 21, further comprising detecting the presence or absence of an IP6K3 variant nucleic acid molecule in a biological sample from the subject.115923230DOCKET NO.: 38120-4404 (12031W001)-88- 23. The method of claim 22, further comprising administering a type 2 diabetes therapeutic agent in an amount that is the same as or less than a standard dosage amount to the subject when the IP6K3 variant nucleic acid molecule is absent from the biological sample.

24. The method of claim 22, further comprising administering a type 2 diabetes therapeutic agent in an amount that is the same as or less than a standard dosage amount to the subject when the subject is heterozygous for the IP6K3 variant nucleic acid molecule.

25. The method of any one of claims 22 to 24, wherein the IP6K3 variant nucleic acid molecule comprises a splice-site variant, a stop-gain variant, a start-loss variant, a stop-loss variant, a frameshift variant, a missense variant, an in-frame indel variant, and / or a variant that encodes a truncated IP6K3 variant polypeptide.

26. The method of any one of claims 22 to 24, wherein the IP6K3 variant nucleic acid molecule comprises the genetic variation listed in Table 1.

27. A method of treating a subject having muscle atrophy or at risk of developing muscle atrophy by administering a muscle atrophy therapeutic agent or muscle atrophy therapy, the method comprising:determining or having determined whether the subject has an Inositol Hexakisphosphate Kinase 3 (IP6K3) variant nucleic acid molecule, by:obtaining or having obtained a biological sample from the subject; and performing or having performed a sequence analysis on the biological sample to determine if the subject has a genotype comprising the IP6K3 variant nucleic acid molecule; andadministering or continuing to administer the muscle atrophy therapeutic agent in an amount that is the same as or less than a standard dosage amount or muscle atrophy therapy, and / or an IP6K3 inhibitor to a subject that is IP6K3 reference;administering or continuing to administer the muscle atrophy therapeutic agent in an amount that is the same as or less than a standard dosage amount or muscle atrophy therapy, and / or an IP6K3 inhibitor to a subject that is heterozygous for the IP6K3 variant nucleic acid molecule; oradministering or continuing to administer the muscle atrophy therapeutic agent in a standard dosage amount or muscle atrophy therapy to a subject that is homozygous for the IP6K3 variant nucleic acid molecule;115923230DOCKET NO.: 38120-4404 (12031W001)- 89- wherein the presence of the IP6K3 variant nucleic acid molecule indicates the subject has a decreased risk of developing muscle atrophy.

28. The method of claim 27, wherein the muscle atrophy is skeletal muscle atrophy.

29. The method of claim 27, wherein the muscle atrophy is cardiac muscle atrophy.

30. The method of claim 27, wherein the subject has: i) a muscular dystrophy, a myotonic dystrophy, or a mitochondrial myopathy; ii) an inflammatory muscle disease; iii) a sarcopenia; iv) a myopathy arising secondary to an environmental influence; v) a myopathy arising secondary to a systemic disease; vi) a neuromuscular condition leading to muscle atrophy; or vii) a weight loss mechanism.

31. The method of claim 30, wherein:the inflammatory muscle disease comprises polymyositis or dermatomyositits; the sarcopenia comprises age-related sarcopenia;the myopathy arising secondary to an environmental influence comprises drug-induced or alcohol-induced;the myopathy arising secondary to a systemic disease comprises thyroid-associated myopathy;the neuromuscular condition leading to muscle atrophy comprises amyotrophic lateral sclerosis or myasthenia gravis; andthe weight loss mechanism comprises bariatric surgery or pharmacologically-induced.

32. The method of any one of claims 1 to 31, wherein the IP6K3 inhibitor comprises an inhibitory nucleic acid molecule that hybridizes to an IP6K3 nucleic acid molecule.

33. The method of claim 32, wherein the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule, a small interfering RNA (siRNA), and / or a short hairpin RNA (shRNA).

34. The method of claim 33, wherein the inhibitory nucleic acid molecule comprises an siRNA.

35. The method of claim 33, wherein the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule.

36. The method of any one of claims T1 to 35, wherein the subject is heterozygous for the IP6K3 variant nucleic acid molecule, and the subject is administered or continued to be administered the muscle atrophy therapeutic agent in an amount that is the same as or less than a standard dosage amount or muscle atrophy therapy and the IP6K3 inhibitor.115923230DOCKET NO.: 38120-4404 (12031W001)- 90- 37. The method of any one of claims 27 to 35, wherein the subject is IP6K3 reference, and the subject is administered or continued to be administered the muscle atrophy therapeutic agent in an amount that is the same as or less than a standard dosage amount or muscle atrophy therapy and the IP6K3 inhibitor.

38. The method of any one of claims 27 to 37, wherein the IP6K3 variant nucleic acid molecule comprises a splice-site variant, a stop-gain variant, a start-loss variant, a stop-loss variant, a frameshift variant, a missense variant, an in-frame indel variant, and / or a variant that encodes a truncated IP6K3 variant polypeptide.

39. The method of any one of claims 1 to 37, wherein the IP6K3 variant nucleic acid molecule comprises the genetic variation listed in Table 1.

40. A method of treating a subject having type 2 diabetes or at risk of developing type 2 diabetes by administering a type 2 diabetes, the method comprising:determining or having determined whether the subject has an Inositol Hexakisphosphate Kinase 3 (IP6K3) variant nucleic acid molecule, by:obtaining or having obtained a biological sample from the subject; and performing or having performed a sequence analysis on the biological sample to determine if the subject has a genotype comprising the IP6K3 variant nucleic acid molecule; andadministering or continuing to administer the type 2 diabetes therapeutic agent in an amount that is the same as or less than a standard dosage amount, and / or an IP6K3 inhibitor to a subject that is IP6K3 reference;administering or continuing to administer the type 2 diabetes therapeutic agent in an amount that is the same as or less than a standard dosage amount, and / or an IP6K3 inhibitor to a subject that is heterozygous for the IP6K3 variant nucleic acid molecule; or administering or continuing to administer the type 2 diabetes therapeutic agent in a standard dosage amount to a subject that is homozygous for the IP6K3 variant nucleic acid molecule;wherein the presence of the IP6K3 variant nucleic acid molecule indicates the subject has a decreased risk of developing type 2 diabetes.

41. The method of claim 40, wherein the IP6K3 inhibitor comprises an inhibitory nucleic acid molecule that hybridizes to an IP6K3 nucleic acid molecule.115923230DOCKET NO.: 38120-4404 (12031W001)- 91- 42. The method of claim 41, wherein the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule, a small interfering RNA (siRNA), and / or a short hairpin RNA (shRNA).

43. The method of claim 42, wherein the inhibitory nucleic acid molecule comprises an siRNA.

44. The method of claim 42, wherein the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule.

45. The method of any one of claims 40 to 44, wherein the subject is heterozygous for the IP6K3 variant nucleic acid molecule, and the subject is administered or continued to be administered the type 2 diabetes therapeutic agent in an amount that is the same as or less than a standard dosage amount and the IP6K3 inhibitor.

46. The method of any one of claims 40 to 44, wherein the subject is IP6K3 reference, and the subject is administered or continued to be administered the type 2 diabetes therapeutic agent in an amount that is the same as or less than a standard dosage amount and the IP6K3 inhibitor.

47. The method of any one of claims 40 to 46, wherein the IP6K3 variant nucleic acid molecule comprises a splice-site variant, a stop-gain variant, a start-loss variant, a stop-loss variant, a frameshift variant, a missense variant, an in-frame indel variant, and / or a variant that encodes a truncated IP6K3 variant polypeptide.

48. The method of any one of claims 40 to 46, wherein the IP6K3 variant nucleic acid molecule comprises the genetic variation listed in Table 1.

49. A method of identifying a subject having an increased risk of developing muscle atrophy or type 2 diabetes, the method comprising:determining or having determined the presence or absence of an Inositol Hexakisphosphate Kinase 3 (IP6K3) variant nucleic acid molecule in a biological sample obtained from the subject;wherein:when the subject is IP6K3 reference, then the subject has an increased risk of developing muscle atrophy or type 2 diabetes; andwhen the subject is heterozygous or homozygous for the IP6K3 variant nucleic acid molecule, then the subject has a decreased risk of developing muscle atrophy or type 2 diabetes.115923230DOCKET NO.: 38120-4404 (12031W001)-92- 50. The method of claim 49, wherein the muscle atrophy is skeletal muscle atrophy.

51. The method of claim 49, wherein the muscle atrophy is cardiac muscle atrophy.

52. The method of claim 49, wherein the subject has: i) a muscular dystrophy, a myotonic dystrophy, or a mitochondrial myopathy; ii) an inflammatory muscle disease; iii) a sarcopenia; iv) a myopathy arising secondary to an environmental influence; v) a myopathy arising secondary to a systemic disease; vi) a neuromuscular condition leading to muscle atrophy; or vii) a weight loss mechanism.

53. The method of claim 52, wherein:the inflammatory muscle disease comprises polymyositis or dermatomyositits; the sarcopenia comprises age-related sarcopenia;the myopathy arising secondary to an environmental influence comprises drug-induced or alcohol-induced;the myopathy arising secondary to a systemic disease comprises thyroid-associated myopathy;the neuromuscular condition leading to muscle atrophy comprises amyotrophic lateral sclerosis or myasthenia gravis; andthe weight loss mechanism comprises bariatric surgery or pharmacologically-induced.

54. The method of any one of claims 49 to 53, wherein the IP6K3 variant nucleic acid molecule is a splice-site variant, a stop-gain variant, a start-loss variant, a stop-loss variant, a frameshift variant, a missense variant, an in-frame indel variant, or a variant that encodes a truncated IP6K3 variant polypeptide.

55. The method of any one of claims 49 to 53, wherein the IP6K3 variant nucleic acid molecule comprises the genetic variation listed in Table 1.

56. A muscle atrophy therapeutic agent for use in the treatment or prevention of muscle atrophy in a subject having an Inositol Hexakisphosphate Kinase 3 (IP6K3) variant nucleic acid molecule.

57. The muscle atrophy therapeutic agent for use of claim 56, wherein the muscle atrophy is skeletal muscle atrophy.

58. The muscle atrophy therapeutic agent for use of claim 56, wherein the muscle atrophy is cardiac muscle atrophy.

59. The muscle atrophy therapeutic agent for use of claim 56, wherein the subject has: i) a muscular dystrophy, a myotonic dystrophy, or a mitochondrial myopathy; ii) an inflammatory115923230DOCKET NO.: 38120-4404 (12031W001)- 93-muscle disease; iii) a sarcopenia; iv) a myopathy arising secondary to an environmental influence; v) a myopathy arising secondary to a systemic disease; vi) a neuromuscular condition leading to muscle atrophy; or vii) a weight loss mechanism.

60. The muscle atrophy therapeutic agent for use of claim 59, wherein:the inflammatory muscle disease comprises polymyositis or dermatomyositits; the sarcopenia comprises age-related sarcopenia;the myopathy arising secondary to an environmental influence comprises drug-induced or alcohol-induced;the myopathy arising secondary to a systemic disease comprises thyroid-associated myopathy;the neuromuscular condition leading to muscle atrophy comprises amyotrophic lateral sclerosis or myasthenia gravis; andthe weight loss mechanism comprises bariatric surgery or pharmacologically-induced.

61. The muscle atrophy therapeutic agent for use of any one of claims 56 to 60, wherein the IP6K3 variant nucleic acid molecule is a splice-site variant, a stop-gain variant, a start-loss variant, a stop-loss variant, a frameshift variant, a missense variant, an in-frame indel variant, or a variant that encodes a truncated IP6K3 variant polypeptide.

62. The muscle atrophy therapeutic agent for use of any one of claims 56 to 60, wherein the IP6K3 variant nucleic acid molecule comprises the genetic variation listed in Table 1.

63. The muscle atrophy therapeutic agent for use of any one of claims 56 to 62, wherein the muscle atrophy therapeutic agent comprises a corticosteroid, testosterone, a selective androgen receptor modulator, a growth hormone, a growth hormone secretagogue, a myostatin inhibitor, an activin type II receptor inhibitor, or a modulator of the activin / inhibin family of ligands and receptors, or any combination thereof.

64. The muscle atrophy therapeutic agent for use of claim 63, wherein:the myostatin inhibitor comprises trevogrumab; andthe activin type II receptor inhibitor comprises bimagrumab.

65. The muscle atrophy therapeutic agent for use of any one of claims 56 to 64, wherein the subject is also treated with a therapeutic agent that induces muscle atrophy.

66. The muscle atrophy therapeutic agent for use of claim 65, wherein the therapeutic agent that induces muscle atrophy comprises a glucagon-like peptide 1 receptor agonist, or a115923230DOCKET NO.: 38120-4404 (12031W001)- 94-combined agonist of glucagon-like peptide 1 receptor and glucose-dependent insulinotropic polypeptide receptor.

67. The muscle atrophy therapeutic agent for use of claim 66, wherein the glucagon-like peptide 1 receptor agonist comprises semaglutide, and the combined agonist of glucagon-like peptide 1 receptor and glucose-dependent insulinotropic polypeptide receptor comprises tirzepatide.

68. A type 2 diabetes therapeutic agent for use in the treatment or prevention of type 2 diabetes in a subject having an Inositol Hexakisphosphate Kinase 3 (IP6K3) variant nucleic acid molecule.

69. The type 2 diabetes therapeutic agent for use of claim 68, wherein the IP6K3 variant nucleic acid molecule is a splice-site variant, a stop-gain variant, a start-loss variant, a stop-loss variant, a frameshift variant, a missense variant, an in-frame indel variant, or a variant that encodes a truncated IP6K3 variant polypeptide.

70. The type 2 diabetes therapeutic agent for use of claim 68 or claim 69, wherein the IP6K3 variant nucleic acid molecule comprises the genetic variation listed in Table 1.

71. The type 2 diabetes therapeutic agent for use of any one of claims 68 to 70, wherein the type 2 diabetes therapeutic agent comprises an alpha-glucosidase inhibitor, a biguanide, a bile acid sequestrant (BAS), a dopamine-2 agonist, a dipeptidyl peptidase-4 (DPP-4) inhibitor, a meglitinide, a sodium-glucose cotransporter-2 (SGLT2) inhibitor, a sulfonylurea, a thiazolidinedione (TZD), a glucagon-like peptide-1 (GLP-1) receptor agonist, an insulin, or a proprotein convertase subtilisin / kexin type 9 (PCSK9) inhibitor, or any combination thereof.

72. The type 2 diabetes therapeutic agent for use of claim 71, wherein:the alpha-glucosidase inhibitor comprises acarbose or miglitol;the biguanide comprises metformin;the BAS comprises colesevelam;the dopamine-2 agonist comprises bromocriptine;the DPP-4 inhibitor comprises alogliptin, linagliptin, saxagliptin, or sitagliptin; the meglitinide comprises nateglinide or repaglinide;the SGLT2 inhibitor comprises canagliflozin, dapagliflozin, or empagliflozin;the sulfonylurea comprises glimepiride, glipizide, or glyburide;the TZD comprises rosiglitazone or pioglitazone;115923230DOCKET NO.: 38120-4404 (12031W001)- 95- the GLP-1 receptor agonist comprises exenatide, liraglutide, dulaglutide, lixisenatide, or semaglutide;the insulin comprises insulin glulisine, insulin lispro, insulin aspart, insulin glargine, insulin detemir, or insulin isophane; andthe PCSK9 inhibitor comprises alirocumab.

73. An Inositol Hexakisphosphate Kinase 3 (IP6K3) inhibitor for use in the treatment or prevention of muscle atrophy in a subject that is IP6K3 reference or is heterozygous for an IP6K3 variant nucleic acid molecule.

74. The IP6K3 inhibitor for use of claim 73, wherein the muscle atrophy is skeletal muscle atrophy.

75. The IP6K3 inhibitor for use of claim 73, wherein the muscle atrophy is cardiac muscle atrophy.

76. The IP6K3 inhibitor for use of claim 73, wherein the subject has: i) a muscular dystrophy, a myotonic dystrophy, or a mitochondrial myopathy; ii) an inflammatory muscle disease; iii) a sarcopenia; iv) a myopathy arising secondary to an environmental influence; v) a myopathy arising secondary to a systemic disease; vi) a neuromuscular condition leading to muscle atrophy; or vii) a weight loss mechanism.

77. The IP6K3 inhibitor for use of claim 76, wherein:the inflammatory muscle disease comprises polymyositis or dermatomyositits; the sarcopenia comprises age-related sarcopenia;the myopathy arising secondary to an environmental influence comprises drug-induced or alcohol-induced;the myopathy arising secondary to a systemic disease comprises thyroid-associated myopathy;the neuromuscular condition leading to muscle atrophy comprises amyotrophic lateral sclerosis or myasthenia gravis; andthe weight loss mechanism comprises bariatric surgery or pharmacologically-induced.

78. The IP6K3 inhibitor for use of any one of claims 73 to 77, wherein the IP6K3 variant nucleic acid molecule is a splice-site variant, a stop-gain variant, a start-loss variant, a stop-loss variant, a frameshift variant, a missense variant, an in-frame indel variant, or a variant that encodes a truncated IP6K3 variant polypeptide.115923230DOCKET NO.: 38120-4404 (12031W001)- 96- 79. The IP6K3 inhibitor for use of any one of claims 73 to 77, wherein the IP6K3 variant nucleic acid molecule comprises the genetic variation listed in Table 1.

80. The IP6K3 inhibitor for use of any one of claims 73 to 79, wherein the IP6K3 inhibitor comprises an inhibitory nucleic acid molecule that hybridizes to an IP6K3 nucleic acid molecule.

81. The IP6K3 inhibitor for use of claim 80, wherein the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule, a small interfering RNA (siRNA), and / or a short hairpin RNA (shRNA).

82. The IP6K3 inhibitor for use of claim 81, wherein the inhibitory nucleic acid molecule comprises an siRNA.

83. The IP6K3 inhibitor for use of claim 81, wherein the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule.

84. An Inositol Hexakisphosphate Kinase 3 (IP6K3) inhibitor for use in the treatment or prevention of type 2 diabetes in a subject that is IP6K3 reference or is heterozygous for an IP6K3 variant nucleic acid molecule.

85. The IP6K3 inhibitor for use of claim 84, wherein the IP6K3 variant nucleic acid molecule is a splice-site variant, a stop-gain variant, a start-loss variant, a stop-loss variant, a frameshift variant, a missense variant, an in-frame indel variant, or a variant that encodes a truncated IP6K3 variant polypeptide.

86. The IP6K3 inhibitor for use of claim 84, wherein the IP6K3 variant nucleic acid molecule comprises the genetic variation listed in Table 1.

87. The IP6K3 inhibitor for use of any one of claims 84 to 86, wherein the IP6K3 inhibitor comprises an inhibitory nucleic acid molecule that hybridizes to an IP6K3 nucleic acid molecule.

88. The IP6K3 inhibitor for use of claim 87, wherein the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule, a small interfering RNA (siRNA), and / or a short hairpin RNA (shRNA).

89. The IP6K3 inhibitor for use of claim 88, wherein the inhibitory nucleic acid molecule comprises an siRNA.

90. The IP6K3 inhibitor for use of claim 88, wherein the inhibitory nucleic acid molecule comprises an antisense nucleic acid molecule.115923230

Images