WO2021202557A1 - Acides nucléiques sphériques (sna) pour la régulation de la frataxine - Google Patents

Acides nucléiques sphériques (sna) pour la régulation de la frataxine Download PDF

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Publication number
WO2021202557A1
WO2021202557A1 PCT/US2021/024922 US2021024922W WO2021202557A1 WO 2021202557 A1 WO2021202557 A1 WO 2021202557A1 US 2021024922 W US2021024922 W US 2021024922W WO 2021202557 A1 WO2021202557 A1 WO 2021202557A1
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synthetic oligonucleotide
nucleic acid
acid sequence
fxn
region
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PCT/US2021/024922
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English (en)
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Grant Corbett
Bart ANDERSON
Pinal PATEL
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Exicure Operating Company
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Publication of WO2021202557A1 publication Critical patent/WO2021202557A1/fr

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    • C12N15/09—Recombinant DNA-technology
    • C12N15/11—DNA or RNA fragments; Modified forms thereof; Non-coding nucleic acids having a biological activity
    • C12N15/113—Non-coding nucleic acids modulating the expression of genes, e.g. antisense oligonucleotides; Antisense DNA or RNA; Triplex- forming oligonucleotides; Catalytic nucleic acids, e.g. ribozymes; Nucleic acids used in co-suppression or gene silencing
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/12—Ketones
    • A61K31/122—Ketones having the oxygen directly attached to a ring, e.g. quinones, vitamin K1, anthralin
    • A61K31/125—Camphor; Nuclear substituted derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7088—Compounds having three or more nucleosides or nucleotides
    • A61K31/712—Nucleic acids or oligonucleotides having modified sugars, i.e. other than ribose or 2'-deoxyribose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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    • C12N2310/00—Structure or type of the nucleic acid
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    • C12N2310/32—Chemical structure of the sugar
    • C12N2310/323—Chemical structure of the sugar modified ring structure
    • C12N2310/3231—Chemical structure of the sugar modified ring structure having an additional ring, e.g. LNA, ENA
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    • C12N2310/33—Chemical structure of the base
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    • C12N2310/341—Gapmers, i.e. of the type ===---===
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/35—Nature of the modification
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    • C12N2310/3515—Lipophilic moiety, e.g. cholesterol
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    • C12N2310/00—Structure or type of the nucleic acid
    • C12N2310/30—Chemical structure
    • C12N2310/35—Nature of the modification
    • C12N2310/352—Nature of the modification linked to the nucleic acid via a carbon atom
    • C12N2310/3525—MOE, methoxyethoxy
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    • C12N2320/00—Applications; Uses
    • C12N2320/10—Applications; Uses in screening processes
    • C12N2320/11—Applications; Uses in screening processes for the determination of target sites, i.e. of active nucleic acids
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    • C12N2330/00—Production
    • C12N2330/30—Production chemically synthesised

Definitions

  • FRDA Friedreich’s ataxia
  • compositions and methods for the treatment of Friedreich's ataxia encompasses the observation that administration of oligonucleotides, incorporated into a spherical nucleic acid (SNA) format, increases transcription of theFXN gene.
  • SNA spherical nucleic acid
  • synthetic oligonucleotides with sequence complementarity to a frataxin (FXN) gene or anFXN gene product, are provided herein.
  • the synthetic oligonucleotide comprises a nucleic acid sequence complementary to a region of anFXN gene or an FXN gene product, wherein the nucleic acid sequence comprises, consists essentially of or consists of the sequence of any one of SEQ ID NO: 1-2031, or a pharmaceutically acceptable salt thereof.
  • the nucleic acid sequence does not comprise or consist of a nucleic acid sequence of SEQ ID NO: 444, 466, 487, 509, 532, 554, 576, 598, 618, 638, 656, 674, 693, 712, 734, 754, 857, or 1350-1398.
  • the nucleic acid sequence does not comprise or consist of a nucleic acid sequence of SEQ ID NO: 598, 693, 1373, 1378, 1379 or 1386.
  • the nucleic acid sequence does not comprise or consist of a nucleic acid sequence of SEQ ID NO: 180, 486, 498, 523, 560, 984, 985, or 986.
  • the nucleic acid sequence does not comprise, consist essentially of or consist of a nucleic acid sequence of SEQ ID NO: 1399, SEQ ID NO: 1400 or SEQ ID NO: 1401. In some embodiments, the nucleic acid sequence does not comprise, consist essentially of or consist of a nucleic acid sequence of SEQ ID NO: 1400-1420, 1426-1456, 1459, 1459, 1461-1496, 1498-1540, 1542-1551, 1553-1579, 1581-1596, 1598-1600, 1602- 1604, 1606, 1608-1640, 1642-1644, 1646-1650, 1652, 1654-1794, 1796-1807, 1809-1811, 1813-1831, 1833-1841, 1843, 1844, 1846-1870, or 1872-1874.
  • the nucleic acid sequence does not comprise, consist essentially of or consist of a nucleic acid sequence of SEQ ID NO: 1402 to SEQ ID NO:
  • the nucleic acid sequence does not comprise, consist essentially of or consist of a nucleic acid sequence of SEQ ID NO: 1404, 1408, 1409, 1411, 1412, or 1416.
  • the region encodes a natural antisense transcript (NAT) or is in a NAT.
  • NAT natural antisense transcript
  • the nucleic acid sequence comprises a modification.
  • the nucleic acid sequence has a gap segment consisting of two to 20 linked nucleosides, a 5’-wing segment consisting of linked nucleosides, and a 3’-wing segment consisting of linked nucleosides, wherein the gap segment is positioned between the 5 ’-wing segment and the 3 ’-wing segment, wherein one or more nucleosides in the 5 ’-wing segment, the 3 ’-wing segment, or both the 5 ’-wing segment and the 3 ’-wing segment comprise the modification.
  • the region is an exon.
  • the region is a 3’ or 5 ’-untranslated region (3’-UTR or 5’-
  • the region is an intron. In some embodiments, the region is the first intron which comprises between 60 and 2,000 GAA trinucleotide repeats.
  • the nucleic acid sequence is 10 to 30 nucleobases in length.
  • the nucleic acid sequence is 20 nucleobases in length.
  • the nucleic acid sequence further comprises a molecular species at one end of the nucleic acid sequence or at both ends of the nucleic acid sequence.
  • the molecular species at both ends of the nucleic acid sequence are the same.
  • the molecular species at both ends of the nucleic acid sequence are different.
  • the molecular species is a lipid or a sterol. In some embodiments, the molecular species is a lipophilic moiety, a folic acid radical, a steroid radical, a carbohydrate radical, a vitamin A radical, a vitamin E radical, or a vitamin K radical.
  • the molecular species is a cholesterol.
  • the molecular species is a cholesteryl ester (N-cholesteryl-3- aminopropyl)-triethyleneglycol-glyceryl-l-0-phosphodiester (CholTEG).
  • the molecular species is directly attached to the nucleic acid sequence.
  • the molecular species is directly attached to the nucleic acid sequence through a covalent bond.
  • the molecular species is directly attached to the nucleic acid sequence through a phosphodiester, phosphorothioate, methylphosphonate or amide linkage.
  • the molecular species is indirectly attached to the nucleic acid sequence through a spacer.
  • the spacer is a non-nucleotidic spacer.
  • the spacer is a dSpacer, oligoethyleneglycol or alkane-diol.
  • the spacer is triethyleneglycol (spacer 9), hexaethylenegylcol (spacer 18) or butanediol.
  • the spacer comprises a hexa-ethyleneglycol.
  • the spacer consists of two hexa-ethyleneglycols.
  • the modification is at least one of a methoxy-ethyl (MOE) modification, a methyl modification, a locked nucleic acid (LNA) modification, and a 7- deaza modification.
  • MOE methoxy-ethyl
  • LNA locked nucleic acid
  • the MOE modification is located at 2’-position, at the 3’ or 5’- position or both at the 2’ and the 3’ or 5 ’-position of the ribose ring in one or more nucleosides of the synthetic oligonucleotide.
  • the methyl modification located at the base of one or more nucleosides of the synthetic oligonucleotide.
  • the nucleic acid comprises a modified backbone.
  • the modified backbone comprises one or more phosphorothioate linkages.
  • more than half of the linkages are phosphorothioate linkages or all linkages are phosphorothioate linkages.
  • the modified backbone comprises a morpholino linkage. In some embodiments, the modification is a 2’ O-methyl modification.
  • the region corresponds to the nucleic acid sequence of SEQ ID NO: 2046, 2059, 2060, or 2061.
  • the region corresponds to the nucleic acid sequence of SEQ ID NO: 2037, 2038, 2039, 2040, or 2041.
  • the region is the nucleic acid sequence of SEQ ID NO: 2051, 2055, 2056, or 2057.
  • the region is the nucleic acid sequence of SEQ ID NO: 2042 or
  • the synthetic oligonucleotide comprises a methyl modification and an LNA modification. In some embodiments, the synthetic oligonucleotide comprises, consist essentially of or consists of lG*lAlGT*A*/iMe- dC/* A*G* A*T*T*T* A*lClAlC/iSp 18//iSp 18//3CholTEG/ (SEQ ID NO: 2030).
  • the synthetic oligonucleotide comprises a methyl modification, an LNA modification, and a 7-deaza modification. In some embodiments, the synthetic oligonucleotide comprises or consists of lG*/7deazaG/*lGT*G*lG/iMe-dC/*/iMe- dC/*lCA*A*lAG*T*lT/iMe-dC/*/iMe-dC/*lA*G*lA/iSp 18//iSp 18//3CholTEG/ (SEQ ID NO: 693).
  • compositions comprising a synthetic oligonucleotide, or pharmaceutically acceptable salt thereof, are provided.
  • the pharmaceutical composition comprises a synthetic oligonucleotide, or the pharmaceutically acceptable salt thereof, as disclosed herein.
  • spherical nucleic acids comprising a core and an oligonucleotide shell
  • the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, or a pharmaceutically acceptable salt thereof.
  • FXN frataxin
  • the core is hollow core or solid core.
  • the hollow core is a liposome core.
  • the solid core comprises a metal
  • the synthetic oligonucleotide is a synthetic oligonucleotide as disclosed herein.
  • the SNA includes 2-1,000 synthetic oligonucleotides.
  • the spherical nucleic acid (SNA) comprises a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide and a second synthetic oligonucleotide targeting a first region, a second region or both a first region and a second region in a frataxin ( FXN) gene and/or an FXN gene product, wherein the first synthetic oligonucleotide and the second synthetic oligonucleotide are not the same.
  • FXN frataxin
  • the first synthetic oligonucleotide is a synthetic oligonucleotide as disclosed herein and the second synthetic oligonucleotide is a synthetic oligonucleotide as disclosed herein.
  • the first region and the second region in the FXN gene or the FXN gene product are the same.
  • the first region and the second region in the FXN gene or the FXN gene product are not the same.
  • the first region encodes a natural antisense transcript (NAT).
  • NAT natural antisense transcript
  • the first region is in a NAT.
  • the second region encodes a NAT.
  • the second region is in a NAT.
  • the first region is an exon.
  • the second region is an exon.
  • the first region is a 3’ or 5 ’-untranslated region (3’ or 5’-UTR).
  • the second region is a 3’ or 5’-UTR.
  • the first region is an intron in the FXN gene and/or the FXN gene product.
  • the second region is an intron in the FXN gene and/or the FXN gene product.
  • the first region encodes a NAT or is in a NAT and the second region is an exon, a 3’ or 5’ UTR or an intron in the FXN gene and/or the FXN gene product.
  • the first region is an exon and the second region encodes a NAT or is in a NAT, is a 3’ or 5’ UTR or is an intron in the FXN gene and/or the FXN gene product.
  • the first region is a 3’ or 5’ UTR and the second region encodes a NAT or is in a NAT, is an exon or is an intron in the FXN gene and/or the FXN gene product. In some embodiments, the first region is an intron in the FXN gene and/or the FXN gene product and the second region encodes a NAT or is in a NAT, is an exon or is a 3’ or 5’- UTR.
  • the core is a hollow core or a solid core.
  • the hollow core is a liposome core.
  • the solid core comprises a metal.
  • the SNA includes 2-1,000 synthetic oligonucleotides.
  • the first synthetic oligonucleotide comprises, consist essentially of or consists of lG*lAlGT*A*/iMe- dC/* A*G* A*T*T*T* A*lClAlC/iSp 18//iSp 18//3CholTEG/ (SEQ ID NO: 2030)
  • the second synthetic oligonucleotide comprises, consist essentially of or consists of lG*/7deazaG/*lGT*G*lG/iMe-dC/*/iMe-dC/*lCA*A*lAG*T*lT/iMe-dC/*/iMe- dC/*lA*G*lA/iSp 18//iSp 18//3CholTEG/ (SEQ ID NO: 693).
  • compositions comprising SNAs are provided.
  • the pharmaceutical composition comprises an SNA as disclosed herein.
  • the method comprises contacting a cell comprising a frataxin (FXN) gene and/or an FXN gene product with a synthetic oligonucleotide as disclosed herein, a pharmaceutical composition as disclosed herein, or a spherical nucleic acid (SNA) as disclosed herein to increase FXN mRNA levels in the cell relative to a reference level.
  • FXN frataxin
  • SNA spherical nucleic acid
  • the increased FXN mRNA levels result in increased FXN protein levels in the cell relative to a reference level.
  • the cell is a fibroblast cell.
  • the cell is at least one of a liver cell, a kidney cell, a heart cell, a skeletal muscle cell and a nerve cell.
  • the cell is a cell of a dorsal root ganglion or a cell of a dentate nucleus of a cerebellum.
  • methods of treating a disease or disorder in a subject comprise administering to a subject in order to treat the disease or disorder in the subject an effective amount of a synthetic oligonucleotide as disclosed herein, a pharmaceutical composition as disclosed herein, or a spherical nucleic acid (SNA) as disclosed herein.
  • the disease or disorder is a mitochondrial disease or disorder.
  • the disease or disorder is Friedreich’s ataxia (FRDA).
  • the subject is homozygous for an FXN gene and/or an FXN gene product.
  • the synthetic oligonucleotide, the pharmaceutical composition, or the SNA increases FXN mRNA levels expressed from one allele of the FXN gene in the subject relative to a reference level.
  • the synthetic oligonucleotide, the pharmaceutical composition, or the SNA increases FXN mRNA levels expressed from both alleles of the FXN gene in the subject relative to a reference level.
  • the FXN mRNA levels are increased in one or more cells in the subject.
  • the cells are at least one of a liver cell, a kidney cell, a heart cell, a skeletal muscle cell and a nerve cell.
  • the cell is a cell of a dorsal root ganglion or a cell of a dentate nucleus of a cerebellum.
  • the synthetic oligonucleotide, the pharmaceutical composition, or the SNA ameliorate or eliminate one or more symptoms or conditions associated with the disease or disorder in the subject.
  • the symptom or condition is at least one of muscle weakness, loss of coordination, loss of balance, vision impairment, hearing impairment, slurred speech, scoliosis, muscle spasticity, pes cavus deformity of one or both feet, diabetes, and a heart disorder or condition.
  • the symptom or condition is at least one of a pathology of the spinal cord, a pathology of the peripheral nerves, degeneration of dorsal root ganglion, pathology of the spinocerebellar tracts, pathology of the lateral corticospinal tracts, a pathology of the posterior columns and a loss of large myelinated fibers.
  • the heart disorder or condition is at least one of atrial fibrillation, tachycardia, hypertrophic cardiomyopathy, cardiomegaly, dilated cardiomyopathy, myocardial fibrosis, heart failure and heart block.
  • the onset of the disease or disorder occurs when the subject is at least about five years old.
  • the onset of the disease or disorder occurs when the subject is between about five years old and about 40 years old. In some embodiments, the onset of the disease or disorder occurs when the subject is between about five years old and about 25 years old.
  • the onset of the disease or disorder occurs when the subject is between about five years old and about 15 years old.
  • the synthetic oligonucleotide, the pharmaceutical composition, or the SNA ameliorate or eliminate loss of a myelin sheath in a nerve cell.
  • the method of treating a disease or disorder in a subject further comprises the administration of a second therapeutic agent.
  • the method of identifying synthetic oligonucleotides that increase FXN mRNA levels or FXN protein levels comprises (a) contacting a population of cells with a plurality of synthetic oligonucleotides targeting one or more regions of an FXN gene and/or an FXN gene product; (b) culturing the population of cells to produce a population of cultured cells; (c) measuring FXN mRNA levels or FXN protein levels in the population of cultured cells to obtain a value; and (d) comparing the value in (c) with a reference level, wherein a value that is greater than the reference level is indicative of a synthetic oligonucleotide that increases FXN mRNA levels or FXN protein levels.
  • methods of identifying synthetic oligonucleotides that increase FXN mRNA levels or FXN protein levels comprises (a) contacting a population of cells with a plurality of spherical nucleic acids (SNAs), each SNA comprising a core and an oligonucleotide shell comprising a synthetic oligonucleotide targeting one or more regions of an FXN gene and/or an FXN gene product; (b) culturing the population of cells to produce a population of cultured cells; (c) measuring FXN mRNA levels or FXN protein levels in the population of cultured cells to obtain a value; and (d) comparing the value in (c) with a reference level, wherein a value that is greater than the reference level is indicative of a synthetic oligonucleotide that increases FXN mRNA levels or FXN protein levels.
  • SNAs spherical nucleic acids
  • libraries comprising pluralities of synthetic oligonucleotides.
  • a library comprises a plurality of synthetic oligonucleotides, each synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin ( FXN) gene, and/or an FXN gene product, or a pharmaceutically acceptable salt thereof.
  • the region is at least one of a region that encodes a natural antisense transcript (NAT), is in a NAT, is an exon, is a 3’ or 5 ’-untranslated region (3’ or 5’- UTR) and is an intron.
  • NAT natural antisense transcript
  • libraries comprising pluralities of spherical nucleic acids (SNAs) are provided.
  • a library comprises a plurality of SNAs, each SNA comprising a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product.
  • FXN frataxin
  • the region is at least one of a region that encodes a natural antisense transcript (NAT), is in a NAT, is an exon, is a 3’ or 5 ’-untranslated region (3’ or 5’- UTR) and is an intron.
  • NAT natural antisense transcript
  • FRDA Friedreich’s ataxia
  • FRDA is an ultra-orphan disease with a prevalence of approximately 6,000-8,000 patients in the US and 20,000 globally.
  • FRDA incidence rate is about 1 out of 40,000-50,000 in the US and 0.7 to 5 per 100,000 in Caucasians globally.
  • FRDA carrier frequency is about 1 in 120 in the European Union.
  • Approximately 3,400 worldwide patients are identified on the Friedreich’s Ataxia Research Alliance’s registry, including over 1,700 in the US.
  • FRDA impacts children and young adults, leading to wheelchair use and severely shortened life expectancy.
  • many of the symptoms and accompanying complications can be treated to help individuals maintain optimal functioning as long as possible.
  • Heart and orthopedic problems such as foot deformities and scoliosis, can be corrected with braces or surgery, while physical therapy may prolong use of the arms and legs.
  • FRDA has an autosomal recessive pattern of inheritance, occurring when the FXN gene located on chromosome 9, which encodes for FXN protein, contains amplified intronic GAA repeats in the first intron of the FXN gene. Frataxin is found in cells throughout the body, with the highest levels in the heart, spinal cord, liver, pancreas, and muscles used for voluntary movement (skeletal muscles).
  • the FXN gene in affected subjects contains expanded GAA triplet repeats in the first intron; in a few FRDA pedigrees, point mutations have been detected.
  • the expanded GAA repeat in the FXN gene of affected subjects forms an intramolecular triple-helix with chromosomal DNA and nascent pre-mRNA, which impairs transcription of the FXN gene and reduces levels of FXN protein in the mitochondria.
  • the mutation does not result in the production of abnormal frataxin proteins. Instead, the mutation causes gene silencing or decreases gene transcription through induction of a heterochromatin structure in a manner similar to position- effect variegation. Deficiency of frataxin in cells leads to mitochondrial iron overload and poor cellular iron regulation, increased sensitivity to oxidative stress, impaired mitochondrial ATP production, and cell death.
  • One healthy copy of the FXN gene, or 50% of normal frataxin protein levels, can prevent the disease phenotype.
  • restoring FXN protein levels to at least 50% of normal levels results in a beneficial phenotype.
  • the number of GAA repeats in the FXN gene is fewer than 12 (referred to as short normal).
  • the GAA segment is repeated 12 to 33 times (referred to as long normal).
  • the GAA segment is abnormally repeated starting for instance from 66 to more than 1,000 times.
  • the length of the GAA trinucleotide repeat appears to be related to the age at which the symptoms of FRDA appear. People with fewer than 300 GAA repeats in the FXN gene tend to have a later appearance of symptoms (after age 25) than those with more GAA repeats.
  • GAA repeat expansion leads to reduced FXN protein levels.
  • therapeutic agents and methods that increase FXN protein levels such as the compositions and methods disclosed herein, would correct the disease-causing defect and are a promising approach to therapy.
  • FXN appears to function as an iron binding mitochondrial matrix protein responsible for forming iron-sulfur clusters. It is a globular protein consisting of two a helices and seven b strands and it is highly conserved, occurring in all eukaryotes and some prokaryotes. FXN assists iron-sulfur cluster synthesis in the electron transport chain to ultimately generate adenosine triphosphate (ATP), the energy currency necessary to carry out metabolic functions in cells. Also, FXN regulates iron transfer in the mitochondria to provide a proper amount of reactive oxygen species (ROS) to maintain normal processes.
  • ROS reactive oxygen species
  • the primary sites of pathology are the spinal cord and peripheral nerves. Sclerosis and degeneration of dorsal root ganglia, spinocerebellar tracts, lateral corticospinal tracts, and posterior columns is also observed. The motor neurons of the spinal cord are spared. In peripheral nerves there is a loss of large myelinated fibers.
  • the lesion of the dentate nucleus consists of progressive and selective atrophy of large glutamatergic neurons and grumose degeneration of corticonuclear synaptic terminals that contain gamma-aminobutyric acid (GABA). Small GABA-ergic neurons and their projection fibers in the dentato-olivary tract survive. Atrophy of Betz cells and corticospinal tracts constitute a second lesion.
  • the ataxia of FRDA results from the degeneration of nerve tissue in the spinal cord, in particular sensory neurons essential (through connections with the cerebellum) for directing muscle movement of the arms and legs.
  • the spinal cord becomes thinner and nerve cells lose some of their myelin sheath (the insulating covering on some nerve cells that helps conduct nerve impulses). Symptoms typically begin sometime between the ages of 5 to 15 years, but in Late Onset FRDA may occur in the 20s or 30s.
  • Symptoms include any combination, but not necessarily all, of the following: muscle weakness in the arms and legs, loss of coordination, vision impairment, hearing impairment, slurred speech, curvature of the spine (scoliosis), high plantar arches (pes cavus deformity of the foot), diabetes (about 20% of people with FRDA develop carbohydrate intolerance and 10% develop diabetes mellitus), and heart disorders (e.g., atrial fibrillation, and resultant tachycardia (fast heart rate) and hypertrophic cardiomyopathy).
  • muscle weakness in the arms and legs loss of coordination, vision impairment, hearing impairment, slurred speech, curvature of the spine (scoliosis), high plantar arches (pes cavus deformity of the foot), diabetes (about 20% of people with FRDA develop carbohydrate intolerance and 10% develop diabetes mellitus), and heart disorders (e.g., atrial fibrillation, and resultant tachycardia (fast heart rate) and hypertrophic cardiomyopathy
  • Typical age of onset of FRDA is commonly before 25 years with progressive staggering or stumbling gait and frequent falling. Lower extremities are more severely involved. The symptoms are slow and progressive. Long-term observation shows that many patients reach a plateau in symptoms in the patient's early adulthood. On average, after 10-15 years with the disease, patients are usually wheelchair bound and require assistance with all activities of daily living.
  • Cerebellar signs may include nystagmus, fast saccadic eye movements, truncal ataxia, dysarthria, dysmetria. Pyramidal signs may include extensor plantar responses, and distal weakness. Additional signs may include the loss of vibratory and proprioceptive sensation in the dorsal column, lower motor neuron lesions, and absent deep tendon reflexes.
  • Cardiac involvement occurs in 91% of patients, including cardiomegaly (up to dilated cardiomyopathy), symmetrical hypertrophy, heart murmurs, and conduction defects. Median age of death is 35 years, while females have better prognosis with a 20-year survival of 100% as compared to 63% in men.
  • a person suffering from FRDA may require some surgical interventions, such as interventions for the spine and heart. Often, titanium screws and rods are inserted in the spine to help prevent or slow the progression of scoliosis. As ataxia progresses, assistive devices such as a cane, walker, or wheelchair are used for mobility assistance and independence. Other assistive technology, such as a standing frame, can help reduce the secondary complications of prolonged use of a wheelchair. The goal of surgery is to keep the patient ambulatory as long as possible.
  • ACE angiotensin-converting enzyme
  • an individual suffering from FRDA benefits from a conservative treatment approach for the management of symptoms (e.g., exercise program through physical therapy and/or occupational therapy) tailored to maximize function and independence.
  • symptoms e.g., exercise program through physical therapy and/or occupational therapy
  • physical therapists can use visual cueing during gait training to help facilitate a more efficient gait pattern.
  • the prescription of an assistive device along with gait training can also prolong independent ambulation.
  • low intensity strengthening exercises are incorporated to maintain functional use of the upper and lower extremities. Fatigability should be monitored closely. Stabilization exercises of the trunk and low back can help with postural control and the management of scoliosis.
  • Balance and coordination training using visual feedback can also be incorporated into activities of daily living. Exercises can reflect functional tasks such as cooking, transfers and self-care. Along with gait training, balance and coordination training can be developed to help minimize the risk of falls. Stretching exercises can be prescribed to help relieve tight musculature due to scoliosis and pes cavus deformities.
  • oligonucleotides e.g., synthetic oligonucleotides
  • SNAs spherical nucleic acids
  • compositions for increasing the expression of an FXN gene.
  • oligonucleotides e.g., synthetic oligonucleotides
  • SNAs spherical nucleic acids
  • compositions increase FXN gene and/or FXN protein expression to levels that promote either partially or completely one or more beneficial phenotype(s) for the treatment, amelioration and/or elimination of one or more characteristics, conditions, and/or symptoms associated with FRDA, as disclosed herein.
  • oligonucleotides e.g., synthetic oligonucleotides
  • SNAs se.g., SNAs
  • compositions target regions in an FXN gene and/or an FXN gene product which are transcribed into FXN mRNA (e.g., at least one of exon 1, exon 1/exon 2, exon 2, exon 2/exon 3, exon 3, exon 3/exon 4, exon 4, exon 4/exon 5, and exon 5).
  • oligonucleotides e.g., synthetic oligonucleotides
  • SNAs e.g., SNAs
  • compositions target one or more regions in an FXN gene which are not transcribed into FXN mRNA (e.g., at least one of intron 1, intron 2, intron 3, intron 4, 5 ’-untranslated region (UTR) and 3’-UTR).
  • regions in an FXN gene e.g., at least one of intron 1, intron 2, intron 3, intron 4, 5 ’-untranslated region (UTR) and 3’-UTR.
  • one oligonucleotide e.g., synthetic oligonucleotide
  • a SNA comprising oligonucleotides (e.g., synthetic oligonucleotides) with one nucleic acid sequence
  • compositions thereof increase FXN mRNA expression and/or increase FXN protein levels through targeting simultaneously two regions in an FXN gene and/or an FXN gene product.
  • one oligonucleotide e.g., synthetic oligonucleotide
  • an SNA comprising oligonucleotides (e.g., synthetic oligonucleotides) with one nucleic acid sequence, or compositions thereof, targets both exon 1 and exon 2, exon 2 and exon 3, exon 3 and exon 4, exon 4 and exon 5, or exon 1 and a 5 ’-UTR.
  • an “oligonucleotide” refers to a nucleic acid sequence with nucleotides (i.e., molecules comprising a sugar (e.g., ribose or deoxyribose) linked to a phosphate group and to an exchangeable organic base, such as pyrimidine (e.g., cytosine (C), thymine (T) or uracil (U)) or a purine (e.g., adenine (A) or guanine (G))), which are between eight to 100 nucleobases in length.
  • nucleotides i.e., molecules comprising a sugar (e.g., ribose or deoxyribose) linked to a phosphate group and to an exchangeable organic base, such as pyrimidine (e.g., cytosine (C), thymine (T) or uracil (U)) or a purine (e.g., adenine
  • the oligonucleotide is a synthetic oligonucleotide.
  • a “synthetic oligonucleotide” refers to a non-naturally occurring oligonucleotide.
  • a synthetic oligonucleotide in some embodiments, refers to a synthetic DNA or synthetic RNA.
  • a synthetic oligonucleotide is produced through an in vitro transcription reaction (e.g., artificial (non-natural) chemical synthesis, solid phase nucleic acid synthesis or through another method known by one of ordinary skill in the art).
  • a synthetic oligonucleotide includes a modification at one or both ends of the nucleic acid sequence in the synthetic oligonucleotide.
  • the synthetic oligonucleotide is produced by nucleic acid synthesis (e.g., in vitro), chemical nucleic acid synthesis, and/or solid phase nucleic acid synthesis, or produced through other methods well known in the art.
  • one or more bases in the oligonucleotide (e.g., synthetic oligonucleotide) or nucleic acid include a modification.
  • an oligonucleotide (e.g., a synthetic oligonucleotide) disclosed herein is 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30,
  • nucleic acid sequence of the synthetic oligonucleotide is 10-30, 10-35, 10-40, 10-45, 10-50, 10-60, 10-70, 10-80, 10-90, 10-100 or more than 100 nucleobases in length.
  • an oligonucleotide e.g., a synthetic oligonucleotide disclosed herein is 18 to 25 nucleobases in length.
  • an oligonucleotide e.g., a synthetic oligonucleotide disclosed herein is 15 to 23 nucleobases in length. In some embodiments, the oligonucleotide (e.g., synthetic oligonucleotide) is 16 nucleobases in length. In some embodiments, the oligonucleotide (e.g., synthetic oligonucleotide) is 17 nucleobases in length. In some embodiments, the oligonucleotide (e.g., synthetic oligonucleotide) is 18 nucleobases in length.
  • the oligonucleotide e.g., synthetic oligonucleotide
  • the oligonucleotide (e.g., synthetic oligonucleotide) is 20 nucleobases in length. In some embodiments, the oligonucleotide (e.g., synthetic oligonucleotide) is 23 nucleobases in length. In some embodiments, the synthetic oligonucleotide comprises, consist essentially of or consists of a nucleic acid sequence complementary to at least one of a frataxin ( FXN) gene, a region of an FXN gene, an FXN gene product, or a region of an FXN gene product.
  • FXN frataxin
  • a nucleic acid sequence of an oligonucleotide is at least or about 45%, at least or about 50%, at least or about 55%, at least or about 60%, at least or about 65%, at least or about 70%, at least or about 75%, at least or about 80%, at least or about 85%, at least or about 90%, at least or about 95%, at least or about 96%, at least or about 97%, at least or about 98%, at least or about 99%, or about 100%, or any range or combination thereof, identical to the nucleic acid sequence of an oligonucleotide (e.g., synthetic oligonucleotide) disclosed herein (e.g., SEQ ID NO: 1-2031).
  • an oligonucleotide e.g., a synthetic oligonucleotide
  • an effect e.g., promote either partially or completely one or more beneficial phenotype(s) for the treatment, amelioration and/or elimination of one or more characteristics, conditions, and/or symptoms associated with FRDA, as disclosed herein).
  • the oligonucleotide (e.g., synthetic oligonucleotide) is single-stranded. In some embodiments, the oligonucleotide (e.g., synthetic oligonucleotide) is hybridized to a second oligonucleotide (e.g., synthetic oligonucleotide) and forms a double- stranded oligonucleotide. In some embodiments, the oligonucleotide (e.g., synthetic oligonucleotide) is not hybridized to a second oligonucleotide and does not form a double-stranded oligonucleotide.
  • an oligonucleotide (e.g., a synthetic oligonucleotide) disclosed herein is a chimeric oligonucleotide.
  • Chimeric oligonucleotides may be formed as composite structures of two or more oligonucleotides, modified oligonucleotides, and/or oligonucleotide mimetics. Such compounds have also been referred to in the art as hybrids or mixed backbone or chimeric or gapmers.
  • a gapmer is an oligonucleotide that has at least three discrete portions, two of which are similar (e.g., include one or more backbone modifications or include one or more nucleoside modifications), and surround a region that is distinct (e.g., does not include backbone modifications or does not include nucleoside modifications).
  • the oligonucleotide (e.g., synthetic oligonucleotide) has a gap segment. In some embodiments, the oligonucleotide does not have a gap segment. In some embodiments, the oligonucleotide comprises, consist essentially of or consists of a 5’-wing segment, a 3 ’-wing segment, and a gap segment. As disclosed herein, a “gap” or “gap segment” corresponds to two or more linked nucleosides in an oligonucleotide (e.g., a synthetic oligonucleotide), which are positioned between a 5 ’-wing segment and a 3 ’-wing segment.
  • a “gap” or “gap segment” corresponds to two or more linked nucleosides in an oligonucleotide (e.g., a synthetic oligonucleotide), which are positioned between a 5 ’-wing segment and a
  • a gap segment refers to one or more linked nucleosides located at the center or near the center of an oligonucleotide, such as a synthetic oligonucleotide.
  • the gap segment consists of two to three, two to four, two to five, two to six, two to seven, two to eight, two to nine, two to 10, two to 20, two to 30, two to 40, two to 50, three to four, three to five, three to six, three to seven, three to eight, three to nine, three to 10, three to 20, three to 30, three to 40, three to 50, four to five, four to six, four to seven, four to eight, four to nine, four to 10, four to 20, four to 30, four to 40, four to 50, five to six, five to seven, five to eight, five to nine, five to 10, five to 20, five to 30, five to 40, five to 50, six to seven, six to eight, six to nine, six to 10, six to 20, six to 30, six to 40, six to 50, seven to eight, seven, seven to 10, seven to 20,
  • the gap segment consists of 8, 9, or 10, linked nucleosides.
  • a “5 ’-wing segment” corresponds to two or more linked nucleosides positioned at the 5 ’-end of an oligonucleotide (e.g., a synthetic oligonucleotide) and corresponding to nucleosides positioned before the first nucleoside at the 5 ’-end of a gap segment.
  • a “3 ’-wing segment” corresponds to two or more linked nucleosides positioned after the last nucleic acid at the 3’ end of the gap segment and including the last nucleic acid at the 3’ end of the oligonucleotide.
  • at least one nucleoside of the 5 ’-wing segment and/or at least one nucleoside of the 3 ’-wing segment comprises a modification.
  • an oligonucleotide (e.g., synthetic oligonucleotide) comprises one or more type of modified sugar and/or unmodified sugar moiety arranged along the oligonucleotide or region thereof in a defined pattern or sugar motif.
  • sugar motifs include but are not limited to any of the sugar modifications discussed herein.
  • an oligonucleotide (e.g., synthetic oligonucleotide) disclosed herein comprises, consist essentially of or consists of a gapmer or a region having a gapmer motif, which is defined by two external regions or “wings” and a central or internal region or
  • gap The three regions of a gapmer motif (the 5’-wing, the gap, and the 3’-wing) form a contiguous sequence of nucleosides wherein at least some of the sugar moieties and/or the intemucleoside linkages of the nucleosides of each of the wings differ from at least some of the sugar moieties of the nucleosides of the gap.
  • the sugar moieties of the nucleosides of each wing that are closest to the gap differ from the sugar moieties of the neighboring gap nucleosides, thus defining the boundary between the wings and the gap (i.e., the wing/gap junction).
  • the sugar moieties within the gap are the same as one another.
  • the gap includes one or more nucleoside having a sugar moiety that differs from the sugar moiety of one or more other nucleosides of the gap.
  • the sugar motifs of the two wings are the same as one another (symmetric gapmer).
  • the sugar motif of the 5’-wing differs from the sugar motif of the 3’-wing (asymmetric gapmer).
  • the wings of a gapmer comprise 1-5 nucleosides.
  • each nucleoside of each wing of a gapmer comprises a modified sugar moiety.
  • at least one nucleoside of each wing of a gapmer comprises a modified sugar moiety.
  • at least two nucleosides of each wing of a gapmer comprise a modified sugar moiety.
  • at least three nucleosides of each wing of a gapmer comprise a modified sugar moiety.
  • at least four nucleosides of each wing of a gapmer comprise a modified sugar moiety.
  • the gap of a gapmer comprises 7-12 nucleosides.
  • each nucleoside of the gap of a gapmer comprises a 2’-P-D-deoxyribosyl sugar moiety.
  • at least one nucleoside of the gap of a gapmer comprises a modified sugar moiety.
  • the gapmer is a deoxy gapmer.
  • the nucleosides on the gap side of each wing/gap junction comprise 2’-deoxyribosyl sugar moieties and the nucleosides on the wing sides of each wing/gap junction comprise modified sugar moieties.
  • each nucleoside of the gap comprises a 2’-P-D- deoxyribosyl sugar moiety.
  • each nucleoside of each wing of a gapmer comprises a modified sugar moiety.
  • modified oligonucleotides comprise, consist essentially of or consist of a region having a fully modified sugar motif.
  • each nucleoside of the fully modified region of the modified oligonucleotide comprises a modified sugar moiety.
  • each nucleoside of the entire modified oligonucleotide comprises a modified sugar moiety.
  • modified oligonucleotides comprise, consist essentially of or consist of a region having a fully modified sugar motif, wherein each nucleoside within the fully modified region comprises the same modified sugar moiety, referred to herein as a uniformly modified sugar motif.
  • a fully modified oligonucleotide is a uniformly modified oligonucleotide.
  • each nucleoside of a uniformly modified comprises the same 2’ -modification.
  • the modification is a 2’ O-methyl modification.
  • the nucleosides in the synthetic oligonucleotide are modified with one or more other modifications disclosed herein.
  • the internucleoside linkages within the gap segment and the linkages connecting the gap segment to the 3 ’-wing segment and/or the 5’-wing segment are all phosphorothioate linkages (*).
  • the intemucleoside linkages connecting the rest of the nucleosides of both the 5’ and 3 ’-wing segments are phosphodiester linkages.
  • the intemucleoside linkages connecting the rest of the nucleosides of both the 5’ and 3 ’-wing segments are phosphorothioate linkages (*). In some embodiments, all intemucleoside linkages connecting the nucleosides of the 5 ’-wing segment, the gap segment, and the 3 ’-wing segment are phosphorothioate linkages (*).
  • nucleic acid refers to multiple nucleotides (i.e., molecules comprising a sugar (e.g., ribose or deoxyribose) linked to a phosphate group and to an exchangeable organic base, which is either a substituted pyrimidine (e.g., cytosine (C), thymine (T) or uracil (U)) or a substituted purine (e.g., adenine (A) or guanine (G))).
  • a substituted pyrimidine e.g., cytosine (C), thymine (T) or uracil (U)
  • purine e.g., adenine (A) or guanine (G)
  • nucleic acid refers to polyribonucleotides as well as polydeoxyribonucleotides.
  • nucleic acid shall also include polynucleosides (i.e., a polynucleotide minus the phosphate) and any other organic base containing polymer.
  • Non limiting examples of nucleic acids include chromosomes, genomic loci, genes or gene segments that encode polynucleotides or polypeptides, coding sequences, non-coding sequences (e.g., intron, 5’-UTR, or 3’-UTR) of a gene, pre-mRNA, mRNA, etc.
  • the nucleic acid and/or oligonucleotide includes a substitution and/or modification.
  • the substitution and/or modification is in one or more bases and/or sugars.
  • a nucleic acid and/or oligonucleotide e.g., a synthetic oligonucleotide
  • a substituted or modified nucleic acid and/or oligonucleotide includes a 2'-0-alkylated ribose group.
  • a modified nucleic acid and/or oligonucleotide includes sugars such as hexose, 2’-F hexose, 2’-amino ribose, constrained ethyl (cEt), locked nucleic acid (LNA), arabinose or 2'- fluoroarabinose instead of ribose.
  • a nucleic acid and/or oligonucleotide e.g., a synthetic oligonucleotide
  • oligonucleotide is heterogeneous in backbone composition thereby containing any possible combination of polymer units linked together such as peptide-nucleic acids (which have an amino acid backbone with nucleic acid bases).
  • a nucleic acid and/or oligonucleotide is DNA, RNA, PNA, cEt, LNA, ENA or hybrids including any chemical or natural modification thereof. Chemical and natural modifications are well known in the art.
  • Non-limiting examples of modifications include modifications designed to increase binding to a target strand (i.e., increase the melting temperature of a hybridized pair of nucleic acid molecules, such as an oligonucleotide and a target nucleic acid), to assist in identification of the oligonucleotide or an oligonucleotide-target complex, to increase cell penetration, to stabilize against nucleases and other enzymes that degrade or interfere with the structure or activity of the oligonucleotides, to provide a mode of disruption (a terminating event) once sequence-specifically bound to a target, and to improve the pharmacokinetic properties of the oligonucleotide.
  • modifications designed to increase binding to a target strand i.e., increase the melting temperature of a hybridized pair of nucleic acid molecules, such as an oligonucleotide and a target nucleic acid
  • modifications designed to increase binding to a target strand i.e., increase the melting temperature of a hybridized pair
  • Modifications include, but are not limited to, for example, (a) end modifications, e.g., 5' end modifications (phosphorylation, dephosphorylation, conjugation, inverted linkages, etc.) and 3' end modifications (conjugation, DNA nucleotides, inverted linkages, etc.); (b) base modifications, e.g., replacement with modified bases, stabilizing bases, destabilizing bases, bases that base pair with an expanded repertoire of partners, or conjugated bases; (c) sugar modifications (e.g., at the 2' position or 4' position) or replacement of the sugar; as well as (d) internucleoside linkage modifications, including modification or replacement of the phosphodiester linkages.
  • An oligonucleotide e.g., a synthetic oligonucleotide disclosed herein
  • the oligonucleotide modification is in one or more bases and/or sugars.
  • an oligonucleotide e.g., a synthetic oligonucleotide
  • an oligonucleotide includes nucleic acids having backbone sugars that are covalently attached to low molecular weight organic groups other than a hydroxyl group or hydrogen at the 2' position and other than a phosphate group or hydroxyl group at the 5' position.
  • a substituted or modified oligonucleotide includes a 2'-
  • a modified oligonucleotide includes sugars such as hexose, 2’-F hexose, 2’-amino ribose, constrained ethyl (cEt), locked nucleic acid (LNA), bridged nucleic acid (BNA), arabinose or 2'-fluoroarabinose instead of ribose.
  • sugars such as hexose, 2’-F hexose, 2’-amino ribose, constrained ethyl (cEt), locked nucleic acid (LNA), bridged nucleic acid (BNA), arabinose or 2'-fluoroarabinose instead of ribose.
  • an oligonucleotide e.g., a synthetic oligonucleotide
  • backbone composition thereby containing any possible combination of polymer units linked together such as peptide-nucleic acids (which have an amino acid backbone with nucleic acid bases).
  • an oligonucleotide (e.g., synthetic oligonucleotide) disclosed herein includes at least one LNA modification or modified nucleoside.
  • An LNA modification or modified nucleoside is a modified RNA nucleoside in which the ribose moiety is modified with an additional linkage connecting the 2’ oxygen and the 4’ carbon.
  • LNA modifications enhance base stacking and backbone organization, and significantly increase the hybridization properties of oligonucleotides.
  • the melting temperature of oligonucleotides comprising an LNA modification(s) can be increased relative to an unmodified oligonucleotide having the same nucleic acid sequence.
  • the LNA modification is, comprises, consist essentially of or consists of (2'-0, 4'-C methylene)-adenosine. In some embodiments, the LNA modification is, comprises, consist essentially of or consists of 5-methyl-(2'-0, 4'-C methylene)-cytidine. In some embodiments, the LNA modification is, comprises, consist essentially of or consists of (2'-0, 4'-C methylene)-cytidine. In some embodiments, the LNA modification is, comprises, consist essentially of or consists of (2'-0, 4'-C methylene)-guanosine.
  • the LNA modification is, comprises, consist essentially of or consists of 5- methyl-(2'-0, 4'-C methylene) -uridine.
  • the oligonucleotide includes two or more LNA modifications, each of which, in some embodiments, comprises, consists of, or consists essentially of an LNA modification disclosed herein.
  • an oligonucleotide (e.g., synthetic oligonucleotide) disclosed herein comprises an internucleoside linkage modification.
  • an intemucleoside linkage modification involves replacement of a “natural” or “native” intemucleoside linkage of a nucleic acid molecule (e.g., an oligonucleotide) with a “non- natural” or “non-native” substituent, or involves chemical modification of a native intemucleoside linkage.
  • an intemucleoside linkage modification may comprise replacement of an oxygen of the phosphate group in the 3’,5’-phosphodiester bond with a substituent atom or a substituent group, or may comprise replacement of the 3 ’-5’- phosphodiester bond or both the 3’,5’-phosphodiester bond and the sugar moiety to facilitate linkage of one nucleobase of a nucleic acid molecule to the next.
  • Non-limiting examples of modified intemucleoside linkages include phosphorothioate, phosphorodithioate, N3’ phosphoramidate, boranophosphate, 2’,5’-phosphodiester, phosphonoacetate (PACE), methylphosphonate, morpholino, amide, and peptide nucleic acid linkages.
  • an intemucleoside linkage modification comprised in an oligonucleotide (e.g., a synthetic oligonucleotide) disclosed herein is a phosphorothioate intemucleoside linkage modification.
  • a nucleic acid and/or oligonucleotide comprises a modified backbone.
  • the modified backbone comprises modified intemucleoside linkages.
  • the modified backbone comprises one or more phosphorothioate intemucleoside linkages.
  • all of the intemucleoside linkages of the oligonucleotide are phosphorothioate intemucleoside linkages.
  • modified intemucleoside linkages e.g., linkages within a modified backbone
  • intemucleoside linkages that are formed by short chain alkyl or cycloalkyl intemucleoside linkages, mixed heteroatoms and alkyl or cycloalkyl intemucleoside linkages, or one or more short chain heteroatomic or heterocyclic intemucleoside linkages.
  • morpholino linkages formed in part from the sugar portion of a nucleoside
  • siloxane backbones sulfide, sulfoxide and sulfone backbones
  • formacetyl and thioformacetyl backbones methylene formacetyl and thioformacetyl backbones
  • alkene containing backbones sulfamate backbones
  • sulfonate and sulfonamide backbones amide backbones; and others having mixed N, O, S and Cth component parts.
  • Non-limiting examples of modified intemucleoside linkages include phosphorothioates, chiral phosphorothioates, phosphorodithioates, phosphotriesters, aminoalkylphosphotriesters, methyl and other alkyl phosphonates including 3'-alkylene phosphonates and chiral phosphonates, phosphinates, phosphoramidates including 3'-amino phosphoramidate and aminoalkylphosphoramidates, thionophosphoramidates, thionoalkylphosphonates, thionoalkylphosphotriesters, and boranophosphates having normal 3'-5' linkages, 2'-5' linked analogs of these, and those having inverted polarity wherein the adjacent pairs of nucleoside units are linked 3'-5' to 5'-3' or 2'-5' to 5'-2'.
  • Various salts, mixed salts and free acid forms are also included.
  • nucleosides of modified oligonucleotides may be linked together using any internucleotide/internucleoside linkage.
  • the two main classes of intemucleotide linking groups are defined by the presence or absence of a phosphorus atom.
  • Representative phosphorus -containing intemucleotide linkages include but are not limited to phosphates, which contain a phosphodiester bond (also referred to as unmodified or naturally occurring linkages), phosphotriesters, methylphosphonates, phosphoramidates, phosphorothioates, and phosphorodithioates.
  • Modified intemucleotide linkages compared to naturally occurring phosphate linkages, can be used to alter, typically increase, nuclease resistance of the oligonucleotide.
  • intemucleotide linkages having a chiral atom can be prepared as a racemic mixture, or as separate enantiomers. Methods of preparation of phosphorous-containing and non-phosphorous-containing intemucleotide linkages are well-known to those skilled in the art.
  • Representative intemucleotide linkages having a chiral center include but are not limited to alkylphosphonates and phosphorothioates.
  • Modified oligonucleotides comprising intemucleotide linkages having a chiral center can be prepared as populations of modified oligonucleotides comprising stereorandom intemucleotide linkages, or as populations of modified oligonucleotides comprising phosphorothioate linkages in particular stereochemical configurations.
  • populations of modified oligonucleotides comprise phosphorothioate intemucleotide linkages wherein all of the phosphorothioate intemucleotide linkages are stereorandom.
  • modified oligonucleotides can be generated using synthetic methods that result in random selection of the stereochemical configuration of each phosphorothioate linkage. Nonetheless, as is well understood by those of skill in the art, each individual phosphorothioate of each individual oligonucleotide molecule has a defined stereochemical configuration.
  • populations of modified oligonucleotides are enriched for modified oligonucleotides comprising one or more particular phosphorothioate intemucleotide linkages in a particular, independently selected stereochemical configuration.
  • the particular configuration of the particular phosphorothioate linkage is present in at least 65% of the molecules in the population.
  • the particular configuration of the particular phosphorothioate linkage is present in at least 70% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 80% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 90% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 99% of the molecules in the population.
  • Such chirally enriched populations of modified oligonucleotides can be generated using synthetic methods known in the art, e.g., methods described in Oka et al, JACS 125, 8307 (2003), Wan et al. Nuc. Acid. Res. 42, 13456 (2014), and WO 2017/015555, the contents of each of which are herein incorporated by reference in their entireties.
  • a population of modified oligonucleotides is enriched for modified oligonucleotides having at least one indicated phosphorothioate in the (Sp) configuration.
  • a population of modified oligonucleotides is enriched for modified oligonucleotides having at least one phosphorothioate in the (Rp) configuration.
  • modified oligonucleotides comprising (Rp) and/or (Sp) phosphorothioates comprise one or more of the following formulas, respectively, wherein “B” indicates a nucleobase:
  • chiral internucleotide linkages of modified oligonucleotides described herein can be stereorandom or in a particular stereochemical configuration.
  • Further neutral intemucleotide linkages include nonionic linkages comprising siloxane (dialkylsiloxane), carboxylate ester, carboxamide, sulfide, sulfonate ester and amides.
  • Further neutral intemucleotide linkages include nonionic linkages comprising mixed N, O, S and CH 2 component parts.
  • oligonucleotides comprise modified and/or unmodified intemucleotide linkages arranged along the oligonucleotide or region thereof in a defined pattern or motif.
  • each intemucleotide linking group is a phosphodiester intemucleotide linkage (PO).
  • PO phosphodiester intemucleotide linkage
  • each intemucleotide linking group of a modified oligonucleotide is a phosphorothioate intemucleotide linkage (PS).
  • each intemucleotide linkage of a modified oligonucleotide is independently selected from a phosphorothioate intemucleotide linkage and phosphodiester intemucleotide linkage.
  • the sugar motif of a modified oligonucleotide is a gapmer and the intemucleotide linkages within the gap are all modified.
  • some or all of the intemucleotide linkages in the wings are unmodified phosphodiester intemucleotide linkages.
  • the terminal intemucleotide linkages are modified.
  • the sugar motif of a modified oligonucleotide is a gapmer
  • the intemucleotide linkage motif comprises at least one phosphodiester intemucleotide linkage in at least one wing, wherein the at least one phosphodiester linkage is not a terminal intemucleotide linkage, and the remaining intemucleotide linkages are phosphorothioate intemucleotide linkages.
  • Substituted sugar moieties include, but are not limited to one of the following at the 2' position: H (deoxyribose); OH (ribose); F; 0-, S-, or N-alkyl; 0-, S-, or N-alkenyl; 0-, S- or N- alkynyl; or O-alkyl- O-alkyl, wherein the alkyl, alkenyl and alkynyl can be substituted or unsubstituted Cl to CIO alkyl or C2 to CIO alkenyl and alkynyl.
  • a synthetic oligonucleotide includes, for example, at least one nucleotide or nucleoside modified at the 2' position of the sugar.
  • the nucleoside modification is a 2'-0-alkyl, 2'-0-alkyl-0-alkyl or 2'-fluoro-modified nucleotide or an end cap.
  • nucleoside modifications include 2'-fluoro, 2'-amino and 2' O-methyl modifications on the ribose of pyrimidines, abasic residues or an inverted base at the 3' end of the oligonucleotide.
  • a synthetic oligonucleotide includes a single modified nucleoside. In some embodiments, a synthetic oligonucleotide includes at least two modified nucleosides, at least 3, at least 4, at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 15, at least 20 or more nucleosides, up to the entire length of the oligonucleotide (e.g., synthetic oligonucleotide). In some embodiments, each nucleoside of the synthetic oligonucleotide is a modified nucleoside.
  • Nucleosides or nucleobases include the natural purine bases adenine (A) and guanine
  • Modified nucleosides include other synthetic and natural nucleobases such as inosine, xanthine, hypoxanthine, nubularine, isoguanisine, tubercidine, 2-(halo)adenine, 2-(alkyl)adenine, 2- (propyl)adenine,
  • aminocarbonylethylenyl-4 (thio)pseudouracil, 1 aminocarbonylethylenyl)-2,4-
  • an oligonucleotide (e.g., synthetic oligonucleotide) disclosed herein comprises a base modification.
  • a base modification involves replacement of a “natural” or “native” nucleobase of an oligonucleotide with a “non-natural” or “non-native” substituent, or involves chemical modification of a native nucleobase.
  • base modifications include methylation, hydroxymethylation, alkylation, methoxyethyl modifications, and substitutions with heterocyclic, stabilizing, destabilizing, promiscuous, or conjugated base moieties.
  • “Natural” nucleobases include the purine bases adenine and guanine, and the pyrimidine bases thymine, cytosine and uracil. “Non-native” or “non-natural” substituents include 5-methyl-cytosine (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 (-CoC-CH3) uracil and cytosine and other alkynyl derivatives of pyrimidine bases,
  • Base modifications also include replacement of the native purine or pyrimidine base with other heterocycles, such as 7-deaza- adenine, 7-deazaguanosine, 2-aminopyridine and 2-pyridone, 5-substituted pyrimidines, 6-azapyrimidines and N-2, N-6 and 0-6 substituted purines, including 2-aminopropyladenine, 5-propynyluracil and 5-propynylcytosine.
  • Base modifications can improve various oligonucleotide properties, including stability (e.g., nuclease resistance, thermostability, chemical stability, biological stability, stability in various salt conditions, etc.), target hybridization, biocompatibility (e.g., reduced hepatotoxicity, nephrotoxicity, immune stimulation, etc.), mismatch discrimination, water solubility, etc.
  • stability e.g., nuclease resistance, thermostability, chemical stability, biological stability, stability in various salt conditions, etc.
  • target hybridization e.g., target hybridization, biocompatibility (e.g., reduced hepatotoxicity, nephrotoxicity, immune stimulation, etc.), mismatch discrimination, water solubility, etc.
  • modified oligonucleotides comprise one or more nucleoside comprising an unmodified nucleobase. In certain embodiments, modified oligonucleotides comprise one or more nucleoside comprising a modified nucleobase. In certain embodiments, modified oligonucleotides comprise one or more nucleoside that does not comprise a nucleobase, referred to as an abasic nucleoside.
  • modified nucleobases are selected from: 5-substituted pyrimidines, 6-azapyrimidines, alkyl or alkynyl substituted pyrimidines, alkyl substituted purines, and N-2, N-6 and 0-6 substituted purines.
  • modified nucleobases are selected from: 2-aminopropyladenine, 5 -hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-N-methylguanine, 6-N-methyladenine, 2-prop yladenine, 2- thiouracil, 2-thiothymine and 2-thiocytosine, 5-propynyl (-CoC-CH3) uracil, 5- propynylcytosine, 6-azouracil, 6-azocytosine, 6-azothymine, 5-ribosyluracil (pseudouracil),
  • nucleobases include tricyclic pyrimidines, such as l,3-diazaphenoxazine-2-one, l,3-diazaphenothiazine-2-one and 9-(2- aminoethoxy)-l,3-diazaphenoxazine-2-one (G-clamp).
  • Modified nucleobases may also include those in which the purine or pyrimidine base is replaced with other heterocycles, for example 7-deaza- adenine, 7-deazaguanosine, 2-aminopyridine and 2-pyridone.
  • Further nucleobases include those disclosed in Merigan et ah, U.S. 3,687,808, those disclosed in Englisch et ah, Angewandte Chemie, International Edition, 1991, 30: 613, the contents of each of which are herein incorporated by reference in their entireties.
  • a modified nucleoside is a 2’ -O-methyl adenosine (mA), a 2’- O-methyl cytidine (mC), a 2'-0-methyl guanosine (mG), a 2'-0-methyl uridine (mU), a deoxy adenosine (A, dA), a deoxycytidine (C, dC), a deoxyguanosine (G, dG), a deoxythymidine (T, dT), a 2'-0-methoxyethoxy adenosine (moeA, 2’-MOE-A), a 2'-0- methoxyethoxy-5-methyl cytidine (5-Me-MOE-C), a 2'-0-Methoxyethoxy Guanosine (moeG, 2’-MOE-G), a 2'-0-Methoxyethoxy-5-Methyl Uridine (mA), a
  • oligonucleotides comprise modified and/or unmodified nucleobases arranged along the oligonucleotide or region thereof in a defined pattern or motif.
  • each nucleobase is modified.
  • none of the nucleobases are modified.
  • each purine or each pyrimidine is modified.
  • each adenine is modified.
  • each guanine is modified.
  • some or all of the guanine nucleobases in a modified oligonucleotide are 7-deaza guanine.
  • all of the guanine nucleobases are 7-deaza guanines and all of the other nucleobases of the modified oligonucleotide are unmodified nucleobases.
  • each thymine is modified.
  • each uracil is modified.
  • each cytosine is modified.
  • some or all of the cytosine nucleobases in a modified oligonucleotide are 5-methyl cytosines.
  • all of the cytosine nucleobases are 5-methyl cytosines and all of the other nucleobases of the modified oligonucleotide are unmodified nucleobases.
  • modified oligonucleotides comprise a block of modified nucleobases.
  • the block is at the 3 ’-end of the oligonucleotide.
  • the block is within 3 nucleosides of the 3 ’-end of the oligonucleotide. In certain embodiments, the block is at the 5’-end of the oligonucleotide. In certain embodiments the block is within 3 nucleosides of the 5 ’-end of the oligonucleotide.
  • the oligonucleotide (e.g., synthetic oligonucleotide) comprises, consist essentially of or consists of a sequence of SEQ ID NO: 444, 466, 487, 509, 532, 554, 576, 598, 618, 638, 656, 674, 693, 712, 734, 754, 857, or 1350-1398 (Table 5).
  • the oligonucleotide (e.g., synthetic oligonucleotide) does not comprise, consist essentially of or consist of a sequence of SEQ ID NO: 444, 466, 487, 509, 532, 554, 576, 598, 618, 638, 656, 674, 693, 712, 734, 754, 857, or 1350-1398 (Table 5).
  • the oligonucleotide (e.g., synthetic oligonucleotide) comprises, consist essentially of or consists of a sequence of SEQ ID NO: 598, 693, 1373, 1378, 1379 or 1386 (Table 6). In some embodiments, the oligonucleotide (e.g., synthetic oligonucleotide) does not comprise, consist essentially of or consist of a sequence of SEQ ID NO: 598, 693, 1373, 1378, 1379 or 1386(Table 6).
  • the oligonucleotide (e.g., synthetic oligonucleotide) comprises, consist essentially of or consists of a sequence of SEQ ID NO: 1399 to SEQ ID NO: 1401 (Table 7). In some embodiments, the oligonucleotide (e.g., synthetic oligonucleotide) does not comprise, consist essentially of or consist of a sequence of SEQ ID NO: 1399 to SEQ ID NO: 1401 (Table 7).
  • the oligonucleotide (e.g., synthetic oligonucleotide) has a nucleic acid sequence comprising, consisting essentially of,, consist essentially of or consisting of a sequence listed in any one of Tables 1, 2, 3, 4, 8, 9, or 10.
  • the oligonucleotide (e.g., synthetic oligonucleotide) comprises, consists essentially of, or consists of a compound shown in any one of Tables 1, 2, 3, 4, 8, 9, or 10.
  • the oligonucleotide (e.g., synthetic oligonucleotide) has a modification pattern of a compound shown in any one of Tables 1, 2, 3, 4, 8, 9, or 10.
  • a “plurality of synthetic oligonucleotides” refers to two or more synthetic oligonucleotides.
  • the plurality of synthetic oligonucleotides comprises two, three, four, five, six, seven, eight, nine, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, 150, 200, 250, 300, 350, 400, 450, 500, 600, 700, 800, 900, 1000, 1500, 2000, 2500, or more than 2,500 synthetic oligonucleotides, or any range or combination thereof.
  • the plurality of synthetic oligonucleotides comprises at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, at least 20, at least 25, at least 30, at least 35, at least 40, at least 45, at least 50, at least 60, at least 70, at least 80, at least 90, at least 100, at least 150, at least 200, at least 250, at least 300, at least 350, at least 400, at least 450, at least 500, at least 600, at least 700, at least 800, at least 900, at least 1000, at least 1500, at least 2000, or at least 2500, or any range or combination thereof.
  • the phrase “the first synthetic oligonucleotide and second synthetic oligonucleotide are not the same” or equivalent phrases are used to refer to two synthetic oligonucleotides which differ in at least one of nucleic acid sequence, structure, and modification (e.g., base and/or backbone modifications).
  • two or more synthetic oligonucleotides which are not the same have different nucleic acid sequences (e.g., the two or more synthetic oligonucleotides have one or more nucleotides which are not the same when the two or more synthetic oligonucleotides are aligned in the same direction, such as 5’ to 3 ’-direction).
  • two or more oligonucleotides which are not the same have sequences which are completely different.
  • the first synthetic oligonucleotide and second synthetic oligonucleotide that are not the same have one or more nucleotide substitutions at one or more corresponding positions within the oligonucleotide relative to one another.
  • two or more oligonucleotides which are not the same have one or more different intemucleoside linkages at one or more positions within the oligonucleotide.
  • an oligonucleotide e.g., a synthetic oligonucleotide
  • a double-stranded nucleic acid or oligonucleotide e.g., synthetic oligonucleotide
  • a double-stranded nucleic acid or oligonucleotide can be “complementary” to another nucleic acid or oligonucleotide if hybridization can occur between one of the strands of the first nucleic acid or oligonucleotide and the second nucleic acid or oligonucleotide.
  • Complementarity e.g., the degree to which one polynucleotide is complementary with another
  • Complementarity is quantifiable in terms of the proportion of bases in opposing strands that are expected to form hydrogen bonds with each other, according to generally accepted base pairing (e.g., Watson-Crick base pairing) rules.
  • An oligonucleotide e.g., a synthetic oligonucleotide
  • two nucleic acids are considered complementary to one another when their sequences are able to form base pairing interactions (e.g., Watson-Crick base pairing interactions) between at least or about 45%, at least or about 50%, at least or about 55%, at least or about 60%, at least or about 65%, at least or about 70%, at least or about 75%, at least or about 80%, at least or about 85%, at least or about 90%, at least or about 95%, at least or about 96%, at least or about 97%, at least or about 98%, at least or about 99%, or about 100% of their nucleotides, or any range or combination thereof.
  • base pairing interactions e.g., Watson-Crick base pairing interactions
  • two nucleic acid sequences are considered complementary to or sufficiently complementary to one another when their nucleic acid sequences form base pairing interactions (e.g., Watson-Crick base pairing interactions) between at least or about 45% of their nucleotides.
  • base pairing interactions e.g., Watson-Crick base pairing interactions
  • two nucleic acid sequences are considered complementary to or sufficiently complementary to one another when their nucleic acid sequences form base pairing interactions between at least or about 50% of their nucleotides.
  • two nucleic acid sequences are considered complementary to or sufficiently complementary to one another when their nucleic acid sequences form base pairing interactions between at least or about 55% of their nucleotides.
  • two nucleic acid sequences are considered complementary to or sufficiently complementary to one another when their nucleic acid sequences form base pairing interactions between at least or about 60% of their nucleotides.
  • two nucleic acid sequences are considered complementary to or sufficiently complementary to one another when their nucleic acid sequences form base pairing interactions between at least or about 65% of their nucleotides.
  • two nucleic acid sequences are considered complementary to or sufficiently complementary to one another when their nucleic acid sequences form base pairing interactions between at least or about 70% of their nucleotides.
  • two nucleic acid sequences are considered complementary to or sufficiently complementary to one another when their nucleic acid sequences form base pairing interactions between at least or about 75% of their nucleotides.
  • two nucleic acid sequences are considered complementary to or sufficiently complementary to one another when their nucleic acid sequences form base pairing interactions between at least or about 80% of their nucleotides. In some embodiments, two nucleic acid sequences are considered complementary to or sufficiently complementary to one another when their nucleic acid sequences form base pairing interactions between at least or about 85% of their nucleotides.
  • two nucleic acid sequences are considered complementary to or sufficiently complementary to one another when their nucleic acid sequences form base pairing interactions between at least or about 90% of their nucleotides.
  • two nucleic acid sequences are considered complementary to or sufficiently complementary to one another when their nucleic acid sequences form base pairing interactions between at least or about 92.5% of their nucleotides.
  • two nucleic acid sequences are considered complementary to or sufficiently complementary to one another when their nucleic acid sequences form base pairing interactions between at least or about 95% of their nucleotides.
  • two nucleic acid sequences are considered complementary to or sufficiently complementary to one another when their nucleic acid sequences form base pairing interactions between at least or about 96% of their nucleotides.
  • two nucleic acid sequences are considered complementary to or sufficiently complementary to one another when their nucleic acid sequences form base pairing interactions between at least or about 97% of their nucleotides.
  • two nucleic acid sequences are considered complementary to or sufficiently complementary to one another when their nucleic acid sequences form base pairing interactions between at least or about 98% of their nucleotides.
  • two nucleic acid sequences are considered complementary to or sufficiently complementary to one another when their nucleic acid sequences form base pairing interactions between at least or about 99% of their nucleotides.
  • two nucleic acid sequences are considered complementary to or sufficiently complementary to one another when their nucleic acid sequences form base pairing interactions between at least or about 100% of their nucleotides.
  • two nucleic acid sequences that are each 20 nucleosides in length are considered 80% complementary if 16 of their respective 20 nucleosides are able to form base-pairing interactions.
  • Two nucleic acid sequences that are of different lengths may also be complementary.
  • a nucleic acid sequence that is 20 nucleosides in length may be complementary to a nucleic acid sequence that is longer if their sequences are able to form base pairing interactions (e.g., Watson-Crick base pairing interactions) between a sufficient number of nucleotides of the 20 nucleoside length nucleic acid sequence and a sufficient number of nucleotides of the longer nucleic acid sequence.
  • a nucleic acid sequence that is 20 nucleosides in length is considered 100% complementary to a longer nucleic acid sequence if all 20 of its nucleosides are able to form base-pairing interactions with 20 sequential nucleosides of the longer nucleic acid sequence.
  • a nucleic acid sequence that is 20 nucleosides in length is considered 80% complementary to a longer nucleic acid sequence if 16 of its 20 nucleosides are able to form base-pairing interactions with 16 nucleosides of the longer nucleic acid sequence in a complementary sequence alignment.
  • oligonucleotides are complementary to the target nucleic acid over the entire length of the oligonucleotide. In certain embodiments, oligonucleotides are 99%, 95%, 90%, 85%, or 80% complementary to the target nucleic acid. In certain embodiments, oligonucleotides are at least 80% complementary to the target nucleic acid over the entire length of the oligonucleotide and comprise a region that is 100% or fully complementary to a target nucleic acid. In certain embodiments, the region of full complementarity is from 6 to 20, 10 to 18, or 18 to 20 nucleobases in length.
  • oligonucleotides comprise one or more mismatched nucleobases relative to the target nucleic acid.
  • activity of the oligonucleotide with respect to its target nucleic acid is reduced by such mismatch, but activity with respect to a non-target nucleic acid is reduced by a greater amount.
  • selectivity of the oligonucleotide is improved by the presence of a mismatch.
  • the mismatch is specifically positioned within an oligonucleotide having a gapmer motif. In certain embodiments, the mismatch is at position 1, 2, 3, 4, 5, 6, 7, or 8 from the 5’-end of the gap region.
  • the mismatch is at position 9, 8, 7, 6, 5, 4, 3, 2, 1 from the 3’-end of the gap region. In certain embodiments, the mismatch is at position 1, 2, 3, or 4 from the 5 ’-end of the wing region. In certain embodiments, the mismatch is at position 4, 3, 2, or 1 from the 3 ’-end of the wing region.
  • a synthetic oligonucleotide comprises a molecular species.
  • the molecular species anchors the synthetic oligonucleotide to the core (e.g., liposome core).
  • a molecular species may be attached at various positions of a synthetic oligonucleotide (e.g., the 3 ’-end or 5 ’-end of a nucleic acid sequence of a synthetic oligonucleotide disclosed herein), where it may serve the purpose to enhance the stability of the synthetic oligonucleotide against 3’- or 5 ’-exonucleases.
  • a molecular species is attached to or associated with an internal nucleotide or a nucleotide on a branch of a synthetic oligonucleotide. In some embodiments, a molecular species is attached to a 2 ’-position of a nucleoside of a synthetic oligonucleotide. In some embodiments, a molecular species is linked to the heterocyclic base of a nucleoside of a synthetic oligonucleotide.
  • the molecular species is a hydrophobic group.
  • the hydrophobic group is a cholesterol or a cholesteryl ester.
  • the molecular species is a lipid, a sterol, lipid moieties such as a cholesterol moiety, cholic acid, a thioether (e.g., hexyl- S-tritylthiol), a thiocholesterol, an aliphatic chain (e.g., dodecandiol or undecyl residues), a phospholipid (e.g., di-hexadecyl-rac-glycerol or triethylammonium l,2-di-0-hexadecyl-rac-glycero-3-H-phosphonate), a polyamine or a polyethylene glycol chain, or adamantane acetic acid, a palmityl moiety, an octadecyl
  • oligonucleotides are anchored to the surface of a core through a molecular species, including but not limited to: tocopherols, sphingolipids such as sphingosine, sphingosine phosphate, methylated sphingosines and sphinganines, ceramides, ceramide phosphates, 1-0 acyl ceramides, dihydroceramides, 2-hydroxy ceramides, sphingomyelin, glycosylated sphingolipids, sulfatides, gangliosides, phosphosphingolipids, and phytosphingosines of various lengths and saturation states and their derivatives, phospholipids such as phosphatidylcholines, lysophosphatidylcholines, phosphatidic acids, lysophosphatidic acids, cyclic LPA, phosphatidylethanolamines
  • phospholipids such as phosphatidylcholines, lys
  • a molecular species is connected to a synthetic oligonucleotide through a linker.
  • the linker is a spacer (e.g., a non-nucleotidic spacer).
  • a spacer are abasic residues (dSpacer), oligoethyleneglycol, such as triethyleneglycol (spacer 9 or iSp9) or hexaethylenegylcol (spacer 18 or iSp 18), or alkane- diol (e.g., butanediol).
  • the synthetic oligonucleotide is attached to the spacer through a covalent bond (e.g., phosphodiester, phosphorodithioate or phosphorothioate bond).
  • the spacer does not comprise, consist essentially of or consist of an oligonucleotide spacer.
  • the spacer in some embodiments appears just once in the molecule or in some embodiments is incorporated several times (e.g., via phosphodiester, phosphorothioate, methylphosphonate, or amide linkages).
  • the spacer comprises a tetraethyleneglycol.
  • FXN refers to a frataxin (FXN) gene refers to an allele, alleles, a genomic locus or genomic loci corresponding to an FXN gene in an organism (e.g., NCBI Reference Number NG_008845.2 in humans).
  • an FXN gene comprises, consist essentially of or consists of a nucleic acid sequence of SEQ ID NO: 2036, a frataxin genomic locus, or an FXN polynucleotide.
  • an “ FXN gene product” refers to an FXN pri-mRNA, an FXN pre-mRNA, an FXN mRNA, an FXN coding sequence (e.g., a cDNA, synthetic RNA coding sequence, or synthetic DNA coding sequence), an FXN polypeptide, an FXN preprotein, or an FXN protein.
  • an FXN gene refers to an allele, alleles, a genomic locus or genomic loci corresponding to an FXN gene in an organism (e.g., NCBI Reference Number NG_008845.2 in humans).
  • an FXN gene comprises a mutation.
  • the mutation in the FXN gene affects at least one of methylation, histone structure, transcription rate, translation rate, stability, interaction with nucleic acids, interaction with proteins, or in another way or ways that are functionally relevant.
  • a “region of a frataxin (FXN) gene” refers to a segment of an allele, a genomic locus, or a polynucleotide corresponding to an FXN gene (e.g., an allele, genomic locus, or polynucleotide corresponding to NCBI reference number NG_008845.2, nucleic acid sequence of SEQ ID NO: 2036, or a mutant form thereof).
  • the region corresponds to at least one of a 5 ’-untranslated region (5’-UTR), a 3 ’-untranslated region (3’-UTR), an enhancer region, a silencer region, a regulatory region, an intron, an exon, a promoter region, a coding region, a termination region, a region encoding a natural antisense transcript (NAT), a region of a NAT or any combination thereof.
  • a “region of an FXN gene product” or equivalent phrases refer to a region in an FXN pre-mRNA, an FXN mRNA, an FXN coding sequence (e.g., a cDNA, synthetic RNA coding sequence, or synthetic DNA coding sequence), an FXN polypeptide, an FXN preprotein, or an FXN protein.
  • a “first region and second region in an FXN gene and/or an FXN gene product are not the same” or equivalent phrases refer to two different regions in an FXN gene and/or an FXN gene product.
  • the first region encodes or is in a NAT and the second region is an exon, a 3’ or 5’ UTR or an intron in an FXN gene and/or an FXN gene product.
  • the first region is an exon and the second region encodes a NAT or is in a NAT, is a 3’ or 5’ UTR or is an intron in an FXN gene and/or an FXN gene product.
  • the first region is a 3’ or 5’ UTR and the second region encodes a NAT or is in a NAT, is an exon or is an intron in an FXN gene and/or an FXN gene product.
  • the first region is an intron in an FXN gene and/or an FXN gene product and the second region encodes a NAT or is in a NAT, is an exon or is a 3’ or 5 ’-UTR.
  • the first region is a 3 ’-UTR and the second region is a 5 ’-UTR.
  • a “natural antisense transcript (NAT)” refers to a non-protein- coding, fully processed RNA that is transcribed from the complementary strand of a protein coding sense transcript. After splicing, the sense and the corresponding antisense transcripts share complementary exons and potentially form RNA-RNA hybrids.
  • NATs interfere with translation initiation and both inhibitory and stimulatory effects may be observed.
  • Inhibitory NATs block or melt hairpin structures in mRNAs that are required for ribosome binding.
  • Activating NATs counteract inhibitory structures and enable efficient translation initiation or elongation.
  • a NAT may act in a cis manner, affecting predominantly the expression of the corresponding sense transcript.
  • a NAT may act in a trans manner, affecting primarily the expression of a sense transcript transcribed from another genomic locus or other genomic loci from the genomic locus from which the NAT was transcribed.
  • the NAT is a NAT of frataxin (FXN).
  • a NAT is the FXN antisense transcript FAST-1.
  • NAT reduces the expression of a sense transcript.
  • NAT reduces the expression of an FXN transcript.
  • NAT reduces the translation of the FXN transcript.
  • the NAT reduces the expression of FXN protein.
  • SNAs Spherical nucleic acids
  • a “spherical nucleic acid” refers to a three-dimensional arrangement of nucleic acids or oligonucleotides, such as synthetic oligonucleotides, comprising an oligonucleotide shell, with radially arranged oligonucleotides on the exterior of a core.
  • the core is a hollow core produced by a three-dimensional arrangement of molecules which form the outer boundary of the core.
  • the molecules may be in the form of a lipid layer (e.g., lipid monolayer or lipid bilayer), which has a hollow center.
  • the molecules may be in the form of lipids, such as amphipathic lipids (e.g., sterols), which are linked to or associated with, either directly or indirectly, an end of the oligonucleotide (e.g., synthetic oligonucleotide).
  • sterols such as cholesterol
  • linked to an end of an oligonucleotide may associate with the outer surface of a core (e.g., a hollow core), such that the oligonucleotides radiate outward from the core.
  • the core may also be a solid or semi-solid core.
  • the core is a liposome core.
  • the core comprises, consist essentially of or consists of a solid core.
  • the core comprises, consist essentially of or consists of a metal core (e.g., any metal).
  • metals include gold, silver, platinum, aluminum, palladium, copper, cobalt, indium, nickel and mixtures thereof.
  • the core comprises gold.
  • the core is a gold core.
  • the core can be a lattice structure including degradable gold.
  • the core may comprise semiconductor and/or magnetic materials.
  • a SNA comprises an oligonucleotide shell comprising a synthetic oligonucleotide and a core.
  • a synthetic oligonucleotide is associated with the core (e.g., liposome core) through a covalent or non-covalent interaction.
  • a synthetic oligonucleotide is associated with the exterior surface of the core. In some embodiments, the synthetic oligonucleotides are associated with the core
  • the synthetic oligonucleotide is associated with a molecular species (e.g., a hydrophobic group), either directly or indirectly.
  • the synthetic oligonucleotide is indirectly associated with a hydrophobic group through a spacer.
  • the hydrophobic group is associated with the core.
  • the core is a liposome core.
  • the liposome core comprises a lipid bilayer.
  • the synthetic oligonucleotide is covalently attached to one or more lipids of the lipid layer.
  • an SNA comprises an oligonucleotide (e.g., synthetic oligonucleotide) having a nucleic acid sequence comprising, consist essentially of or consisting of a sequence listed in any one of Tables 1, 2, 3, 4, 8, 9, or 10.
  • an SNA comprises a synthetic oligonucleotide comprising, consist essentially of or consisting of a sequence listed in any one of Tables 1, 2, 3, 4, 8, 9, or 10.
  • an SNA comprises an oligonucleotide (e.g., synthetic oligonucleotide) having a modification pattern of a sequence listed in any one of Tables 1, 2, 3, 4, 8, 9, or 10.
  • an SNA disclosed herein comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence and a second synthetic oligonucleotide comprising a second nucleic acid sequence.
  • a nucleic acid sequence e.g., a nucleic acid sequence of a synthetic oligonucleotide
  • a molecular species e.g., a nucleic acid sequence of a synthetic oligonucleotide
  • a first molecular species is indirectly attached to a first nucleic acid sequence (e.g., a first nucleic acid sequence of a first synthetic oligonucleotide) and a second molecular species is indirectly attached to a second nucleic acid sequence (e.g., a second nucleic acid sequence of a second synthetic oligonucleotide).
  • the first molecular species is indirectly attached to the 3 ’-end of the first nucleic acid sequence and the second molecular species is indirectly attached to the 5 ’-end of the second nucleic acid sequence.
  • the first molecular species is indirectly attached to the 5 ’-end of the first nucleic acid sequence and the second molecular species is indirectly attached to the 3 ’-end of the second nucleic acid sequence. In some embodiments, the first molecular species is indirectly attached to the 5 ’-end of the first synthetic oligonucleotide and the second molecular species is indirectly attached to the 5 ’-end of the second synthetic oligonucleotide. In some embodiments, the first molecular species is indirectly attached to the 3 ’-end of the first synthetic oligonucleotide and the second molecular species is indirectly attached to the 3 ’-end of the second synthetic oligonucleotide. In some embodiments, the first molecular species and the second molecular species are the same. In some embodiments, the first molecular species and the second molecular species are different.
  • an SNA disclosed herein comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence and a second synthetic oligonucleotide comprising a second nucleic acid sequence.
  • a nucleic acid sequence e.g ., a nucleic acid sequence of a synthetic oligonucleotide
  • a molecular species e.g ., a nucleic acid sequence of a synthetic oligonucleotide
  • a first molecular species is directly attached to a first nucleic acid sequence (e.g., a first nucleic acid sequence of a first synthetic oligonucleotide) and a second molecular species is directly attached to a second nucleic acid sequence (e.g., a second nucleic acid sequence of a second synthetic oligonucleotide).
  • the first molecular species is directly attached to the 3 ’-end of the first nucleic acid sequence and the second molecular species is directly attached to the 5 ’-end of the second nucleic acid sequence.
  • the first molecular species is directly attached to the 5 ’-end of the first nucleic acid sequence and the second molecular species is directly attached to the 3 ’-end of the second nucleic acid sequence. In some embodiments, the first molecular species is directly attached to the 5 ’-end of the first synthetic oligonucleotide and the second molecular species is directly attached to the 5 ’-end of the second synthetic oligonucleotide. In some embodiments, the first molecular species is directly attached to the 3 ’-end of the first synthetic oligonucleotide and the second molecular species is directly attached to the 3 ’-end of the second synthetic oligonucleotide.
  • the first population of synthetic oligonucleotides comprises one or more first synthetic oligonucleotides disclosed herein having a nucleotide sequence complementary to a first region of an FXN gene or an FXN gene product.
  • the second population of synthetic oligonucleotides comprises one or more second synthetic oligonucleotides disclosed herein having a nucleotide sequence complementary to a second region of an FXN gene or an FXN gene product.
  • the first region is a 5 ’-untranslated region (5’-UTR), a 3 ’-untranslated region
  • the second region is a 5’- untranslated region (5’-UTR), a 3 ’-untranslated region (3’-UTR), an enhancer region, a silencer region, a regulatory region, an intron, an exon, a promoter region, a coding region, a termination region, a region encoding a natural antisense transcript (NAT), or a region of a NAT.
  • the second region is a 5’- untranslated region (5’-UTR), a 3 ’-untranslated region (3’-UTR), an enhancer region, a silencer region, a regulatory region, an intron, an exon, a promoter region, a coding region, a termination region, a region encoding a natural antisense transcript (NAT), or a region of a
  • the first region is in exon to of an FXN gene and/or an FXN gene product. In some embodiments, the first region is in exon 1, exon 2, exon 3, exon 4, exon 5, or at an exon-exon junction. In some embodiments, the first region is in exon 2 of an FXN gene and/or an FXN gene product. In some embodiments, the first synthetic oligonucleotide is capable of specifically binding to exon 2 of an FXN gene and/or an FXN gene product. In some embodiments, the second region is in a region encoding a NAT or is in a NAT.
  • the second synthetic oligonucleotide is capable of specifically binding to a region encoding a NAT or to a NAT. In some embodiments, the second synthetic oligonucleotide is complementary to a region encoding a NAT or to a NAT.
  • the core is a solid core or a hollow core.
  • a solid core is a spherical- shaped material with or without a hollow center.
  • a “spherical shape” refers to a general shape and does not imply or is not limited to a perfect sphere or round shape. In some embodiments, a spherical shape includes imperfections.
  • Solid cores can be constructed from a wide variety of materials known to those skilled in the art including but not limited to: noble metals (gold, silver), transition metals (iron, cobalt) and metal oxides (silica).
  • a solid core may be inert, paramagnetic, or superparamagnetic.
  • the solid cores can be constructed from either pure compositions of described materials, or in combinations of mixtures of any number of materials, or in layered compositions of materials.
  • a solid core can be composed of a polymeric core such as amphiphilic block copolymers, hydrophobic polymers such as polystyrene, poly(lactic acid), poly(lactic co-glycolic acid), poly(glycolic acid), poly(caprolactone) and other biocompatible polymers known to those skilled in the art.
  • a hollow core has at least some space in the center region of a shell material.
  • a hollow core is a liposome core.
  • a liposome core as used herein refers to a centrally located core compartment formed by a component of the lipids or phospholipids that form a lipid bilayer.
  • “Liposomes” are artificial, self-closed vesicular structures of various sizes and shapes, where one or several membranes encapsulate an aqueous core. Most typically liposome membranes are formed from lipid bilayer membranes, where the hydrophilic head groups are oriented towards aqueous environments, and the lipid chains are oriented away from aqueous environments.
  • Liposomes can be formed as well from other amphiphilic monomeric and polymeric molecules, such as polymers, like block copolymers, or polypeptides.
  • Unilamellar vesicles are liposomes defined by a single membrane (e.g., a single lipid bilayer membrane) enclosing an aqueous space.
  • oligo- or multilamellar vesicles are built up of several membranes.
  • the membranes are roughly 4 nm thick and are composed of amphiphilic lipids, such as phospholipids, of natural or synthetic origin.
  • the membrane properties can be modified by the incorporation of other lipids such as sterols or cholic acid derivatives.
  • the lipid bilayer is composed of two layers of lipid molecules. Each lipid molecule in a layer is oriented substantially parallel to adjacent lipid molecules, and two layers of lipid molecules that form a bilayer have the polar ends of their molecules exposed to the aqueous phase and the non-polar ends adjacent to each other. The two lipid layers that form the lipid bilayer are substantially parallel to one another.
  • the central aqueous region of the liposomal core may be empty or filled fully or partially with water, an aqueous emulsion, oligonucleotides, or other therapeutic or diagnostic agents or aqueous solutions thereof.
  • a lipid bilayer or liposome core can be constructed from one or more lipids known to those in the art including but not limited to: l,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dimyristoyl-sn-phosphatidylcholine (DMPC), l-palmitoyl-2-oleoyl-sn- phosphatidylcholine (POPC), l,2-distearoyl-sn-glycero-3-phospho-(l'-rac-glycerol) (DSPG), l,2-dioleoyl-sn-glycero-3-phospho-(l'-rac-glycerol) (DOPG), l,2-distearoyl-sn-glycero-3- phosphocholine (DSPC), l,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), l,2-di-(9Z
  • lipid refers to its conventional sense as a generic term encompassing fats, lipids, and alcohol-ether-soluble constituents of protoplasm, which are insoluble in water.
  • Lipids usually consist of a hydrophilic and a hydrophobic moiety. In water lipids can self-organize to form bilayer membranes, where the hydrophilic moieties (head groups) are oriented towards the aqueous phase, and the lipophilic moieties (acyl chains) are embedded in the hydrophobic region between the two hydrophilic layers comprised within the bilayer.
  • Lipids can also comprise two hydrophilic moieties (bola amphiphiles). In that case, membranes may be formed from a single lipid layer, and not a bilayer.
  • lipids are fats, fatty oils, essential oils, waxes, steroids, sterols, phospholipids, glycolipids, sulpholipids, aminolipids, chromolipids, and fatty acids.
  • the term encompasses both naturally occurring and synthetic lipids.
  • the lipids are steroids, sterols (e.g., cholesterol), phospholipids, including phosphatidyl, phosphatidylcholines and phosphatidylethanolamines and sphingomyelins.
  • sterols e.g., cholesterol
  • phospholipids including phosphatidyl, phosphatidylcholines and phosphatidylethanolamines and sphingomyelins.
  • fatty acids could be about 12-24 carbon chains in length, containing up to 6 double bonds.
  • the fatty acids are linked to a backbone, which may be derived from glycerol.
  • the fatty acids within one lipid can be different (asymmetric), or there may be only 1 type of fatty acid chain present, e.g., lysolecithins.
  • Mixed formulations are also possible, particularly when the non-cationic lipids are derived from natural sources, such as lecithins (phosphatidylcholines) pur
  • the SNA includes a neutral lipid.
  • the neutral lipid may be, for example, l,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC), 1,2-dimyristoyl-sn- phosphatidylcholine (DMPC), l-palmitoyl-2-oleoyl-sn-phosphatidylcholine (POPC), 1,2- distearoyl-sn-glycero-3-phospho-(l'-rac-glycerol) (DSPG), l,2-dioleoyl-sn-glycero-3- phospho-(l'-rac-glycerol) (DOPG), l,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2- dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), l,2-di-(9Z-octadecenoyl)-
  • the core is a niosome core.
  • a noisome is a vesicle formed from non-ionic surfactant oriented in a bilayer.
  • Niosomes commonly have cholesterol added as an excipient, but other lipid-based and non-lipid-based constituents can also be included. Methods for preparation of niosomes are known in the art.
  • polyethylene glycol (PEG) is included during or following niosome preparation.
  • Niosome vesicles are structurally and functionally analogous to liposomes, but are based on non-ionic surfactant rather than lipid as the primary constituent.
  • Common non-ionic surfactants used include sorbitans (spans) or polysorbates (tween); however, a wide variety of non-ionic surfactants can be used to prepare niosomes.
  • conjugation means two entities stably bound to one another by any physiochemical means. It is important that the nature of the attachment is such that it does not impair substantially the effectiveness of either entity. Keeping these parameters in mind, any covalent or non-covalent linkage known to those of ordinary skill in the art may be employed. In some embodiments, covalent linkage is preferred.
  • Noncovalent conjugation includes hydrophobic interactions, ionic interactions, high affinity interactions such as biotin avidin and biotin streptavidin complexation and other affinity interactions. Such means and methods of attachment are well known to those of ordinary skill in the art.
  • a SNA comprises an oligonucleotide shell.
  • an oligonucleotide shell includes one or more oligonucleotides (e.g., synthetic oligonucleotides) on the exterior of the core.
  • the oligonucleotide shell comprises, consist essentially of or consists of one, two, three, four, five, six, seven, eight, nine, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, about 25, about 30, about 40, about 50, about 60, about 70, about 80, about 90, about 100, about 150, about 200, about 250, about 300, about 400, about 500, about 600, about 700, about 800, about 900, about 1000, about 1500, about 2000, about 3000, about 4000, about 5000, about 10,000, about 15,000, about 20,000 or more synthetic oligonucleotides, or any range or combination thereof.
  • the oligonucleotide shell comprises, consist essentially of or consists of 2- 1000, 2-900, 2-800, 2-700, 2-600, 2-500, 2-400, 2-300, 2-200, 2-100, 2-90, 2-80, 2-70, 2-60, 2-50, 2-45, 2-40, 2-35, 2-30, 2-25, 2-20, 2-15 or 2-10 oligonucleotides (e.g., synthetic oligonucleotides).
  • the oligonucleotide shell comprises, consist essentially of or consists of 5-100, 10-100, 15-100, 20-100, 25-100, 50-100, 5-50, 10-50, 15- 50, 20-50, 25-50, 5-40, 10-40, 15-40, 20-40, 25-40, 5-30, 10-30, 15-30, 20-30, 25-30, 5-25, 10-25, 15-25 or 20-25 oligonucleotides (e.g., synthetic oligonucleotides).
  • the oligonucleotide shell comprises, consist essentially of or consists of 30 or about 30 oligonucleotides (e.g., synthetic oligonucleotides).
  • the oligonucleotides of an SNA each have the same nucleotide sequence.
  • the oligonucleotides of an SNA have two or more (e.g., 2,
  • the oligonucleotides of an SNA each have one of two distinct nucleotide sequences (i.e., each of the oligonucleotides has either a first nucleotide sequence or a second nucleotide sequence). In some embodiments, the oligonucleotides of an SNA each have one of three distinct nucleotide sequences (i.e., each of the oligonucleotides has either a first, a second, or a third nucleotide sequence).
  • the oligonucleotides of an SNA each have one of four distinct nucleotide sequences (i.e., each of the oligonucleotides has either a first, a second, a third, or a fourth nucleotide sequence).
  • the oligonucleotides of an SNA each have the same pattern of modifications. In some embodiments, the oligonucleotides of an SNA have two or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) distinct patterns of modifications. In some embodiments, the oligonucleotides of an SNA each have one of two distinct patterns of modifications (i.e., each of the oligonucleotides has either a first pattern of modifications or a second pattern of modifications).
  • the oligonucleotides of an SNA each have one of three distinct patterns of modifications (i.e., each of the oligonucleotides has either a first, a second, or a third pattern of modifications). In some embodiments, the oligonucleotides of an SNA each have one of four distinct patterns of modifications (i.e., each of the oligonucleotides has either a first, a second, a third, or a fourth pattern of modifications).
  • each distinct nucleotide sequence may be equally represented amongst the oligonucletodes (e.g., the distinct nucleotide sequences are in a ratio of 1:1,
  • one nucleotide sequence is more highly represented amongst the oligonucleotides (e.g., the distinct nucleotide sequences are in a ratio of 2:1, 2:1:1, or 2: 1:1:1, etc.). In some embodiments, the ratio between any given two nucleotide sequences of oligonucleotides of an SNA is 1:1, 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1,
  • the ratio between any given two nucleotide sequences of oligonucleotides of an SNA is 1:1. In some embodiments, the ratio between any given two nucleotide sequences of oligonucleotides of an SNA is 3:2. In some embodiments, the ratio between any given two nucleotide sequences of oligonucleotides of an SNA is 2:1. In some embodiments, the ratio between any given two nucleotide sequences of oligonucleotides of an SNA is 5:2.
  • the ratio between any given two nucleotide sequences of oligonucleotides of an SNA is 3:1. In some embodiments, the ratio between any given two nucleotide sequences of oligonucleotides of an SNA is 7:2. In some embodiments, the ratio between any given two nucleotide sequences of oligonucleotides of an SNA is 4:1. In some embodiments, the ratio between any given two nucleotide sequences of oligonucleotides of an SNA is 9:2. In some embodiments, the ratio between any given two nucleotide sequences of oligonucleotides of an SNA is 5:1.
  • each modification pattern may be equally represented amongst the oligonucletodes (e.g., the distinct modification patterns are in a ratio of 1:1,
  • one modification pattern is more highly represented amongst the oligonucleotides (e.g., the distinct modification patterns are in a ratio of 2:1, 2:1:1, or 2: 1:1:1, etc.). In some embodiments, the ratio between any given two modification patterns of oligonucleotides of an SNA is 1:1, 2: 1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, or more. In some embodiments, the ratio between any given two modification patterns of oligonucleotides of an SNA is 1:1.
  • an SNA disclosed herein comprises lipid molecules and oligonucleotides (e.g., synthetic oligonucleotides) at a molar ratio between 100 to 1 and 10 to 1, between 100 to 1 and 20 to 1, between 100 to 1 and 30 to 1, between 100 to 1 and 40 to 1, between 100 to 1 and 50 to 1, between 100 to 1 and 60 to 1, between 100 to 1 and 70 to 1, between 100 to 1 and 80 to 1, between 100 to 1 and 90 to 1, between 90 to 1 and 10 to 1, between 90 to 1 and 20 to 1, between 90 to 1 and 30 to 1, between 90 to 1 and 40 to 1, between 90 to 1 and 50 to 1, between 90 to 1 and 60 to 1, between 90 to 1 and 70 to 1, between 90 to 1 and 80 to 1, between 80 to 1 and 10 to 1, between 80 to 1 and 20 to 1, between 80 to 1 and 30 to 1, between 80 to 1 and 40 to 1, between 80 to 1 and 50 to 1, between 80 to 1 and 60 to 1, between 80 to 1 and 70 to 1, between 70 to 1 and 10 to 1, between 70 to 1 and 20 to 1, between 80 to 1
  • an SNA disclosed herein comprises lipid molecules and oligonucleotides (e.g., synthetic oligonucleotides) at a molar ratio of at least or about 10 to 1, 15 to 1, 20 to 1, 25 to 1, 30 to 1, 35 to 1, 40 to 1, 45 to 1, 50 to 1, 55 to 1, 60 to 1, 65 to 1, 70 to 1, 75 to 1, 80 to 1, 85 to 1, 90 to 1, 95 to 1, or 100 to 1 of lipid to oligonucleotide, or any range or combination thereof.
  • oligonucleotides e.g., synthetic oligonucleotides
  • an SNA disclosed herein comprises lipid molecules and oligonucleotides (e.g., synthetic oligonucleotides) at a molar ratio of between 55 to 1 and 45 to 1 of lipid to oligonucleotide. In some embodiments, an SNA disclosed herein comprises lipid molecules and oligonucleotides (e.g., synthetic oligonucleotides) at a molar ratio of between 45 to 1 and 35 to 1 of lipid to oligonucleotide.
  • an SNA disclosed herein comprises lipid molecules and oligonucleotides (e.g., synthetic oligonucleotides) at a molar ratio of between 35 to 1 and 25 to 1 of lipid to oligonucleotide. In some embodiments, an SNA disclosed herein comprises lipid molecules and oligonucleotides (e.g., synthetic oligonucleotides) at a molar ratio of or about 50 to 1 of lipid to oligonucleotide.
  • an SNA disclosed herein comprises lipid molecules and oligonucleotides (e.g., synthetic oligonucleotides) at a molar ratio of or about 45 to 1 of lipid to oligonucleotide. In some embodiments, an SNA disclosed herein comprises lipid molecules and oligonucleotides (e.g., synthetic oligonucleotides) at a molar ratio of or about 40 to 1 of lipid to oligonucleotide.
  • an SNA disclosed herein comprises lipid molecules and oligonucleotides (e.g., synthetic oligonucleotides) at a molar ratio of or about 35 to 1 of lipid to oligonucleotide. In some embodiments, an SNA disclosed herein comprises lipid molecules and oligonucleotides (e.g., synthetic oligonucleotides) at a molar ratio of or about 30 to 1 of lipid to oligonucleotide.
  • an SNA disclosed herein comprises lipid molecules and oligonucleotides (e.g., synthetic oligonucleotides) at a molar ratio of or about 25 to 1 of lipid to oligonucleotide.
  • oligonucleotides e.g., synthetic oligonucleotides
  • an SNA comprising a first population of synthetic oligonucleotides and a second population of synthetic oligonucleotides may comprise lipids or lipid molecules at a molar ratio of 50 to 0.5 to 0.5 of lipids or lipid molecules to first population of synthetic oligonucleotides to second population of synthetic oligonucleotides.
  • an SNA comprising a first population of synthetic oligonucleotides and a second population of synthetic oligonucleotides may comprise different amounts of the first population of synthetic oligonucleotides and the second population of synthetic oligonucleotides, such that the molar ratio of lipids or lipid molecules to the first population of synthetic oligonucleotides to the second population of synthetic oligonucleotides is, for example, 50 to 0.1 to 0.9, 50 to 0.2 to 0.8, 50 to 0.3 to 0.7, 50 to 0.4 to 0.6, 50 to 0.6 to 0.4,
  • an SNA comprising a first population of synthetic oligonucleotides and a second population of synthetic oligonucleotides comprises the first population of synthetic oligonucleotides and the second population of synthetic oligonucleotides in a particular ratio.
  • the ratio is 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9, or 1:10. In some embodiments, the ratio is 1:1.
  • the oligonucleotides are on the exterior surface of the core (e.g., liposome core).
  • At least one oligonucleotide (e.g., a synthetic oligonucleotide) has its 5 ’-terminus exposed on the exterior surface away from the core (e.g., the 5 ’-terminus is located at the end of the oligonucleotide distal from the core).
  • all of the oligonucleotides (e.g., synthetic oligonucleotides) in a SNA have their 5 ’-termini exposed on the exterior surface away from the core (e.g., the 5 ’-termini are located at the ends of the oligonucleotides distal from the core).
  • At least one oligonucleotide has its 3 ’-terminus exposed on the exterior surface away from the core (e.g., the 3 ’-terminus is located at the end of the oligonucleotide distal from the core).
  • all of the oligonucleotides (e.g., synthetic oligonucleotides) in a SNA have their 3 ’-termini exposed on the exterior surface away from the core (e.g., the 3’- termini are located at the ends of the oligonucleotides distal from the core).
  • the SNA does not include an oligonucleotide (e.g., a synthetic oligonucleotide) inside the core (e.g., liposome core).
  • an SNA comprises a first synthetic oligonucleotide and a second synthetic oligonucleotide.
  • the 5’-terminus of the first synthetic oligonucleotide is exposed on the exterior surface of the SNA away from the core
  • the 3’- terminus of the second synthetic oligonucleotide is exposed on the surface of the SNA away from the core.
  • the 3 ’-terminus of the first synthetic oligonucleotide is exposed on the exterior surface of the SNA away from the core
  • the 5 ’-terminus of the second synthetic oligonucleotide is exposed on the surface of the SNA away from the core.
  • the 3 ’-terminus of the first synthetic oligonucleotide is exposed on the exterior surface of the SNA away from the core, and the 3 ’-terminus of the second synthetic oligonucleotide is exposed on the surface of the SNA away from the core.
  • the 5 ’-terminus of the first synthetic oligonucleotide is exposed on the exterior surface of the SNA away from the core, and the 5 ’-terminus of the second synthetic oligonucleotide is exposed on the surface of the SNA away from the core.
  • two or more of the oligonucleotides (e.g., synthetic oligonucleotides) in a SNA are crosslinked to one another. In some embodiments, all of the oligonucleotides (e.g., synthetic oligonucleotides) in a SNA are crosslinked to one or more additional oligonucleotides. In some embodiments, the oligonucleotides (e.g., synthetic oligonucleotides) in a SNA are not crosslinked.
  • a SNA disclosed herein has a diameter of, or a population of SNAs disclosed herein has a mean diameter of about 10 to about 150 nm.
  • the mean diameter of the population of SNAs is from about 15 nm to about 100 nm, about 20 nm to about 100 nm, about 25 nm to about 100 nm, about 15 nm to about 50 nm, about 20 nm to about 50 nm, about 10 nm to about 70 nm, about 15 nm to about 70 nm about 20 nm to about 70 nm, about 10 nm to about 30 nm, about 15 nm to about 30 nm, about 20 nm to about 30 nm, about 10 nm to about 40 nm, about 15 nm to about 40 nm, about 20 nm to about 40 nm, about 10 nm to about 80 nm, about 15 nm to about 80 nm, or about 20
  • the mean diameter of the population of SNAs is from about 15 nm to about 45 nm.
  • a SNA disclosed herein has a diameter, or a population of SNAs disclosed herein has a mean diameter of about 10 nm, about 15 nm, about 20 nm, about 30 nm, about 40 nm, about 50 nm, about 60 nm, about 70 nm, about 80 nm, about 90 nm, or about 100 nm.
  • a SNA disclosed herein has a diameter, or a population of SNAs disclosed herein has a mean diameter of about 30nm.
  • the core (e.g., liposome core) of a SNA disclosed herein has a diameter of, or the cores (e.g., liposome cores) of a population of SNAs disclosed herein has a mean diameter of about 10 to about 150 nm.
  • the diameter of the core or the mean diameter of the population of cores is from about 15 nm to about 100 nm, about 20 nm to about 100 nm, about 25 nm to about 100 nm, about 15 nm to about 50 nm, about 20 nm to about 50 nm, about 10 nm to about 70 nm, about 15 nm to about 70 nm, about
  • the core (e.g., liposome core) of a SNA disclosed herein has a diameter of, or the cores (e.g., liposome cores) of a population of SNAs disclosed herein has a mean diameter of aboutl5 nm to about 45 nm.
  • the core (e.g., liposome core) of a SNA disclosed herein has a diameter of, or the cores (e.g., liposome cores) of a population of SNAs disclosed herein has a mean diameter of about 10 nm, about 15 nm, about 20 nm, about 30 nm, about 40 nm, about 50 nm, about 60 nm, about 70 nm, about 80 nm, about 90 nm, or about 100 nm.
  • the core (e.g., liposome core) of a SNA disclosed herein has a diameter of, or the cores (e.g., liposome cores) of a population of SNAs disclosed herein has a mean diameter of about 30 nm.
  • the core (e.g., liposome core) of a SNA disclosed herein has a diameter, or the cores (e.g., liposome cores) of a population of SNAs disclosed herein has a mean diameter of about or less than about 10 nm, 15 nm, 20 nm, 25 nm, 30 nm, 35 nm, and/or 40 nm, or any range or combination thereof.
  • the core (e.g., liposome core) of a SNA disclosed herein has a diameter, or the cores (e.g., liposome cores) of a population of SNAs disclosed herein has a mean diameter of about or less than 40nm.
  • the SNAs disclosed herein may be stable self-assembling nanostructures.
  • the SNA may comprise an oligonucleotide (e.g., a synthetic oligonucleotide) of 18- 21 nucleosides in length having a sequence disclosed herein, wherein a hydrophobic group at the 3’ or 5’ terminus of the oligonucleotide self-associates to form the core or associates with the core of the nanostructure in water or other suitable solvents.
  • an oligonucleotide e.g., a synthetic oligonucleotide of 18- 21 nucleosides in length having a sequence disclosed herein, wherein a hydrophobic group at the 3’ or 5’ terminus of the oligonucleotide self-associates to form the core or associates with the core of the nanostructure in water or other suitable solvents.
  • a hydrophobic group as used herein may include cholesterol, a cholesteryl or modified cholesteryl residue, adamantine, dihydrotesterone, long chain alkyl, long chain alkenyl, long chain alkynyl, olely-lithocholic, cholenic, oleoyl-cholenic, palmityl, heptadecyl, myrisityl, bile acids, cholic acid or taurocholic acid, deoxycholate, oleyl litocholic acid, oleoyl cholenic acid, glycolipids, phospholipids, sphingolipids, isoprenoids, such as steroids, vitamins, such as vitamin E, fatty acids either saturated or unsaturated, fatty acid esters, such as triglycerides, pyrenes, porphyrines, Texaphyrine, adamantane, acridines, biotin, coumarin, fluorescein, rhodamine
  • a disease or disorder refers to a disease or disorder in a subject.
  • the disease or disorder is a mitochondrial disease or disorder. In some embodiments, the disease or disorder is FRDA.
  • a “cell” refers to a cell obtained from a subject or existing within a subject.
  • the cell may be a fibroblast, a liver cell, a kidney cell, a heart cell, a muscle cell
  • the cell is from a subject having a disease or disorder.
  • the cell is from a subject having a mitochondrial disease or disorder.
  • the cell is from a subject having Friedreich’s ataxia.
  • the cell is contacted with an oligonucleotide (e.g., synthetic oligonucleotide), a SNA, or a composition thereof (e.g., pharmaceutical composition thereof) disclosed herein at a concentration of at least 0.001 nM, at least 0.01 nM, at least 0.1 nM, at least 1 nM, at least 10 nM, at least 100 nM, at least 1000 nM, at least 10 mM, at least 100 pM, at least 1000 pM, or above 1000 pM.
  • an oligonucleotide e.g., synthetic oligonucleotide
  • SNA e.g., synthetic oligonucleotide
  • a composition thereof e.g., pharmaceutical composition thereof
  • the cell is contacted with oligonucleotide (e.g., synthetic oligonucleotide), a SNA, or a composition (e.g., pharmaceutical composition) disclosed herein at a concentration range of 0.001 nM to 0.01 nM, 0.01 nM to 0.1 nM, 0.1 nM to 1 nM, 1 nM to 10 nM, 10 nM to 100 nM, 100 nM to 1000 nM, 1000 nM to 10 pM, 10 pM to 100 pM, or 100 pM to 1000 pM.
  • oligonucleotide e.g., synthetic oligonucleotide
  • SNA e.g., SNA
  • a composition e.g., pharmaceutical composition
  • the cell is contacted with oligonucleotide (e.g., synthetic oligonucleotide), a SNA, or a composition (e.g., pharmaceutical composition) disclosed herein at a concentration of 0.001 nM, 0.01 nM, 0.1 nM, 1 nM, 10 nM, 100 nM, 1000 nM, 10 pM, 100 pM, 1000 pM or above 1000 pM.
  • the concentration refers to the total weight or total mass of an oligonucleotide (e.g., synthetic oligonucleotide) disclosed herein in a volume of solution.
  • a concentration of 0.001 nM refers to 0.001 nmoles of oligonucleotide (e.g., synthetic oligonucleotide) per liter of solution (e.g., pharmaceutically acceptable carrier).
  • the concentration refers to the total weight or total mass of a SNA disclosed herein in a volume of solution.
  • a concentration of 0.001 nM refers to 0.001 nmoles of SNA per liter of solution (e.g., pharmaceutically acceptable carrier).
  • one healthy (“wild-type”) copy of the FXN gene is sufficient to prevent the disease phenotype.
  • restoring FXN protein levels and/or FXN protein function in a subject or in certain cells of a subject to at least 50% of normal levels improves symptoms, and/or slows or halts progression of a disease or disorder (e.g., FRDA).
  • a disease or disorder e.g., FRDA
  • onset of the disease or disorder refers to the age of a subject having the disease or disorder at which symptoms of the disease or disorder become apparent in the subject, or the age of a subject having the disease or disorder at which the disease or disorder is diagnosed in the subject.
  • the onset of the disease or disorder may correspond to the onset of FRDA.
  • the onset of the disease or disorder may occur when the subject having the disease or disorder is at least about five years old. In some instances, the onset may occur when the subject is between about five years old and about 40 years old. In some instances, the onset may occur when the subject is between about five years old and about 25 years old. In some instances, the onset may occur when the subject is between about five years old and about 15 years old.
  • ameliorating or eliminating a disease or symptom refers to decreasing the severity of the disease or the symptom or removing evidence of the disease or the symptom in a subject.
  • ameliorating or eliminating a disease or symptom may refer to a change in a metric associated with the disease or symptom as evaluated by a medical professional or as measured by a laboratory test.
  • ameliorating or eliminating a disease, disorder or symptom may refer to a change in a metric associated with the disease, disorder or symptom as reported by the subject having the disease or symptom.
  • ameliorating or eliminating a disease or symptom may refer to a decrease or elimination of pain associated with the disease, disorder or symptom.
  • a “second therapeutic agent” refers to a therapeutic agent other than an oligonucleotide (e.g., synthetic oligonucleotide), SNA or composition disclosed herein.
  • the second therapeutic agent may refer to any composition, compound, or device that is administered to or utilized on a subject having a disease or disorder, which may enhance the therapeutic effect of the synthetic oligonucleotide or SNA disclosed herein.
  • the second therapeutic agent is at least one of omaveloxolone, etravirine, recombinant frataxin protein, and compounds that modify histone acetylation status (e.g.,
  • the subject is a mammal.
  • the subject is a primate.
  • the subject is a human.
  • the mammal is a vertebrate animal including, but not limited to, a mouse, rat, dog, cat, horse, cow, pig, sheep, goat, turkey, chicken, monkey, fish (e.g., aquaculture species, salmon, etc.).
  • the disclosure herein can also be used to treat diseases or disorders, such as mitochondrial diseases (e.g., FRDA), in human or non-human subjects.
  • an oligonucleotide e.g., a synthetic oligonucleotide
  • SNA comprising an oligonucleotide disclosed herein
  • two or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) SNAs each comprising a synthetic oligonucleotide disclosed herein are administered to a subject.
  • each SNA of the two or more SNAs comprises a distinct synthetic oligonucleotide disclosed herein.
  • the synthetic oligonucleotide on each SNA of the two or more SNAs has a distinct nucleic acid sequence and/or a distinct modification pattern.
  • a first SNA comprising a first synthetic oligonucleotide disclosed herein and a second SNA comprising a second synthetic oligonucleotide disclosed herein are administered to a subject.
  • an SNA comprising two synthetic oligonucleotides e.g., a first synthetic oligonucleotide and a second synthetic oligonucleotide
  • the two synthetic oligonucleotides of an SNA have distinct nucleic acid sequences and/or distinct modification patterns.
  • the SNA or each of the two or more SNAs are SNAs having oligonucleotides disclosed herein, e.g., SNAs having oligonucleotides disclosed in any one of Tables 1, 2, 3, 4, 8, 9, or 10.
  • a composition comprising an SNA comprising a synthetic oligonucleotide disclosed herein is administered to a subject.
  • two or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) compositions each comprising an SNAs comprising a synthetic oligonucleotide disclosed herein are combined prior to being administered to a subject.
  • two or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) compositions each comprising an SNAs disclosed herein are administered to a subject at the same time or substantially the same time.
  • the two or more compositions each comprising an SNAs disclosed herein are administered to a subject separately.
  • the two or more compositions each comprising an SNA disclosed herein are administered to a subject together.
  • the SNA or each of the two or more SNAs are SNAs having oligonucleotides disclosed herein, e.g.,
  • methods are provided for administering an oligonucleotide (e.g., a synthetic oligonucleotide) or an SNA disclosed herein to a subject.
  • the method comprises administering an SNA comprising a synthetic oligonucleotide disclosed herein to a subject.
  • the method comprises administering two or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) SNAs disclosed herein to a subject.
  • the method comprises administering a mixture of two or more
  • compositions each comprising an SNA disclosed herein to a subject comprises mixing two or more compositions each comprising an SNA disclosed herein and subsequently administering the resulting mixture to a subject.
  • the method comprises administering a composition comprising an SNA comprising two or more (e.g., 2, 3, 4, 5, 6, 7, 8, 9, 10, or more) synthetic oligonucleotides disclosed herein to a subject.
  • the two or more synthetic oligonucleotides comprise two or more distinct nucleic acid sequences and/or two or more distinct modification patterns.
  • the SNA is an SNA having an oligonucleotide disclosed herein, e.g., an SNA disclosed in any one of Tables 1, 2, 3, 4, 8, 9, or 10.
  • the oligonucleotide e.g., synthetic oligonucleotide
  • SNA is administered in a pharmaceutical composition.
  • routes of administration include but are not limited to cutaneous, subcutaneous, nodal, systemic, intravenous, intrathecal, intracranial, oral, parenteral, intracranial, intramuscular, intranasal, sublingual, intratracheal, inhalation, ocular, vaginal, and rectal.
  • An oligonucleotide e.g., synthetic oligonucleotide
  • SNA or compositions thereof (e.g., pharmaceutical composition thereof) disclosed herein can be administered intravenously, intradermally, intraarterially, intralesionally, intratumorally, intracranially, intrathecally, intraarticularly, intraprostatically, intrapleurally, intratracheally, intranasally, intravitreally, intravaginally, intrarectally, topically, intramuscularly, intraperitoneally, subcutaneously, subconjunctival, intravascularly, mucosally, intrapericardially, intraumbilically, intraocularly, via eyedrops, orally, topically, locally, via inhalation (e.g., aerosol inhalation), via injection, via infusion, via continuous infusion, via localized perfusion bathing target cells directly, via a catheter, via a lavage, in creams, in gels, in lipid compositions (e.g., lipo
  • the oligonucleotide e.g., synthetic oligonucleotide
  • SNA oligonucleotide
  • composition thereof e.g., pharmaceutical composition thereof
  • the oligonucleotide e.g., synthetic oligonucleotide
  • SNA oligonucleotide
  • composition thereof e.g., pharmaceutical composition thereof
  • oligonucleotide e.g., synthetic oligonucleotide
  • SNA syrene-like peptide-like peptide-like peptide-like peptide-like peptide-like peptide-like peptide-like peptide-like peptide-like peptide-like peptide-like peptide-like peptide-like peptide-like peptide-like peptide.g., SNA, or compositions thereof
  • tissue administration may be achieved by direct injection, topical application, or local application.
  • the compounds may be administered once, or alternatively they may be administered in a plurality of administrations. If administered multiple times, the compounds may be administered via different routes. For example, the first (or the first few) administrations may be made directly into the affected tissue while later administrations may be systemic.
  • the dose as it relates to administration of an oligonucleotide (e.g., synthetic oligonucleotide) and/or a SNA disclosed herein (e.g., without limitation the phrases “an effective amount of a synthetic oligonucleotide,” “an effective amount of a pharmaceutical composition,” “an effective amount of a spherical nucleic acid”, etc.) refers to the total weight or total mass of active agent (e.g., total weight or total mass of the synthetic oligonucleotides) in the SNA administered to the subject (e.g., subject with a disease or disorder).
  • an “effective amount” refers to an amount that is capable of improving one or more symptoms of a disease or disorder or an amount that is capable of improving a metric associated with a disease or disorder.
  • a dose disclosed herein is considered a fixed dose or a discrete dose.
  • a dose disclosed herein can be adjusted to depend on body weight or be made dependent on body weight.
  • a non-limiting example includes a dose of 2 mg of an oligonucleotide (e.g., synthetic oligonucleotide), an SNA, or a composition thereof (e.g., pharmaceutical composition thereof) disclosed herein, that can also be administered as 2 mg/kg body weight, which depends on kg of body weight.
  • a dose disclosed herein is independent of body weight.
  • an oligonucleotide e.g., synthetic oligonucleotide
  • an SNA or a composition thereof (e.g., pharmaceutical composition thereof) disclosed herein is administered once a day, once every three days, once a week, once every two weeks, once every three weeks, once every four weeks, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every nice weeks, once every 10 weeks, once every 12 weeks, once every 18 weeks, once every 24 weeks, once a month, once every two months, once every three months, once every four months, once every five months, once every six months, once every seven months, once every eight months, once every nine months, once every 10 months, once every 11 months, once a year, once every two years, once every three years, once every four years.
  • an oligonucleotide e.g., synthetic oligonucleotide
  • a SNA a composition thereof (e.g., pharmaceutical composition thereof) disclosed herein is administered to a subject once a week, twice a week or three times per week, for four weeks, six weeks, eight weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 24 weeks, one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, 10 months, 11 months, one year, two years, three years, four years, five years, six years.
  • a composition thereof e.g., pharmaceutical composition thereof
  • an oligonucleotide e.g., synthetic oligonucleotide
  • a SNA or a composition thereof (e.g., pharmaceutical composition thereof) disclosed herein is administered to a subject every three weeks for four weeks, six weeks, eight weeks, 10 weeks, 12 weeks, 14 weeks, 16 weeks, 18 weeks, 20 weeks, 24 weeks, one month, two months, three months, four months, five months, six months, seven months, eight months, nine months, 10 months, 11 months, one year, two years, three years, four years, five years, six years, seven years, eight years, nine years, or 10 years.
  • the SNA is administered every three weeks.
  • the SNA is administered about or at least about every four weeks, five weeks, six weeks, 2 months, three months, six months, nine months, one year, 1.5 years, two years, 2.5 years, three years, 3.5 years, four years, 4.5 years, five years, 5.5 years, or six years.
  • the duration of the method for treating a disease or disorder (e.g., FRDA) with an oligonucleotide (e.g., synthetic oligonucleotide), a SNA, or a composition thereof (e.g., pharmaceutical composition thereof) disclosed herein is for about or at least 3 months, for about or at least six months, for about or at least nine months, for about or at least one year, for about or at least 1.5 years, for about or at least two years, for about or at least 2.5 years, for about or at least 3 years, for about or at least 3.5 years, for about or at least 4 years, for about or at least 4.5 years, for about or at least 5 years, for about or at least 5.5 years, for about or at least 6 years, for about or at least 6.5 years, for about or at least 7 years, for about or at least 7.5 years, for about or at least 8 years, for about or at least 8.5 years, for about or at least 9 years, for about or at least 9.5 years, for about or
  • an effective amount is from about 0.1 pg to 10,000 mg per dose, at least about 1 pg to 8000 mg per dose, or 10 pg to 100 pg per dose.
  • the dose administered is about or at least about 1 microgram, about or at least about 5 microgram, about or at least about 10 microgram, about or at least about 50 microgram, about or at least about 100 micro gram, about or at least about 200 microgram, about or at least about 350 microgram, about or at least about 500 microgram, about or at least about 1 milligram, about or at least about 5 milligram, about or at least about 10 milligram, about or at least about 50 milligram, about or at least about 100 milligram, about or at least about 200 milligram, about or at least about 350 milligram, about or at least about 500 milligram, about or at least about 1000 mg or more per dose, and any range or combination thereof.
  • the dose administered is about or at least about 1 microgram/kg of body weight, about or at least about 5 microgram/kg of body weight, about or at least about 10 microgram/kg of body weight, about or at least about 50 microgram/kg of body weight, about or at least about 100 microgram/kg of body weight, about or at least about 200 microgram/kg of body weight, about or at least about 350 microgram/kg of body weight, about or at least about 500 microgram/kg of body weight, about or at least about 1 milligram/kg of body weight, about or at least about 5 milligram/kg of body weight, about or at least about 10 milligram/kg of body weight, about or at least about 50 milligram/kg of body weight, about or at least about 100 milligram/kg of body weight, about or at least about 200 milligram/kg of body weight, about or at least about 350 milligram/kg of body weight, about or at least about 500 milligram/kg of body weight, to about or at least about at least about
  • a range of about 5 mg/kg of body weight to about 100 mg/kg of body weight, about 5 microgram/kg of body weight to about 500 milligram/kg of body weight, etc. can be administered, based on the numbers disclosed above.
  • the absolute amount (e.g., a discrete dose) will depend upon a variety of factors including the concurrent treatment, the number of doses and the individual patient parameters including age, physical condition, size and weight. These are factors well known to those of ordinary skill in the art and can be addressed with no more than routine experimentation. It is preferred generally that a maximum dose be used, that is, the highest safe dose according to sound medical judgment.
  • an oligonucleotide e.g., a synthetic oligonucleotide
  • an SNA or composition thereof (e.g., pharmaceutical composition thereof) disclosed herein is administered at a dose between 0.1 mg and 10 mg, between 0.2 mg and 10 mg, between 0.3 mg and 10 mg, between 0.4 mg and 10 mg, between 0.5 mg and 10 mg, between 0.6 mg and
  • 500 mg between 1 mg and 450 mg, between 1 mg and 400 mg, between 1 mg and 350 mg, between 1 mg and 300 mg, between 1 mg and 250 mg, between 1 mg and 200 mg, between 1 mg and 150 mg, between 1 mg and 100 mg, between 1 mg and 90 mg, between 1 mg and 80 mg, between 1 mg and 70 mg, between 1 mg and 60 mg, between 1 mg and 60 mg, between 1 mg and 50 mg, between 1 mg and 49 mg, between 1 mg and 48 mg, between 1 mg and 47 mg, between 1 mg and 46 mg, between 1 mg and 45 mg, between 1 mg and 44 mg, between 1 mg and 43 mg, between 1 mg and 42 mg, between 1 mg and 41 mg, between 1 mg and 40 mg, between 1 mg and 39 mg, between 1 mg and 38 mg, between 1 mg and 37 mg, between 1 mg and 36 mg, between 1 mg and 35 mg, between 1 mg and 34 mg, between 1 mg and 33 mg, between 1 mg and 32 mg, between 1 mg and 31 mg, between 1 mg and 30 mg, between 1 mg and 29 mg, between 1 mg in 28 mg
  • an oligonucleotide e.g., a synthetic oligonucleotide
  • an SNA or composition thereof (e.g., pharmaceutical composition thereof) disclosed herein is administered at a dose of or about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg,
  • an oligonucleotide e.g., a synthetic oligonucleotide
  • an SNA or composition thereof (e.g., pharmaceutical composition thereof) disclosed herein is administered at a dose of at least or at least about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg, 1.9 mg, 2 mg, 2.1 mg, 2.2 mg, 2.3 mg, 2.4 mg, 2.5 mg, 2.6 mg, 2.7 mg, 2.8 mg, 2.9 mg, 3 mg, 3.1 mg, 3.2 mg, 3.3 mg, 3.4 mg, 3.5 mg, 3.6 mg, 3.7 mg, 3.8 mg, 3.9 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg,
  • an oligonucleotide e.g., a synthetic oligonucleotide
  • an SNA or composition thereof (e.g., pharmaceutical composition) disclosed herein is administered at a dose greater than or greater than about 0.1 mg, 0.2 mg, 0.3 mg, 0.4 mg, 0.5 mg, 0.6 mg, 0.7 mg, 0.8 mg, 0.9 mg, 1 mg, 1.1 mg, 1.2 mg, 1.3 mg, 1.4 mg, 1.5 mg, 1.6 mg, 1.7 mg, 1.8 mg,
  • a “reference level,” refers to a corresponding level in a subject with a disease or disorder (e.g., FRDA) who has been administered a linear oligonucleotide
  • a synthetic oligonucleotide disclosed herein which is not in a SNA format or pharmaceutical composition thereof; to a corresponding level in a subject with a disease or disorder (e.g., FRDA) who has not been administered a SNA (e.g., a SNA disclosed herein) or pharmaceutical composition thereof; to a corresponding level in a subject with a disease or disorder (e.g., FRDA) who has not been administered a linear oligonucleotide (e.g., synthetic oligonucleotide) disclosed herein; to a corresponding level in a subject with the disease or disorder (e.g., FRDA) prior to administration of an oligonucleotide (e.g., synthetic oligonucleotide), SNA or composition thereof (e.g., pharmaceutical composition thereof) disclosed herein to the subject with the disease or disorder (e.g., FRDA); to a corresponding level in a subject with a disease or disorder (e.g
  • an oligonucleotide e.g., synthetic oligonucleotide
  • an SNA e.g., SNA
  • a composition thereof e.g., pharmaceutical composition thereof
  • the level is increased in the subject by at least or about 5%, at least or about 10%, at least or about 15%, at least or about 16%, at least or about 17%, at least or about 18%, at least or about 19%, at least or about 20%, at least or about 21%, at least or about 22%, at least or about 23%, at least or about 24%, at least or about 25%, at least or about 26%, at least or about 27%, at least or about 28%, at least or about 29%, at least or about 30%, at least or about 31%, at least or about 32%, at least or about 33%, at least or about 34%, at least or about 35%, at least or about 36%, at least or about 37%, at least or about 38%, at least or about 39%, at least or about 40%, at least or about 41%, at least or about 42%, at least or about 43%, at least or about 44%, at least or about 45%, at least or about 46%, at least or about 47%, at least or or
  • administering increases FXN mRNA levels or FXN protein levels by at least or about 2-fold, at least or about 3 -fold, at least or about 4-fold, at least or about 5-fold, at least or about 6-fold, at least or about 7-fold, at least or about 8-fold, at least or about 9-fold, at least or about 10-fold, at least or about 11-fold, at least or about 12-fold, at least or about 13 -fold, at least or about 14-fold, at least or about 15-fold, at least or about 16-fold, at least or about 17-fold, at least or about 18-fold, at least or about 19-fold, at least or about 20-fold, at least or about 21 -fold, at least or about 22-fold, at least or about 23 -fold, at least or about 24-fold, at least or about
  • the FXN mRNA levels or FXN protein levels are increased in a cell or cells of a subject with a disease or disorder (e.g., FRDA). In some embodiments, the FXN mRNA levels or FXN protein levels are increased in a tissue or tissues of a subject with a disease or disorder (e.g., FRDA). In some embodiments, the FXN mRNA levels or FXN protein levels are increased in an organ or organs of a subject with a disease or disorder (e.g., FRDA).
  • an oligonucleotide e.g., synthetic oligonucleotide
  • a SNA a cell to increase FXN mRNA levels or FXN protein levels in the cell.
  • the level in the cell is increased by at least or about 5%, at least or about 10%, at least or about 15%, at least or about 16%, at least or about 17%, at least or about 18%, at least or about
  • 95% at least or about 100%, at least or about 150%, at least or about 200%, at least or about 250%, at least or about 300%, at least or about 400% at least or about 500%, at least or about 600%, at least or about 700%, at least or about 800%, at least or about 900%, at least or about 1000% relative to a reference level.
  • an oligonucleotide e.g., synthetic oligonucleotide
  • an SNA or a composition thereof (e.g., pharmaceutical composition thereof) is contacted with a cell to increase FXN mRNA levels or FXN protein levels by at least or about 2-fold, at least or about
  • FXN mRNA levels or FXN protein levels are increased in a mitochondrion or mitochondria of a cell.
  • an oligonucleotide e.g., synthetic oligonucleotide
  • a SNA a composition thereof
  • a composition thereof e.g., pharmaceutical composition thereof
  • is administered to a subject at a dose which results in one or more of increased mRNA expression, increased mRNA translation, or increased protein expression e.g., increased FXN mRNA expression, increased FXN pri-mRNA expression, increased FXN pre-mRNA expression, increased FXN mRNA translation, or increased FXN protein expression
  • an oligonucleotide e.g., synthetic oligonucleotide
  • a SNA a composition thereof
  • a composition thereof e.g., pharmaceutical composition thereof
  • is administered to a subject at a dose which results in one or more of increased mRNA expression, increased mRNA translation, or increased protein expression e.g., increased FXN mRNA expression, increased
  • FXN pri-mRNA expression increased FXN pre-mRNA expression, increased FXN mRNA translation, or increased FXN protein expression
  • the FXN ruRNA expression, FXN pre-mRNA expression, FXN ruRNA translation, and/or FXN protein expression are increased in a cell or cells of a subject. In some embodiments, the FXN ruRNA expression, FXN pre-mRNA expression, FXN ruRNA translation, and/or FXN protein expression are increased in a mitochondrion or mitochondria of a subject. In some embodiments, the FXN ruRNA expression, FXN pre-mRNA expression, FXN ruRNA translation, and/or FXN protein expression are increased in a tissue or tissues of a subject.
  • the FXN ruRNA expression, FXN pre-mRNA expression, FXN ruRNA translation, and/or FXN protein expression are increased in an organ or organs of a subject (e.g., subject with FRDA).
  • measuring frataxin ( FXN) mRNA levels or “measuring frataxin (FXN) protein levels” refers to quantifying or qualitatively evaluating the amount of FXN mRNA or FXN protein in a given sample.
  • measuring FXN mRNA levels may refer to using laboratory methods known to those of ordinary skill in the art to quantify or qualitatively evaluate the amount of FXN mRNA in a given sample, using methods including but not limited to quantitative real-time reverse transcription polymerase chain reaction (qRT-PCR), Northern blotting, in situ hybridization, or spectrophotometric analysis.
  • qRT-PCR quantitative real-time reverse transcription polymerase chain reaction
  • measuring FXN protein levels may refer to using laboratory methods known to those of ordinary skill in the art to quantify or qualitatively evaluate the amount of FXN protein in a given sample, using methods including but not limited to Western blotting, enzyme-linked immunosorbent assays (ELISA), immunohistochemical staining, immunofluorescent staining, mass spectrometry, spectrophotometric analysis, or colorimetric analysis such as bis-cinchinonic acid (BCA) assays.
  • ELISA enzyme-linked immunosorbent assays
  • immunohistochemical staining immunofluorescent staining
  • mass spectrometry mass spectrometry
  • spectrophotometric analysis or colorimetric analysis such as bis-cinchinonic acid (BCA) assays.
  • BCA bis-cinchinonic acid
  • “pharmaceutically acceptable salts” are physiologically and pharmaceutically acceptable salts of the nucleic acids (e.g., salts that retain the desired biological activity of the compound of interest and do not impart undesired toxicological effects thereto).
  • Pharmaceutically acceptable salts include but are not limited to (a) salts formed with cations such as sodium, potassium, ammonium, magnesium, calcium, polyamines such as spermine and spermidine, etc.; (b) acid addition salts formed with inorganic acids, for example hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, nitric acid and the like; (c) salts formed with organic acids such as, for example, acetic acid, oxalic acid, tartaric acid, succinic acid, maleic acid, fumaric acid, gluconic acid, citric acid, malic acid, ascorbic acid, benzoic acid, tannic acid, palmitic acid, alginic acid, polyglutamic acid, na
  • compositions of the present invention comprise an effective amount of one or more agents, dissolved or dispersed in a pharmaceutically acceptable carrier.
  • salts include the acid addition salts, e.g., those formed with the free amino groups of a proteinaceous composition, or which are formed with inorganic acids such as for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric or mandelic acid. Salts formed with the free carboxyl groups also can be derived from inorganic bases such as for example, sodium, potassium, ammonium, calcium or ferric hydroxides; or such organic bases as isopropylamine, trimethylamine, histidine or procaine.
  • inorganic acids such as for example, hydrochloric or phosphoric acids, or such organic acids as acetic, oxalic, tartaric or mandelic acid.
  • Salts formed with the free carboxyl groups also can be derived from inorganic bases such as for example, sodium, potassium, ammonium, calcium or ferric hydroxides; or such organic bases as isopropylamine, trimethylamine, histidine or procaine
  • a carrier can be a solvent or dispersion medium comprising but not limited to, water, ethanol, polyol (e.g., glycerol, propylene glycol, liquid polyethylene glycol, etc.), lipids (e.g., triglycerides, vegetable oils, liposomes) and combinations thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating, such as lecithin; by the maintenance of the required particle size by dispersion in carriers such as, for example liquid polyol or lipids; by the use of surfactants such as, for example hydroxypropylcellulose; or combinations thereof such methods.
  • isotonic agents such as, for example, sugars, sodium chloride or combinations thereof.
  • a pharmaceutical composition comprises a modified SNA and artificial cerebrospinal fluid. In certain embodiments, a pharmaceutical composition consists of an SNA and artificial cerebrospinal fluid. In certain embodiments, a pharmaceutical composition consists essentially of an SNA and artificial cerebrospinal fluid.
  • the artificial cerebrospinal fluid is pharmaceutical grade. In certain embodiments, each 1 mL of artificial cerebrospinal fluid contains the following ingredients:
  • a “pharmaceutical or pharmacologically acceptable” composition refers to molecular entities and compositions that do not produce an adverse, allergic or other untoward reaction when administered to an animal, such as, for example, a human, as appropriate.
  • animal e.g., human
  • preparations should meet sterility, pyrogenicity, general safety and purity standards as required by FDA Office of Biological Standards.
  • the compounds are generally suitable for administration to humans. This term requires that a compound or composition be nontoxic and sufficiently pure so that no further manipulation of the compound or composition is needed prior to administration to humans.
  • compositions may comprise, for example, at least about 0.000001% (w/w) of an active agent (e.g., an oligonucleotide, such as a synthetic oligonucleotide, or a SNA disclosed herein).
  • an active agent e.g., an oligonucleotide, such as a synthetic oligonucleotide, or a SNA disclosed herein.
  • the active compound may comprise between about 2% to about 75% of the weight of the unit (w/w), or between about 25% to about 60%, for example, and any range or combination thereof.
  • the active agent e.g., an oligonucleotide, such as a synthetic oligonucleotide, or a SNA disclosed herein
  • the active agent comprises between 0.000001% and 0.00001%, between 0.00001% and 0.0001%, between 0.0001% and 0.001%, between 0.001% and 0.01%, between 0.01% and 0.1%, between 0.1% and 1%, between 1% and 5%, between 5% and 10%, between 10% and 15%, between 15% and 20%, between 20% and 25%, between 25% and 30%, between 30% and 40%, between 40% and 50% (w/w), and any range or combination thereof.
  • the active agent e.g., oligonucleotide, such as a synthetic oligonucleotide or an SNA disclosed herein
  • the active agent comprises 0.00007%, 0.007%, 0.01%, 0.1%, 1% (w/w).
  • “pharmaceutically acceptable carrier” includes any and all solvents, dispersion media, coatings, surfactants, antioxidants, preservatives (e.g., antibacterial agents, antifungal agents), isotonic agents, absorption delaying agents, salts, preservatives, drugs, drug stabilizers, gels, binders, excipients, disintegration agents, lubricants, sweetening agents, flavoring agents, dyes, such like materials and combinations thereof, as would be known to one of ordinary skill in the art.
  • the agent may comprise different types of carriers depending on whether it is to be administered in solid, liquid, gel, cream, or aerosol form, and whether it need to be sterile for such routes of administration as injection.
  • the composition may comprise various antioxidants to retard oxidation of one or more components.
  • the prevention of the action of microorganisms can be brought about by preservatives such as various antibacterial and antifungal agents, including but not limited to parabens (e.g., methylparabens, propylparabens), chlorobutanol, phenol, sorbic acid, thimerosal or combinations thereof.
  • parabens e.g., methylparabens, propylparabens
  • chlorobutanol phenol
  • sorbic acid thimerosal or combinations thereof.
  • the agent may be formulated into a composition in a free base, neutral or salt form.
  • compositions are administered in pharmaceutically acceptable compositions, which may routinely contain pharmaceutically acceptable concentrations of salt, buffering agents, preservatives, compatible carriers, adjuvants, excipients, and optionally other therapeutic ingredients.
  • a composition disclosed herein e.g., synthetic oligonucleotide,
  • a pharmaceutical composition comprises the composition and a pharmaceutically-acceptable carrier.
  • a pharmaceutically-acceptable carrier means a non-toxic material that does not interfere with the effectiveness of the biological activity of the active ingredients.
  • Pharmaceutically acceptable carriers include diluents, fillers, salts, buffers, stabilizers, solubilizers and other materials which are well-known in the art. Such preparations may routinely contain salt, buffering agents, preservatives, compatible carriers, and optionally other therapeutic agents.
  • the salts should be pharmaceutically acceptable, but non-pharmaceutically acceptable salts may conveniently be used to prepare pharmaceutically-acceptable salts thereof and are not excluded from the scope of the disclosure.
  • Such pharmacologically and pharmaceutically-acceptable salts include, but are not limited to, those prepared from the following acids: hydrochloric, hydrobromic, sulfuric, nitric, phosphoric, maleic, acetic, salicylic, citric, formic, malonic, succinic, and the like.
  • pharmaceutically-acceptable salts can be prepared as alkaline metal or alkaline earth salts, such as sodium, potassium or calcium salts.
  • a composition disclosed herein may be formulated into preparations in solid, semi-solid, liquid or gaseous forms such as tablets, capsules, powders, granules, ointments, solutions, depositories, inhalants and injections, and usual ways for oral, parenteral or surgical administration.
  • the disclosure also embraces pharmaceutical compositions which are formulated for local administration, such as by implants.
  • a composition disclosed herein when it is desirable to deliver them systemically, may be formulated for parenteral administration by injection, e.g., by bolus injection or continuous infusion.
  • Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative.
  • the compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents.
  • Preparations for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate.
  • Aqueous carriers include water, alcoholic/aqueous solutions, emulsions or suspensions, including saline and buffered media.
  • Parenteral vehicles include sodium chloride solution, Ringer’s dextrose, dextrose and sodium chloride, lactated Ringer’s, or fixed oils.
  • Intravenous vehicles include fluid and nutrient replenishers, electrolyte replenishers (such as those based on Ringer’s dextrose), and the like. Preservatives and other additives may also be present such as, for example, antimicrobials, anti-oxidants, chelating agents, and inert gases and the like. Lower doses will result from other forms of administration, such as intravenous administration. In the event that a response in a subject is insufficient at the initial doses applied, higher doses (or effectively higher doses by a different, more localized delivery route) may be employed to the extent that patient tolerance permits. Multiple doses per day are contemplated to achieve appropriate systemic levels of compounds.
  • a delivery vehicle is a biocompatible microparticle or implant that is suitable for implantation into the mammalian recipient.
  • Other delivery systems can include time-release, delayed release or sustained release delivery systems. Such systems can avoid repeated administrations of the compound, increasing convenience to the subject and the physician.
  • Many types of release delivery systems are available and known to those of ordinary skill in the art. They include polymer base systems such as poly(lactide-glycolide), copolyoxalates, polycaprolactones, polyesteramides, polyorthoesters, polyhydroxybutyric acid, and polyanhydrides.
  • Oligonucleotides were synthesized at lpmole scale with Universal UnyLinker
  • oligonucleotides were cleaved from the support and deprotected using AMA (ammonium hydroxide/40% aqueous methylamine 1:1 v/v) at 55 °C for 2 hours.
  • the oligonucleotides were purified via high performance liquid chromatography (HPLC) techniques. Molecular weights and extinction coefficients were determined using IDT OligoAnalyzer. Verification of oligonucleotide molecular weight was performed using Electrospray Ionization (ESI) mass spectrometry, purity was determined by Ion-exchange chromatography. Oligonucleotide concentration was determined by UV-absorbance at 260nm on a microplate reader (Molecular Devices).
  • AMA ammonium hydroxide/40% aqueous methylamine 1:1 v/v
  • Liposome were prepared from dried DOPC (l,2-dioleoyl-sn-glycero-3- phosphocholine), rehydrated in PBS by agitating overnight, homogenized under pressure until mean diameter of 18-20 nm and polydispersity of ⁇ 0.2 were reached. SNAs were formed under sterile conditions by mixing oligonucleotides with liposomes at 50 to 1 molar ratio of lipid to oligonucleotide.
  • DOPC l,2-dioleoyl-sn-glycero-3- phosphocholine
  • Oligonucleotide Design, Synthesis, and SNA Functionalization Oligonucleotides were synthesized via phosphoramidite chemistry at scale of at least 50 nmol. Phosphodiester
  • iSp 18 moieties. Oligonucleotides were purified via high performance liquid chromatography (HPLC) and molecular weights verified using electrospray ionization (ESI) mass spectrometry. Final oligonucleotide concentration was determined by UV-absorbance spectroscopy at 260 nm and calculated extinction coefficients. Oligonucleotides were loaded onto 20 nm diameter 1 ,2-diolcoyl-.s»-glycciO-3-phosphocholinc (DOPC) liposomes at a molar ratio of 50:1 DOPC :oligo nucleotide. Bispecific SNAs were loaded with equimolar concentrations of each oligonucleotide (50%:50%).
  • HPLC high performance liquid chromatography
  • ESI electrospray ionization
  • FXN- NAT gapmers were modified as follows: i) PS content was reduced by removing 4 and 5 PS- linkages from the 5' and 3' wings, respectively, ii) the cholesterol moiety was moved from the 3' to the 5' end, iii) ribose modifications in the gaps (100%) and wings (5': 20%; 3': 40%) were changed to LNA, iv) the length of the gap was shortened by two bases, and v) gapmers were changed to blockers by replacing the DNA gap with RNA.
  • FXN mRNA- targeting compounds were modified as follows: i) PS content was reduced by converting every other linkage to PO or by replacing 4 and 5 PS linkages with PO linkages in the 5' and 3' ends, respectively, ii) the cholesterol moiety was moved from the 3' to the 5' end, iii) the length of the oligonucleotide was reduced or increased by 3 bases, iv) ribose modification patterns were adjusted to incorporate ENA, and v) blockers were changed to gapmers by replacing the middle 10 bases with DNA.
  • RNA was amplified on a QuantStudio 12K PCR system using manufacturer-recommended thermocycler settings.
  • FXN cycle threshold (Ct) values were first normalized to GAPDFl expression by calculating the ACt values. Changes in FXN GE were determined by normalizing each treatment to GE in untreated cells using the 2 DDa method.
  • Modified oligonucleotides as synthesized are shown in Tables 8 and 9.
  • Modified oligonucleotides used to make bispecific SNA are shown in Table 10.
  • Tables 8-10 also show GE as a function of oligonucleotide treatment concentration. SNAs shown in Tables 8 and 9 were tested at a range of concentrations from 10,000 nM to 370 nM oligonucleotide. Preferred SNA from these tables were used as a basis for bispecific SNAs listed in Table 10, which were each tested at 370 nM (oligonucleotide concentration).
  • GE effects of bispecific SNAs on frataxin mRNA expression are also shown in Table 10.
  • SNA compounds were next tested in patient-derived fibroblasts, primary cells and induced neurons.
  • the cell lines, characteristics, and their sources are listed in Table 11 below.
  • the SNA ID and name of oligonucleotide component(s) thereof are listed in Table 12.
  • the nucleotide sequences and modification patterns corresponding to these compounds are shown in Tables 1-8. Brief descriptions of cell maintenance and assays to determine frataxin levels are provided below.
  • iPSCs Patient-derived induced pluripotent stem cells
  • DMEM/F12 Knockout Serum Replacement
  • penicillin/streptomycin/glutamine MEM- NEAA
  • 2-mercaptoethanol All from Invitrogen
  • Neuronal differentiation was performed via doxycycline induction of neurogenin 2 (NGN-2).
  • iPSCs were plated at a density of 95,000 cells/cm 2 for viral infection.
  • Fentiviruses were obtained from Alstem with “ultrapure titres” and used at the following concentrations: pTet-0-NGN2-puro: 0.1 pF/ 50,000 cells; Tet-O-FUW-eGFP: 0.05 pF/ 50,000 cells; Fudelta GW-rtTA: 0.11 pF / 50,000 cells.
  • doxycycline was added on “induced neuron (iN) day 1” at a concentration of 2 pg/mF.
  • puromycin was added at 10 mg/mF and was maintained in the media at all times thereafter.
  • iN day 4 cells were seeded in 24-well plates or 100 mm dishes and matured for 17 days prior to treatment.
  • Frataxin ELISA Frataxin protein was measured in whole cell lysates using a commercially available sandwich enzyme-linked immunosorbent assay (EFISA; Abeam abl76112). Ninety-six or 120 hours post-treatment, cells were lysed in 1% CHAPS detergent buffer, and protein concentrations in post-nuclear supernatants were determined by UV absorbance spectroscopy at 280 nm. Fysates were diluted 1:15 with assay-provided assay buffer, and the EFISA was conducted according to the manufacturer’s protocol. Frataxin protein concentrations were normalized to total protein prior to analysis.
  • EFISA sandwich enzyme-linked immunosorbent assay
  • Mitochondrial Isolation Mitochondria were partially purified from cells using a commercially available kit (Abeam abl 10170). One hundred twenty hours post-treatment, cells were lysed and processed according to the manufacturer’s protocol, except that the pellet was resuspended in 1% CHAPS detergent buffer. Protein concentrations were determined by UV absorbance spectroscopy at 280 nm. Mitochondrial enrichment was confirmed by Western blot.
  • Frataxin Lateral Flow Immunoassay Frataxin protein was measured in mitochondrial extracts using a commercially available lateral flow immunoassay (FFI; Abeam abl09881). Extracts were diluted to a protein concentration of 4 mg/mF using 1% CHAPS, then diluted to 320 pg/mF with Buffer A from the commercial kit such that 8 pg total extract was applied to assay strips. After drying and imaging, frataxin band optical densities were quantified using image analysis software and normalized to goat anti-mouse (GaM) positive control band intensities. Succinate Dehydrogenase (SDH) Assay. SDH activity was measured in partially purified mitochondrial extracts according to manufacturer protocols (BioVision Incorporated).
  • iNs derived from iPSCs were treated with SNAs at various doses for 120 hours prior to measurement of frataxin protein by ELISA.
  • Data represent the mean and are expressed as percent relative to non-disease control (NDC) neurons.
  • Table 15 shows that SNAs elevated mitochondrial frataxin and improved mitochondrial respiration in patient-derived iNs.
  • iNs derived from iPSCs GM23913 were treated with SNAs (500 nM oligonucleotide) for 120 hours before mitochondria were isolated and assessed for frataxin protein expression by LFI and for succinate dehydrogenate (SDH) activity by SDH assay.
  • Data represent the mean and are expressed as percent relative to non-disease control (NDC) neurons.
  • Table 15 Frataxin protein and SDH activity in SNA-treated patient-derived iNs.
  • Example 4 Dose response in patient derived cells
  • SNAs Two select SNA compounds were tested in the same patient-derived fibroblasts from Table 11 at a range of concentrations. Cells were maintained as described above. SNAs were prepared with compounds hFXNvl 461-LNA-7dzG and hFXN-NAT 540-LNA at a DOPC to oligonucleotide molar ratio of 50 to 1, as described above. The results, shown in Table 16, demonstrate that SNAs strongly upregulate FXN mRNA levels in patient-derived primary fibroblasts. The values in Table 16 are shown relative to untreated cells from the same cell line.
  • Example 5 SNA compounds in mouse model of Friedreich’s ataxia
  • mice i3 ⁇ 4n em2 1Lutzy Tg(FXN)YG8Pook/800J; Jackson Laboratory Stock 030395. Briefly, animals were anesthetized using isoflurane and placed in ventral recumbency on a stereotaxic instrument or across a cervical support allowing the neck to be flexed at a 45-degree angle ventrally. The skin of the neck was shaved using clippers and disinfected using alternating applications of surgical scrub (iodine or chlorhexidine) and 70% ethanol.
  • surgical scrub iodine or chlorhexidine
  • a skin incision was made on the dorsal midline immediately rostral to the external occipital protuberance and extending caudally ⁇ 2 cm.
  • the dura mater of the cisterna magna was then visualized after careful blunt dissection of the overlying dorsal cervical muscle layers.
  • a 30-32-gauge Hamilton needle was used to slowly inject 10 pL of SNA or vehicle at a rate of 3pL/min into the cisterna magna. Thereafter, muscle layers were reopposed and 0.1% bupivacaine was applied to edges of the skin incision, which was then closed with 6-0 suture with tissue adhesive. Animals were returned to clean cages, allowed to recover on warming pads, and monitored daily for 3 days post injection to monitor for adverse effects. No adverse events were reported.
  • Frataxin ELISA Frataxin protein was measured in tissue lysates using a commercially available sandwich enzyme-linked immunosorbent assay (ELISA; Abeam abl76112). Tissue lysates were prepared according to manufacturer instructions, and protein concentrations were determined by Rapid Gold BCA Assay (ThermoFisher). Lysates were diluted 1:50 (spinal cord and dorsal root ganglion (DRG)) or 1: 100 (brain) with assay-provided assay buffer prior. Frataxin protein concentrations were normalized to total protein.
  • ELISA sandwich enzyme-linked immunosorbent assay
  • Embodiment 1 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1132, or a pharmaceutically acceptable salt thereof.
  • FXN frataxin
  • Embodiment 2 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 475, or a pharmaceutically acceptable salt thereof.
  • Embodiment 3 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 121, or a pharmaceutically acceptable salt thereof.
  • Embodiment 4 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 301, or a pharmaceutically acceptable salt thereof.
  • Embodiment 5 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 361, or a pharmaceutically acceptable salt thereof.
  • Embodiment 6 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 368, or a pharmaceutically acceptable salt thereof.
  • Embodiment 7 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 379, or a pharmaceutically acceptable salt thereof.
  • Embodiment 8. A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 468, or a pharmaceutically acceptable salt thereof.
  • Embodiment 9 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 486, or a pharmaceutically acceptable salt thereof.
  • Embodiment 10 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 498, or a pharmaceutically acceptable salt thereof.
  • Embodiment 11 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 513, or a pharmaceutically acceptable salt thereof.
  • Embodiment 12 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 523, or a pharmaceutically acceptable salt thereof.
  • Embodiment 13 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 548, or a pharmaceutically acceptable salt thereof.
  • Embodiment 14 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 550, or a pharmaceutically acceptable salt thereof.
  • Embodiment 15 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 560, or a pharmaceutically acceptable salt thereof.
  • Embodiment 16 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 565, or a pharmaceutically acceptable salt thereof.
  • Embodiment 17 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 601, or a pharmaceutically acceptable salt thereof.
  • Embodiment 18 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 605, or a pharmaceutically acceptable salt thereof.
  • Embodiment 19 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 694, or a pharmaceutically acceptable salt thereof.
  • Embodiment 20 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 696, or a pharmaceutically acceptable salt thereof.
  • Embodiment 21 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 699, or a pharmaceutically acceptable salt thereof.
  • Embodiment 22 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 708, or a pharmaceutically acceptable salt thereof.
  • Embodiment 23 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 711, or a pharmaceutically acceptable salt thereof.
  • Embodiment 24 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 756, or a pharmaceutically acceptable salt thereof.
  • Embodiment 25 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 755, or a pharmaceutically acceptable salt thereof.
  • Embodiment 26 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 758, or a pharmaceutically acceptable salt thereof.
  • Embodiment 27 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 715, or a pharmaceutically acceptable salt thereof.
  • Embodiment 28 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 763, or a pharmaceutically acceptable salt thereof.
  • Embodiment 29 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 820, or a pharmaceutically acceptable salt thereof.
  • Embodiment 30 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 822, or a pharmaceutically acceptable salt thereof.
  • Embodiment 31 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 827, or a pharmaceutically acceptable salt thereof.
  • Embodiment 32 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 984, or a pharmaceutically acceptable salt thereof.
  • Embodiment 33 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 985, or a pharmaceutically acceptable salt thereof.
  • Embodiment 34 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 986, or a pharmaceutically acceptable salt thereof.
  • Embodiment 35 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 990, or a pharmaceutically acceptable salt thereof.
  • Embodiment 36 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1114, or a pharmaceutically acceptable salt thereof.
  • Embodiment 37 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1127, or a pharmaceutically acceptable salt thereof.
  • Embodiment 38 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 28, or a pharmaceutically acceptable salt thereof.
  • Embodiment 39 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 35, or a pharmaceutically acceptable salt thereof.
  • Embodiment 40 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 78, or a pharmaceutically acceptable salt thereof.
  • Embodiment 41 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 107, or a pharmaceutically acceptable salt thereof.
  • Embodiment 42 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 119, or a pharmaceutically acceptable salt thereof.
  • Embodiment 43 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 120, or a pharmaceutically acceptable salt thereof.
  • Embodiment 44 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 122, or a pharmaceutically acceptable salt thereof.
  • Embodiment 45 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 123, or a pharmaceutically acceptable salt thereof.
  • Embodiment 46 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 124, or a pharmaceutically acceptable salt thereof.
  • Embodiment 47 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 180, or a pharmaceutically acceptable salt thereof.
  • Embodiment 48 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 244, or a pharmaceutically acceptable salt thereof.
  • Embodiment 49 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 256, or a pharmaceutically acceptable salt thereof.
  • Embodiment 50 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of moeA*moeA*/5-Me-moeC/*/5-
  • Embodiment 51 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of moeG*/5-Me- moeC/*moeA*moeA*moeA*moeG*/5-Me-moeC/*moeA*/5-Me- moeC/*moeG*moeG*moeA*moeG*moeT*moeG*/5-Me-moeC/*moeA*moeA*/5-Me- moeC/*/5-Me-moeC/*/5-Me-moeC/*/5-Me-moeC//iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 475), or a pharmaceutically acceptable salt thereof.
  • Embodiment 52 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of moeG*moeG*moeG*moeA*moeG*/5-Me-moeC/*moeA*moeG*/5-Me- moeC/*moeT*moeA*moeG*moeA*moeG*moeG*moeT*moeT*moeA*moeG*moeA/iSpl8/ /iSpl8//3CholTEG/ (SEQ ID NO: 121), or a pharmaceutically acceptable salt thereof.
  • Embodiment 53 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of /5-Me- moeC/*moeA*moeG*moeG*/5-Me-moeC/*moeA*/5-Me-moeC/*moeT*/5-Me- moeC/* moeT * moeT*/5 -Me-moeC/* moeT * moeT*/5 -Me-moeC/* moeT * moeG*moeT*moeG*moeG*moeG*moeG*moeG/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 301), or a pharmaceutically acceptable salt thereof.
  • Embodiment 54 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of /5-Me- moeC/*moeT*moeG*moeG*moeT*moeG*moeG*/5-Me-moeC/*/5-Me-moeC/*moeA*/5- Me-moeC/*moeT*moeG*moeG*/5-Me-moeC/*/5-Me-moeC/*moeG*/5-Me- moeC/*moeA*moeG/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 361), or a pharmaceutically acceptable salt thereof.
  • Embodiment 55 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of /5-Me-moeC/*moeG*moeA*/5- Me-moeC/*/5-Me-moeC/*/5 -Me-moeC/*/5 -Me- moeC/*moeT*moeG*moeG*moeT*moeG*moeG*/5-Me-moeC/*/5-Me-moeC/*moeA*/5- Me-moeC/*moeT*moeG*moeG/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 368), or a pharmaceutically acceptable salt thereof.
  • Embodiment 56 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of moeG*moeG*moeT*moeG*/5- Me-moeC/*moeT*moeG*/5-Me-moeC/* moeG*moeG*/5-Me-moeC/*moeG*moeA*/5-Me- moeC/*/5-Me-moeC/*/5-Me-moeC/*/5-Me- moeC/*moeT*moeG*moeG/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 379), or a pharmaceutically acceptable salt thereof.
  • Embodiment 57 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of /5-Me-moeC/*moeG*/5-Me- moeC/*/5-Me-moeC/*moeA*moeG* moeG*moeA*moeG*moeG*/5-Me-moeC/*/5-Me- moeC/*moeG*moeG*/5-Me-moeC/*moeT*moeA*/5-Me- moeC/*moeT*moeA*/5-Me- moeC/*moeT*moeA*/5-Me- moeC/*moeT*moeA*/5-Me- moeC/*m
  • Embodiment 58 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of moeT*moeG*moeG*moeG*/5- Me-moeC/*moeT*moeG*moeG*moeG*/5-Me- moeC/*moeT*moeG*moeG*moeG*moeT*moeG*moeA*/5-Me-moeC/*moeG*/5-Me- moeC//iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 486), or a pharmaceutically acceptable salt thereof.
  • Embodiment 59 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of moeG*moeG*moeG*moeT*/5- Me-moeC/*moeT*moeG*moeG*moeG*/5-Me-moeC/*/5-Me- moeC/*moeT*moeG*moeG*moeG*/5-Me- moeC/*moeT*moeG*moeG*moeG*/5-Me- moeC/*moeT*moeG*moeG*moeG/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 498), or a pharmaceutically acceptable salt thereof.
  • Embodiment 60 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of /5-Me- moeC/*moeG*moeG*moeG*moeA*/5-Me-moeC/*/5-Me-moeC/*/5-Me- moeC/*moeG*moeG*moeT*moeG*moeA*moeG* moeG*moeG*moeT*/5-Me- moeC/*moeT/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 513), or a pharmaceutically acceptable salt thereof.
  • Embodiment 61 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of moeT*moeG*/5-Me-moeC/*/5- Me-moeC/*moeG*moeG*/5-Me-moeC/*/5-Me-moeC/*moeG*/5-Me- moeC/*moeG*moeG*moeG*moeA*/5-Me-moeC/*/5-Me-moeC/*/5-Me- moeC/*moeG*moeG*moeG/iSp 18//iSp 18//3CholTEG/ (SEQ ID NO: 523), or a pharmaceutically acceptable salt thereof.
  • Embodiment 62 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of moeG*moeG*/5-Me-moeC/*/5- Me-moeC/*moeG*/5-Me- moeC/*moeA*moeG*moeA*moeG*moeT*moeG*moeG*moeG*moeG*/5-Me-moeC/*/5- Me-moeC/*moeA*moeA*/5-Me-moeC//iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 548), or a pharmaceutically acceptable salt thereof.
  • Embodiment 63 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of moeG*/5-Me- moeC/*moeG*moeG*/5-Me-moeC/*/5-Me-moeC/*moeG*/5-Me- moeC/*moeA*moeG*moeA*moeG*moeT*moeG*moeG*moeG*moeG*/5-Me-moeC/*/5- Me-moeC/*moeA/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 550), or a pharmaceutically acceptable salt thereof.
  • Embodiment 64 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of /5-Me- moeC/*moeA*moeG*moeG*/5-Me-moeC/*/5-Me-moeC/*moeA*/5-Me- moeC/*moeG*moeG*/5-Me-moeC/*moeG*moeG*/5-Me-moeC/*/5-Me-moeC/*moeG*/5-Me-moeC/*/5-Me-moeC/*moeG*/5- Me-moeC/*moeA*moeG*moeA/iSpl8//iSpl8//3CholTEG
  • Embodiment 65 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of moeT*moeG*/5-Me- moeC/*moeG*/5-Me-moeC/*moeA*moeG*moeG*/5-Me-moeC/*/5-Me-moeC/*moeA*/5- Me-moeC/*moeG*moeG*/5-Me-moeC/*moeG*moeG*/5-Me-moeC/*/5-Me- moeC/*moeG/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 565), or a pharmaceutically acceptable salt thereof.
  • Embodiment 66 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of moeG*moeG*/5-Me- moeC/*moeG*moeG*moeG*moeG*/5-Me-moeC/*moeG*moeT*moeG*/5-Me- moeC/*moeA*moeG*moeG*moeT*/5-Me-moeC/*moeG*/5-Me- moeC/*moeA/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 598), or a pharmaceutically acceptable salt thereof.
  • Embodiment 67 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of /5-Me-moeC/*moeG*/5-Me- moeC/*moeG*moeG*/5-Me-moeC/*moeG* moeG*moeG*moeG*/5-Me- moeC/*moeG*moeT*moeG*/5-Me-moeC/*moeA*moeG*moeG*moeT*/5-Me- moeC//iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 601), or a pharmaceutically acceptable salt thereof.
  • Embodiment 68 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of /5-Me- moeC/*moeT*moeT*moeG*/5-Me-moeC/*moeG*/5-Me-moeC/*moeG*moeG*/5-Me- moeC/*moeG*moeG*moeG*moeG*/5-Me-moeC/*moeG*moeT*moeG*/5-Me- moeC/*moeA/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 605), or a pharmaceutically acceptable salt thereof.
  • Embodiment 69 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of moeT*moeG*moeG*moeG*moeT*moeG*moeG*/5-Me-moeC/*/5-Me-moeC/*/5-Me- moeC/*moeA*moeA*moeA*moeG*moeT*moeT*/5-Me-moeC/*/5-Me- moeC/*moeA*moeG/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 694), or a pharmaceutically acceptable salt thereof.
  • Embodiment 70 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of moeG*moeG*moeG*moeT*moeG*moeG*/5-Me-moeC/*/5-Me-moeC/*/5-Me- moeC/*moeA*moeA*moeA*moeG*moeT*moeT*/5-Me-moeC/*/5-Me- moeC/*moeA*moeG*moeA/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 693), or a pharmaceutically acceptable salt thereof.
  • Embodiment 71 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of /5-Me-moeC/*/5-Me- moeC/*moeT*moeG*moeG*moeG*moeT*moeG*moeG* /5-Me-moeC/*/5- Me-moeC/*moeA*moeA*moeA*moeG* moeT*moeT*/5-Me-moeC/*/5-Me- moeC//iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 696), or a pharmaceutically acceptable salt thereof.
  • Embodiment 72 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of moeG*moeA*moeG*/5-Me- moeC/*/5-Me-moeC/*moeT*moeG*moeG* moeG*moeT*moeG*moeG*/5-Me-moeC/*/5- Me-moeC/*/5-Me-moeC/*moeA*moeA*moeA*moeG*moeT/iSp 18//iSp 18//3CholTEG/ (SEQ ID NO: 699), or a pharmaceutically acceptable salt thereof.
  • Embodiment 73 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of /5-Me- moeC/*moeT*moeA*moeG*moeA*moeG*moeA*moeG*/5-Me-moeC/*/5-Me- moeC/*moeT*moeG*moeG*moeG*moeT*moeG*moeG*/5-Me-moeC/*/5-Me-moeC/*/5-Me-moeC/*/5-Me-moeC/*/5- Me-moeC//iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 704), or a pharmaceutically acceptable
  • Embodiment 74 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of /5-Me-moeC/*moeT*/5-Me- moeC/*moeA*moeT*/5-Me-moeC/*moeT*moeA*moeG*moeA*moeG*moeA*moeG*/5- Me-moeC/*/5-Me-moeC/*moeT*moeG*moeG*moeG*moeT/iSp 18//iSp 18//3CholTEG/ (SEQ ID NO: 708), or a pharmaceutically acceptable salt thereof.
  • Embodiment 75 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of moeG*moeG*moeT*/5-Me- moeC/*moeT*/5-Me-moeC/*moeA*moeT*/5-Me- moeC/*moeT*moeA*moeG*moeA*moeG*moeA*moeG*/5-Me-moeC/*/5-Me- moeC/*moeT*moeG/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 711), or a pharmaceutically acceptable salt thereof.
  • Embodiment 76 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of /5-Me-moeC/*moeT*/5-Me- moeC/* moeT * moeG*/5 -Me-moeC/* moeT* moe A * moeA*moeA*moeG*moeA*moeG*moeT*/5-Me-moeC/*/5-Me-moeC/*moeA*moeG*/5- Me-moeC/*moeG/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 756), or a pharmaceutically acceptable salt thereof.
  • Embodiment 77 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of /5-Me-moeC/*moeT*moeG*/5- Me-moeC/*moeT*moeA*moeA*moeA* moeG*moeA*moeG*moeT*/5-Me-moeC/*/5-Me- moeC/*moeA*moeG*/5-Me-moeC/*moeG*moeT*moeT/iSp 18//iSp 18//3CholTEG/ (SEQ ID NO: 755), or a pharmaceutically acceptable salt thereof.
  • Embodiment 78 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of moeA*moeA*/5-Me- moeC/*moeT*/5-Me-moeC/*moeT*moeG*/5-Me- moeC/*moeT*moeA*moeA*moeA*moeG*moeA*moeG*moeT*/5-Me-moeC/*/5-Me- moeC/*moeA*moeA*moeG/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 758), or a pharmaceutically acceptable salt thereof.
  • Embodiment 79 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of moeA*moeG*moeG*moeT*moeG*moeG*moeT*/5-Me-moeC/*moeT*/5-Me- moeC/* moe A* moeT */5 -Me- moeC/*moeT*moeA*moeG*moeA*moeG*moeA*moeG/iSp 18//iSp 18//3CholTEG/ (SEQ ID NO: 715), or a pharmaceutically acceptable salt thereof.
  • Embodiment 80 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of moeA*moeA*moeA*moeA*moeA*/5-Me-moeC/*moeT*/5-Me- moeC/*moeT*moeG*/5-Me- moeC/*moeT*moeA*moeA*moeA*moeG*moeA*moeG*moeA*moeG*moeT/iSp 18//iSp 18//3CholTEG/ (SEQ ID NO: 763), or a pharmaceutically acceptable salt thereof.
  • Embodiment 81 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of moeT*/5-Me-moeC/*/5-Me- moeC/*moeA*/5-Me-moeC/*/5 -Me-moeC/*/5 -Me- moeC/*moeA*moeG*moeT*moeT*moeT*moeG*moeA*/5-Me- moeC/*moeA*moeG*moeT*moeT*moeA*moeA*moeA*moeA/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 820), or a pharmaceutically acceptable salt thereof.
  • Embodiment 82 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of moeG*moeA*moeT*/5-Me- moeC/*moeT*/5 -Me-moeC/*/5 -Me-moeC/*moeA*/5 -Me-moeC/*/5 -Me-moeC/*/5-Me-moeC/*/5-Me- moeC/*moeA*moeG*moeT*moeT*moeT*moeG*moeA*/5-Me- moeC/*moeA/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 822), or a pharmaceutically acceptable salt thereof.
  • Embodiment 83 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of /5-Me-moeC/*/5-Me- moeC/*moeT*moeA*moeG*moeA*moeT*/5-Me-moeC/* moeT*/5-Me-moeC/*/5-Me- moeC/*moeA*/5-Me-moeC/*/5 -Me-moeC/*/5 -Me-moeC/*/5 -Me-moeC/*/5 -Me- moeC/*/5 -Me- moeC/*/5 -Me- moeC/*moeA*moeG*moeT*moeT*mo
  • Embodiment 84 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of moeA*moeA*moeG*moeA*moeT*moeA*moeG*/5-Me-moeC/*/5-Me- moeC/*moeA*moeG*moeA*moeT*moeT*moeT*moeG*/5-Me- moeC/*moeT*moeT*moeT*moeG*/5-Me- moeC/*moeT*moeT*moeG/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 882), or a pharmaceutically acceptable salt thereof.
  • Embodiment 85 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of moeG*moeG*moeT*/5-Me- moeC/*/5-Me-moeC/*moeA*/5-Me- moeC/*moeT*moeG*moeG*moeA*moeT*moeG*moeG*moeA*moeA*moeA*moeA*moeA*moeG*moeA*moeA*moeG*moeA*moeG*moeA*moeG*moeA*moeG*moeA*moeG*moeA*moeG*moeA*moeG*m
  • Embodiment 86 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of /5-Me-moeC/*moeT*moeG*/5- Me-moeC/*moeG*moeG*/5-Me-moeC/*/5-Me-moeC/*moeA*moeG*/5-Me- moeC/*moeA*moeG*/5-Me-moeC/*moeT*/5-Me- moeC/*moeA*moeT*moeG*moeG/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 984), or a pharmaceutically acceptable salt thereof.
  • Embodiment 87 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of moeT*/5-Me- moeC/*moeT*moeG*/5-Me-moeC/*moeG*moeG*/5-Me-moeC/*/5-Me- moeC/*moeA*moeG*/5-Me-moeC/*moeA*moeG*/5-Me-moeC/*moeT*/5-Me- moeC/*moeA*moeT*moeG/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 985), or a pharmaceutically acceptable salt thereof.
  • Embodiment 88 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of /5-Me-moeC/*moeT*/5-Me- moeC/*moeT*moeG*/5-Me-moeC/*moeG*moeG* /5-Me-moeC/*/5-Me- moeC/*moeA*moeG*/5-Me-moeC/*moeA*moeG*/5-Me-moeC/*moeT*/5-Me- moeC/*moeA*moeT/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 986), or a pharmaceutically acceptable salt thereof.
  • Embodiment 89 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of moeG*moeA*moeG*/5-Me- moeC/*moeT*/5-Me-moeC/*moeT*moeG*/5-Me-moeC/*moeG*moeG*/5-Me-moeC/*/5- Me-moeC/*moeA*moeG*/5-Me-moeC/*moeA*moeG*/5-Me- moeC/*moeT/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 990), or a pharmaceutically acceptable salt thereof.
  • Embodiment 90 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of moeG*moeT*moeT*moeG*moeG*moeT*moeT*moeT*moeT*moeT*moeT*moeA*moeA* moeG*moeG*/5-Me-moeC/*moeT*moeT*moeT*moeA/iSp 18//iSp 18//3CholTEG/ (SEQ ID NO: 1014), or a pharmaceutically acceptable salt thereof.
  • Embodiment 91 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of moeT*moeG*moeG*moeG*moeG*moeT*/5-Me-moeC/*moeT*moeT*moeG* moeG*/5- Me-moeC/*/5-Me-moeC/*moeT*moeG*moeA* moeT*moeA*moeG*/5-Me- moeC//iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 1114), or a pharmaceutically acceptable salt thereof.
  • Embodiment 92 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of moeG*/5-Me- moeC/*moeA*moeT*moeA*moeA*moeT*moeG*moeA* moeA*moeG*/5-Me- moeC/*moeT*moeG*moeG*moeG*moeG*moeT*/5-Me- moeC/*moeT*moeG*moeG*moeG*moeT*/5-Me- moeC/*moeT/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 1127), or a pharmaceutically acceptable salt thereof.
  • Embodiment 93 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of /5-Me- moeC/*moeA*moeG*moeA*moeA*/5-Me- moeC/*moeT*moeT*moeG*moeG*moeG*moeG*moeG*/5-Me- moeC/*moeA*moeA*moeG*moeG*moeT*moeA/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO:
  • Embodiment 94 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of moeT*moeA*moeA*moeA*moeA*moeT*/5-Me-moeC/*moeA*moeG* moeA*moeA*/5-Me-moeC/*moeT*moeT*moeG*moeG*moeG*moeG* moeG/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 35), or a pharmaceutically acceptable salt thereof.
  • Embodiment 95 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of moeG*moeA*moeG*moeG*moeG*moeA*moeG*moeA*moeA*moeA*moeA*moeT*/5-
  • Embodiment 96 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of /5-Me- moeC/*moeA*moeT*moeT*moeA*moeT*moeA*moeA*moeA*moeA* moeG*moeA*moeT*moeA*moeA*moeG*moeG*moeG*moeG*moeG*moeG*moeG*moeT /iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 107), or a pharmaceutically acceptable salt thereof.
  • Embodiment 97 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of moeA*moeG*moeG*/5-Me- moeC/*moeA*moeT*moeA*moeA*moeG*moeA*/5-Me- moeC/*moeA*moeT*moeA*moeT*moeA*moeA*moeA*moeA*moeA*moeA*moeA*moeA /iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 119), or a pharmaceutically acceptable salt thereof.
  • Embodiment 98 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of moeT*moeA*moeG*moeG*/5- Me-moeC/*moeA*moeT*moeA*moeA* moeG*moeA*/5-Me- moeC/*moeA*moeT*moeT*moeA*moeT*moeA*moeA* moeA/iSp 18//iSp 18//3CholTEG/ (SEQ ID NO: 120), or a pharmaceutically acceptable salt thereof.
  • Embodiment 99 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of moeA*moeT*moeA*moeG*moeG*/5-Me-moeC/*moeA*moeT*moeA*moeA* moeG*moeA*/5-Me-moeC/*moeA*moeT*moeT*moeA*moeT*moeA*moeA*moeA*moeA*moeA*moeA*moeA*moeA*moeA /iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 122), or a pharmaceutically acceptable salt thereof.
  • Embodiment 100 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of moeG*moeT*moeA*moeT*moeA*moeG*moeG*/5-Me- moeC/*moeA*moeT*moeA*moeA*moeG*moeA*/5-Me- moeC/*moeA*moeT*moeT*moeT/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 123), or a pharmaceutically acceptable salt thereof.
  • Embodiment 101 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of moeG*moeG*moeT*moeA*moeT*moeA*moeG*moeG*/5-Me- moeC/*moeA*moeT*moeA*moeA*moeG*moeA*/5-Me- moeC/*moeA*moeT*moeT*moeA/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 124), or a pharmaceutically acceptable salt thereof.
  • Embodiment 102 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of /5-Me- moeC/*moeT*moeG*moeG*moeA*moeA*moeT*moeT*moeT*moeT* moeT*/5-Me- moeC/*/5-Me-moeC/*moeT*moeT*/5-Me- moeC/*moeT*moeT*moeT*moeA*moeT/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 180), or a pharmaceutically acceptable salt thereof.
  • Embodiment 103 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of moeT*moeT*/5-Me- moeC/*moeA*moeT*moeG*moeT*moeA*/5-Me-moeC/*moeT*moeT*/5-Me- moeC/*moeT*moeT*moeG*/5-Me- moeC/*moeA*moeG*moeT*moeA/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 244), or a pharmaceutically acceptable salt thereof.
  • Embodiment 104 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of moeA*/5-Me-moeC/*/5-Me- moeC/*moeT*moeT*/5-Me-moeC/* moeA*moeT*moeG*moeT*moeA*/5-Me- moeC//iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 256), or a pharmaceutically acceptable salt thereof.
  • Embodiment 105 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1402, or a pharmaceutically acceptable salt thereof.
  • Embodiment 106 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1403, or a pharmaceutically acceptable salt thereof.
  • Embodiment 107 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1404, or a pharmaceutically acceptable salt thereof.
  • Embodiment 108 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1405, or a pharmaceutically acceptable salt thereof.
  • Embodiment 109 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1406, or a pharmaceutically acceptable salt thereof.
  • Embodiment 110 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1407, or a pharmaceutically acceptable salt thereof.
  • Embodiment lll A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1408, or a pharmaceutically acceptable salt thereof.
  • Embodiment 112 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1409, or a pharmaceutically acceptable salt thereof.
  • Embodiment 113 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1410, or a pharmaceutically acceptable salt thereof.
  • Embodiment 114 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1411, or a pharmaceutically acceptable salt thereof.
  • Embodiment 115 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1412, or a pharmaceutically acceptable salt thereof.
  • Embodiment 116 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1413, or a pharmaceutically acceptable salt thereof.
  • Embodiment 117 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1414, or a pharmaceutically acceptable salt thereof.
  • Embodiment 118 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1415, or a pharmaceutically acceptable salt thereof.
  • Embodiment 119 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1416, or a pharmaceutically acceptable salt thereof.
  • Embodiment 120 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1417, or a pharmaceutically acceptable salt thereof.
  • Embodiment 121 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1418, or a pharmaceutically acceptable salt thereof.
  • Embodiment 122 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1419, or a pharmaceutically acceptable salt thereof.
  • Embodiment 123 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1420, or a pharmaceutically acceptable salt thereof.
  • Embodiment 124 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1421, or a pharmaceutically acceptable salt thereof.
  • Embodiment 125 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1422, or a pharmaceutically acceptable salt thereof.
  • Embodiment 126 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1423, or a pharmaceutically acceptable salt thereof.
  • Embodiment 127 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1424, or a pharmaceutically acceptable salt thereof.
  • Embodiment 128 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1425, or a pharmaceutically acceptable salt thereof.
  • Embodiment 129 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeC*moeG*moeC*moeC*moeG*T*G*G*C*C*T*G*C*G*C*moeA*moeC*moeC*moeG
  • Embodiment 130 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeG*moeG*moeC*moeC*moeG*C*C*G*T*G*G*C*C*T*G*moeC*moeG*moeC*moeA
  • Embodiment 131 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeC*moeC*moeG*moeG*moeG*T*C*C*C*G*G*G*C*C*moeG*moeG*moeC*moeA
  • Embodiment 132 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeG*moeG*moeC*moeC*moeT*C*C*T*G*G*C*G*T*C*A*moeC*moeC*moeC*moeA
  • Embodiment 133 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeG*moeC*moeG*moeC*moeA*G*T*A*G*C*C*G*G*C*C*moeT*moeC*moeC*moeT
  • Embodiment 134 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeG*moeG*moeA*moeG*moeC*G*G*G*C*G*G*C*A*G*A*moeC*moeC*moeC*moe G*moeG*moeT*moeA*moeA/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 1407), or a pharmaceutically acceptable salt thereof.
  • Embodiment 135. A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeG*moeG*moeG*moeC*moeG*G*A*G*C*G*G*G*C*G*G*moeC*moeA*moeG*moe A*moeC*moeA*moeA*moeA/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 1408), or a pharmaceutically acceptable salt thereof.
  • Embodiment 136 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeT*moeG*moeG*moeA*moeG*G*G*C*G*G*A*G*C*G*G*G*moeG*moeC*moeG*moe G*moeC*moeT*moeA*moeT/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 1409), or a pharmaceutically acceptable salt thereof.
  • Embodiment 137 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeG*moeC*moeT*moeG*moeG*A*G*G*G*C*G*G*A*G*C*moeG*moeG*moe C*moeG*moeA*moeA*moeT/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 1410), or a pharmaceutically acceptable salt thereof.
  • Embodiment 138 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeC*moeC*moeA*moeG*moeT*G*G*C*C*A*C*C*A*G*G*moeG*moeT*moeC * moeG*moeA*moeA*moeA/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 1411), or a pharmaceutically acceptable salt thereof.
  • Embodiment 139 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeG*moeC*moeG*moeG*moeC*C*A*G*T*G*G*C*C*A*C*moeC*moeA*moeG*moe G* moeG*moeA*moeA*moeA/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 1412), or a pharmaceutically acceptable salt thereof.
  • Embodiment 140 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeG*moeT*moeG*moeC*moeC*T*G*C*G*G*C*C*A*G*T*moeG*moeG*moeC*moeC * moeA*moeA*moeA*moeT/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 1413), or a pharmaceutically acceptable salt thereof.
  • Embodiment 141 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeG*moeA*moeG*moeT*moeG*C*C*T*G*C*G*G*C*C*A*moeG*moeT*moeG*moeG*moeG
  • Embodiment 142 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeG*moeG*moeC*moeT*moeG*C*A*G*T*C*T*C*C*T*moeT*moeG*moeG*moeG*moeG*moeG*moeG*moeG*moeG*moeG*moeG*moeG*moeG*moeG*moeG*moeG*moeG*moeG
  • Embodiment 143 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeC*moeG*moeG*moeC*moeG*G*G*C*C*A*C*C*A*G*G*moeC*moeT*moeG*moe C* moeA*moeA*moeA*moeA/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 1416), or a pharmaceutically acceptable salt thereof.
  • Embodiment 144 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeG*moeA*moeA*moeG*moeC*G*G*C*G*G*G*C*C*A*C*moeC*moeA*moeG*moe G*moeC*moeA*moeA*moeA/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 1417), or a pharmaceutically acceptable salt thereof.
  • Embodiment 145 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeT*moeC*moeC*moeT*moeC*C*T*G*T*T*T*A*G*A*A*moeT*moeT*moeT*moeT* moeA*moeA*moeT*moeT/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 1418), or a pharmaceutically acceptable salt thereof.
  • Embodiment 146 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeG*moeC*moeA*moeG*moeC*T*C*C*C*A*A*G*T*T*C*moeC*moeT*moeC*moeC*moeC*moeC*moeC*moeC*moeC*moeC*moeC*moeC*moeC*moeC*moeC
  • Embodiment 147 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeG*moeT*moeG*moeC*moeA*T*G*C*A*C*C*C*A*C*T*moeT*moeC*moeC*moeC*moeC*moeC*moeC*moeC*moeC*moeC*moeC*moeC*moeC*moeC*moeC*moeC*moeC*moeC*moeC*moeC*moeC*moeC*moeC*moeC*moeC
  • Embodiment 148 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeC*moeC*moeC*moeA*moeA*C*T*G*C*T*G*T*A*A*moeC*moeC*moeC*moeC*moeAmoeA
  • Embodiment 149 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeC*moeA*moeA*moeG*moeG*C*A*T*C*C*G*T*C*T*C*moeC*moeT*moeG*moeG*moeG
  • Embodiment 150 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeA*moeG*moeA*moeT*moeT*T*A*C*A*C*A*A*G*G*C*moeA*moeT*moeC*moeC*moeC*moeC
  • Embodiment 151 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeC*moeA*moeG*moeA*moeG*T*A*C*A*G*A*T*T*A*moeC*moeA*moeC*moeA*moeC*moeA*moeA*moeA*moeA*moeA*moeA*moeA*moeA*moeA*moeA*moeA*moeA*moeA*moeA*moeA*moeA*moeA*moeA*moeA*moeA*moeA*moeA*moeA*moeA
  • Embodiment 152 * moeA*moeA*moeA*moeA*moeA/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 1424), or a pharmaceutically acceptable salt thereof.
  • a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeG*moeG*moeG*moeC*moeA*G*A*G*T*A*C*A*G*A*T*moeT*moeA*moeC * moeA*moeA*moeT*moeT/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 1425), or a pharmaceutically acceptable salt thereof.
  • Embodiment 153 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof.
  • Embodiment 154 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1350, or a pharmaceutically acceptable salt thereof.
  • Embodiment 155 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1351, or a pharmaceutically acceptable salt thereof.
  • Embodiment 156 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1352, or a pharmaceutically acceptable salt thereof.
  • Embodiment 157 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 5, or a pharmaceutically acceptable salt thereof.
  • Embodiment 158 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1353, or a pharmaceutically acceptable salt thereof.
  • Embodiment 159 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 6, or a pharmaceutically acceptable salt thereof.
  • Embodiment 160 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:7, or a pharmaceutically acceptable salt thereof.
  • Embodiment 16 E A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1354, or a pharmaceutically acceptable salt thereof.
  • Embodiment 162 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1355, or a pharmaceutically acceptable salt thereof.
  • Embodiment 163 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:8, or a pharmaceutically acceptable salt thereof.
  • Embodiment 164 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:9, or a pharmaceutically acceptable salt thereof.
  • Embodiment 165 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 10, or a pharmaceutically acceptable salt thereof.
  • Embodiment 166 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 11, or a pharmaceutically acceptable salt thereof.
  • Embodiment 167 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 12, or a pharmaceutically acceptable salt thereof.
  • Embodiment 168 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 160, or a pharmaceutically acceptable salt thereof.
  • Embodiment 169 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1356, or a pharmaceutically acceptable salt thereof.
  • Embodiment 170 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1357, or a pharmaceutically acceptable salt thereof.
  • Embodiment 171 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 161, or a pharmaceutically acceptable salt thereof.
  • Embodiment 172 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 162, or a pharmaceutically acceptable salt thereof.
  • Embodiment 173 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 163, or a pharmaceutically acceptable salt thereof.
  • Embodiment 174 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 165, or a pharmaceutically acceptable salt thereof.
  • Embodiment 175. A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 166, or a pharmaceutically acceptable salt thereof.
  • Embodiment 176 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 192, or a pharmaceutically acceptable salt thereof.
  • Embodiment 177 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1358, or a pharmaceutically acceptable salt thereof.
  • Embodiment 178 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 193, or a pharmaceutically acceptable salt thereof.
  • Embodiment 179 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 194, or a pharmaceutically acceptable salt thereof.
  • Embodiment 180 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 195, or a pharmaceutically acceptable salt thereof.
  • Embodiment 181 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 196, or a pharmaceutically acceptable salt thereof.
  • Embodiment 182 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 198, or a pharmaceutically acceptable salt thereof.
  • Embodiment 183 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:313, or a pharmaceutically acceptable salt thereof.
  • Embodiment 184 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1359, or a pharmaceutically acceptable salt thereof.
  • Embodiment 185 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:314, or a pharmaceutically acceptable salt thereof.
  • Embodiment 186 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:315, or a pharmaceutically acceptable salt thereof.
  • Embodiment 187 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:316, or a pharmaceutically acceptable salt thereof.
  • Embodiment 188 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:317, or a pharmaceutically acceptable salt thereof.
  • Embodiment 189 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:318, or a pharmaceutically acceptable salt thereof.
  • Embodiment 190 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:357, or a pharmaceutically acceptable salt thereof.
  • Embodiment 191 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1360, or a pharmaceutically acceptable salt thereof.
  • Embodiment 192 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1361, or a pharmaceutically acceptable salt thereof.
  • Embodiment 193 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1362, or a pharmaceutically acceptable salt thereof.
  • Embodiment 194. A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:358, or a pharmaceutically acceptable salt thereof.
  • Embodiment 195 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:359, or a pharmaceutically acceptable salt thereof.
  • Embodiment 196 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:360, or a pharmaceutically acceptable salt thereof.
  • Embodiment 197 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:361, or a pharmaceutically acceptable salt thereof.
  • Embodiment 198 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:362, or a pharmaceutically acceptable salt thereof.
  • Embodiment 199 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:371, or a pharmaceutically acceptable salt thereof.
  • Embodiment 200 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1363, or a pharmaceutically acceptable salt thereof.
  • Embodiment 201 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1364, or a pharmaceutically acceptable salt thereof.
  • Embodiment 202 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1365, or a pharmaceutically acceptable salt thereof.
  • Embodiment 203 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:372, or a pharmaceutically acceptable salt thereof.
  • Embodiment 204 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:373, or a pharmaceutically acceptable salt thereof.
  • Embodiment 205 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:374, or a pharmaceutically acceptable salt thereof.
  • Embodiment 206 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:375, or a pharmaceutically acceptable salt thereof.
  • Embodiment 207 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:376, or a pharmaceutically acceptable salt thereof.
  • Embodiment 208 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:394, or a pharmaceutically acceptable salt thereof.
  • Embodiment 209 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1366, or a pharmaceutically acceptable salt thereof.
  • Embodiment 210 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1367, or a pharmaceutically acceptable salt thereof.
  • Embodiment 211 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1368, or a pharmaceutically acceptable salt thereof.
  • Embodiment 212 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:395, or a pharmaceutically acceptable salt thereof.
  • Embodiment 21 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:396, or a pharmaceutically acceptable salt thereof.
  • Embodiment 214 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:397, or a pharmaceutically acceptable salt thereof.
  • Embodiment 215. A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:399, or a pharmaceutically acceptable salt thereof.
  • Embodiment 216 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:400, or a pharmaceutically acceptable salt thereof.
  • Embodiment 217 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:401, or a pharmaceutically acceptable salt thereof.
  • Embodiment 218 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1369, or a pharmaceutically acceptable salt thereof.
  • Embodiment 21 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1370, or a pharmaceutically acceptable salt thereof.
  • Embodiment 220 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1371, or a pharmaceutically acceptable salt thereof.
  • Embodiment 22 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:402, or a pharmaceutically acceptable salt thereof.
  • Embodiment 222 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:403, or a pharmaceutically acceptable salt thereof.
  • Embodiment 223 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:404, or a pharmaceutically acceptable salt thereof.
  • Embodiment 224 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:405, or a pharmaceutically acceptable salt thereof.
  • Embodiment 225 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:420, or a pharmaceutically acceptable salt thereof.
  • Embodiment 226 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:444, or a pharmaceutically acceptable salt thereof.
  • Embodiment 227 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:466, or a pharmaceutically acceptable salt thereof.
  • a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:487, or a pharmaceutically acceptable salt thereof.
  • Embodiment 229. A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:509, or a pharmaceutically acceptable salt thereof.
  • Embodiment 230 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:532, or a pharmaceutically acceptable salt thereof.
  • Embodiment 23 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:554, or a pharmaceutically acceptable salt thereof.
  • Embodiment 232 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:576, or a pharmaceutically acceptable salt thereof.
  • Embodiment 233 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 598, or a pharmaceutically acceptable salt thereof.
  • Embodiment 23 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:612, or a pharmaceutically acceptable salt thereof.
  • Embodiment 235 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1372, or a pharmaceutically acceptable salt thereof.
  • Embodiment 236 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:618, or a pharmaceutically acceptable salt thereof.
  • Embodiment 237 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:638, or a pharmaceutically acceptable salt thereof.
  • Embodiment 238 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:656, or a pharmaceutically acceptable salt thereof.
  • Embodiment 23 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:674, or a pharmaceutically acceptable salt thereof.
  • Embodiment 240 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:693, or a pharmaceutically acceptable salt thereof.
  • Embodiment 241 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:704, or a pharmaceutically acceptable salt thereof.
  • Embodiment 242 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1373, or a pharmaceutically acceptable salt thereof.
  • Embodiment 243 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:712, or a pharmaceutically acceptable salt thereof.
  • Embodiment 244 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:734, or a pharmaceutically acceptable salt thereof.
  • Embodiment 245. A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:754, or a pharmaceutically acceptable salt thereof.
  • Embodiment 246 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:787, or a pharmaceutically acceptable salt thereof.
  • Embodiment 247 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1374, or a pharmaceutically acceptable salt thereof.
  • Embodiment 248 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:804, or a pharmaceutically acceptable salt thereof.
  • Embodiment 249. A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1375, or a pharmaceutically acceptable salt thereof.
  • Embodiment 250 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:813, or a pharmaceutically acceptable salt thereof.
  • Embodiment 251 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1376, or a pharmaceutically acceptable salt thereof.
  • Embodiment 252 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:814, or a pharmaceutically acceptable salt thereof.
  • Embodiment 253 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 833, or a pharmaceutically acceptable salt thereof.
  • Embodiment 254 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1377, or a pharmaceutically acceptable salt thereof.
  • Embodiment 255 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:835, or a pharmaceutically acceptable salt thereof.
  • Embodiment 256 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:857, or a pharmaceutically acceptable salt thereof.
  • Embodiment 257 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:881, or a pharmaceutically acceptable salt thereof.
  • Embodiment 258 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1378, or a pharmaceutically acceptable salt thereof.
  • Embodiment 25 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:882, or a pharmaceutically acceptable salt thereof.
  • Embodiment 260 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:898, or a pharmaceutically acceptable salt thereof.
  • Embodiment 261 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1379, or a pharmaceutically acceptable salt thereof.
  • Embodiment 262. A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:899, or a pharmaceutically acceptable salt thereof.
  • Embodiment 263 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:924, or a pharmaceutically acceptable salt thereof.
  • Embodiment 264 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1380, or a pharmaceutically acceptable salt thereof.
  • Embodiment 265. A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:925, or a pharmaceutically acceptable salt thereof.
  • Embodiment 266 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:948, or a pharmaceutically acceptable salt thereof.
  • Embodiment 267 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1381, or a pharmaceutically acceptable salt thereof.
  • Embodiment 268 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:949, or a pharmaceutically acceptable salt thereof.
  • Embodiment 269. A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:968, or a pharmaceutically acceptable salt thereof.
  • Embodiment 270 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1382, or a pharmaceutically acceptable salt thereof.
  • Embodiment 271 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:969, or a pharmaceutically acceptable salt thereof.
  • Embodiment 272 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:991, or a pharmaceutically acceptable salt thereof.
  • Embodiment 273 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1383, or a pharmaceutically acceptable salt thereof.
  • Embodiment 274 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO:992, or a pharmaceutically acceptable salt thereof.
  • Embodiment 275 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1009, or a pharmaceutically acceptable salt thereof.
  • Embodiment 276 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1384, or a pharmaceutically acceptable salt thereof.
  • Embodiment 277 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1385, or a pharmaceutically acceptable salt thereof.
  • Embodiment 278 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1010, or a pharmaceutically acceptable salt thereof.
  • Embodiment 279. A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1012, or a pharmaceutically acceptable salt thereof.
  • Embodiment 280 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1013, or a pharmaceutically acceptable salt thereof.
  • Embodiment 281 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1014, or a pharmaceutically acceptable salt thereof.
  • Embodiment 282 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1386, or a pharmaceutically acceptable salt thereof.
  • Embodiment 283 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1015, or a pharmaceutically acceptable salt thereof.
  • Embodiment 284 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1038, or a pharmaceutically acceptable salt thereof.
  • Embodiment 285. A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1387, or a pharmaceutically acceptable salt thereof.
  • Embodiment 286 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1039, or a pharmaceutically acceptable salt thereof.
  • Embodiment 287 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1059, or a pharmaceutically acceptable salt thereof.
  • Embodiment 288 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1388, or a pharmaceutically acceptable salt thereof.
  • Embodiment 289. A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1060, or a pharmaceutically acceptable salt thereof.
  • Embodiment 290 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1082, or a pharmaceutically acceptable salt thereof.
  • Embodiment 29 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1389, or a pharmaceutically acceptable salt thereof.
  • Embodiment 292 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1083, or a pharmaceutically acceptable salt thereof.
  • Embodiment 293 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1105, or a pharmaceutically acceptable salt thereof.
  • Embodiment 294 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1390, or a pharmaceutically acceptable salt thereof.
  • Embodiment 295. A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1106, or a pharmaceutically acceptable salt thereof.
  • Embodiment 296 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1113, or a pharmaceutically acceptable salt thereof.
  • Embodiment 297 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1391, or a pharmaceutically acceptable salt thereof.
  • Embodiment 298 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1392, or a pharmaceutically acceptable salt thereof.
  • Embodiment 29 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1114, or a pharmaceutically acceptable salt thereof.
  • Embodiment 300 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1115, or a pharmaceutically acceptable salt thereof.
  • Embodiment 301 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1116, or a pharmaceutically acceptable salt thereof.
  • Embodiment 302. A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1117, or a pharmaceutically acceptable salt thereof.
  • Embodiment 303 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1118, or a pharmaceutically acceptable salt thereof.
  • Embodiment 304 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1126, or a pharmaceutically acceptable salt thereof.
  • Embodiment 305 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1393, or a pharmaceutically acceptable salt thereof.
  • Embodiment 306 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1394, or a pharmaceutically acceptable salt thereof.
  • Embodiment 307 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1127, or a pharmaceutically acceptable salt thereof.
  • Embodiment 308 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1128, or a pharmaceutically acceptable salt thereof.
  • Embodiment 309 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1129, or a pharmaceutically acceptable salt thereof.
  • Embodiment 310 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1130, or a pharmaceutically acceptable salt thereof.
  • Embodiment 311 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1131, or a pharmaceutically acceptable salt thereof.
  • Embodiment 312 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1136, or a pharmaceutically acceptable salt thereof.
  • Embodiment 313. A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1395, or a pharmaceutically acceptable salt thereof.
  • Embodiment 31 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1137, or a pharmaceutically acceptable salt thereof.
  • Embodiment 315 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1162, or a pharmaceutically acceptable salt thereof.
  • Embodiment 316 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1396, or a pharmaceutically acceptable salt thereof.
  • Embodiment 317 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1163, or a pharmaceutically acceptable salt thereof.
  • Embodiment 318 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1191, or a pharmaceutically acceptable salt thereof.
  • Embodiment 319 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1397, or a pharmaceutically acceptable salt thereof.
  • Embodiment 320 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1192, or a pharmaceutically acceptable salt thereof.
  • Embodiment 32 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1216, or a pharmaceutically acceptable salt thereof.
  • Embodiment 322 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1398, or a pharmaceutically acceptable salt thereof.
  • Embodiment 323 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1217, or a pharmaceutically acceptable salt thereof.
  • Embodiment 324 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1579, or a pharmaceutically acceptable salt thereof.
  • Embodiment 325 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1399, or a pharmaceutically acceptable salt thereof.
  • Embodiment 326 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1400, or a pharmaceutically acceptable salt thereof.
  • Embodiment 327 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1400, or a pharmaceutically acceptable salt thereof.
  • Embodiment 328 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1401, or a pharmaceutically acceptable salt thereof.
  • Embodiment 329 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1401, or a pharmaceutically acceptable salt thereof.
  • Embodiment 330 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1402, or a pharmaceutically acceptable salt thereof.
  • Embodiment 33 E A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1403, or a pharmaceutically acceptable salt thereof.
  • Embodiment 332 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1404, or a pharmaceutically acceptable salt thereof.
  • Embodiment 333 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1405, or a pharmaceutically acceptable salt thereof.
  • Embodiment 334 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1406, or a pharmaceutically acceptable salt thereof.
  • Embodiment 335 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1407, or a pharmaceutically acceptable salt thereof.
  • Embodiment 336 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1408, or a pharmaceutically acceptable salt thereof.
  • Embodiment 337 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1409, or a pharmaceutically acceptable salt thereof.
  • Embodiment 338 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1410, or a pharmaceutically acceptable salt thereof.
  • Embodiment 339 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1411, or a pharmaceutically acceptable salt thereof.
  • Embodiment 340 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1412, or a pharmaceutically acceptable salt thereof.
  • Embodiment 341 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1413, or a pharmaceutically acceptable salt thereof.
  • Embodiment 342. A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1414, or a pharmaceutically acceptable salt thereof.
  • Embodiment 343 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1415, or a pharmaceutically acceptable salt thereof.
  • Embodiment 344 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1416, or a pharmaceutically acceptable salt thereof.
  • Embodiment 345 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1417, or a pharmaceutically acceptable salt thereof.
  • Embodiment 346 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1418, or a pharmaceutically acceptable salt thereof.
  • Embodiment 347 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1419, or a pharmaceutically acceptable salt thereof.
  • Embodiment 348 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1420, or a pharmaceutically acceptable salt thereof.
  • Embodiment 349 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1402, or a pharmaceutically acceptable salt thereof.
  • Embodiment 350 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1403, or a pharmaceutically acceptable salt thereof.
  • Embodiment 351 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1404, or a pharmaceutically acceptable salt thereof.
  • Embodiment 352 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1405, or a pharmaceutically acceptable salt thereof.
  • Embodiment 353 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1406, or a pharmaceutically acceptable salt thereof.
  • Embodiment 354 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1407, or a pharmaceutically acceptable salt thereof.
  • Embodiment 355. A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1408, or a pharmaceutically acceptable salt thereof.
  • Embodiment 356 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1409, or a pharmaceutically acceptable salt thereof.
  • Embodiment 357 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1410, or a pharmaceutically acceptable salt thereof.
  • Embodiment 358 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1411, or a pharmaceutically acceptable salt thereof.
  • Embodiment 359. A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1412, or a pharmaceutically acceptable salt thereof.
  • Embodiment 360 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1413, or a pharmaceutically acceptable salt thereof.
  • Embodiment 361 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1414, or a pharmaceutically acceptable salt thereof.
  • Embodiment 362 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1415, or a pharmaceutically acceptable salt thereof.
  • Embodiment 363 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1416, or a pharmaceutically acceptable salt thereof.
  • Embodiment 364. A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1417, or a pharmaceutically acceptable salt thereof.
  • Embodiment 365 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1418, or a pharmaceutically acceptable salt thereof.
  • Embodiment 366 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1419, or a pharmaceutically acceptable salt thereof.
  • Embodiment 367 A synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of an FXN gene and/or an FXN gene product, wherein the nucleic acid sequence does not comprise, consist essentially of or consist of the nucleic acid sequence of SEQ ID NO: 1420, or a pharmaceutically acceptable salt thereof.
  • Embodiment 368 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 598.
  • SNA spherical nucleic acid
  • Embodiment 369 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeG*moeG*/5-Me-moeC/*moeG*moeG*moeG*/5-Me- moeC/*moeG*moeT*moeG*/5-Me-moeC/*moeA*moeG*moeG*moeT*/5-Me- moeC/*moeA/moeG*moeG*moeT*/5-Me- moeC/*moeG
  • Embodiment 370 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 693.
  • SNA spherical nucleic acid
  • FXN frataxin
  • a spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeG*moeG*moeG*moeT*moeG*moeG*/5-Me-moeC/*/5-Me- moeC/*/5-Me-moeC/*moeA*moeA*moeA*moeG*moeT*moeT*/5-Me-moeC/*/5-Me- moeC/*moeA*moeA*moeG*moeT*moeT*/5-Me
  • Embodiment 372 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 704.
  • SNA spherical nucleic acid
  • Embodiment 373 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of /5-Me- moeC/*moeT*moeA*moeG*moeA*moeG*moeA*moeG*/5-Me-moeC/*/5-Me- moeC/*moeT*moeG*moeG*moeG*moeT*moeG*moeG*/5-Me-moeC/*/5-Me-moeC/*/5-Me- moeC/*m
  • Embodiment 374 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 882.
  • SNA spherical nucleic acid
  • a spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeA*moeA*moeG*moeA*moeT*moeA*moeG*/5-Me- moeC/*/5-Me-moeC/*moeA*moeG*moeT*moeT*moeT*moeT*moeG*/5-Me- moeC/*moeT*moeT*moeT*moeT*moeG*/5-Me- moeC/*moeT*m
  • Embodiment 376 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 899.
  • SNA spherical nucleic acid
  • Embodiment 377 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeG*moeG*moeT*/5-Me-moeC/*/5-Me-moeC/*moeA*/5-Me- moeC/*moeT*moeG*moeG*moeA*moeT*moeG*moeA*moeT*moeG*moeG*moeA*moeA*moeA*moeA*moeA*moeA*moeA
  • Embodiment 378 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1014.
  • SNA spherical nucleic acid
  • Embodiment 379 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeG*moeT*moeT*moeG*moeG*moeT*moeT*moeT*moeT*moeT*moeT*moeT*moeT*moeT*moeA* moeG*moeG*/5-Me-moeC/*moeT*moeT*moeT*moeA/iSp 18//iSp 18//3CholTEG/ (SEQ ID
  • Embodiment 380 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1404.
  • SNA spherical nucleic acid
  • Embodiment 38 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeC*moeC*moeG*moeG*moeG*T*C*C*C*G*G*G*C*C*moeG*moeC*moeA * moeG*moeT*moeA*moeA/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 1404).
  • SNA spherical nucleic acid
  • Embodiment 382 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1408.
  • SNA spherical nucleic acid
  • Embodiment 383 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeG*moeG*moeG*moeC*moeG*G*A*G*C*G*G*G*G*G*moeC*moeA*moeG*moe A*moeC*moeA*moeA/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 1408).
  • SNA spherical nucleic acid
  • Embodiment 384 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1409.
  • SNA spherical nucleic acid
  • Embodiment 385 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeT*moeG*moeG*moeA*moeG*G*G*G*C*G*G*A*G*C*G*G*G*moeG*moeC*moeG*moe G*moeC*moeT*moeA*moeT/iSp 18//iSp 18//3CholTEG/ (SEQ ID NO: 1409).
  • SNA spherical nucleic acid
  • Embodiment 386 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1411.
  • SNA spherical nucleic acid
  • Embodiment 387 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeC*moeC*moeA*moeG*moeT*G*G*C*C*A*C*C*A*G*G*moeG*moeT*moeC * moeG*moeA*moeA/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 1411).
  • SNA spherical nucleic acid
  • Embodiment 388 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1412.
  • SNA spherical nucleic acid
  • Embodiment 389 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeG*moeC*moeG*moeG*moeC*C*A*G*T*G*G*C*C*A*C*moeC*moeA*moeG*moe G* moeG*moeA*moeA/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 1412).
  • SNA spherical nucleic acid
  • Embodiment 390 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1416.
  • SNA spherical nucleic acid
  • Embodiment 391 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeC*moeG*moeG*moeC*moeG*G*G*C*C*A*C*C*A*G*G*moeC*moeT*moeG*moe C* moeA*moeA*moeA*moeA/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 1416).
  • SNA spherical nucleic acid
  • Embodiment 392 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 28.
  • SNA spherical nucleic acid
  • FXN frataxin
  • a spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeC*moeA*moeG*moeA*moeA*moeC*moeT*moeT*moeG*moeG*/7deazaG/*moeG* moeG*moeC*moeA*moeA*moeG*moeG*moeT*moeA/iSp 18//iSp 18//3CholTEG/ (SEQ ID NO: 28).
  • Embodiment 394 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 122.
  • SNA spherical nucleic acid
  • Embodiment 395 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeA*moeT*moeA*moeG*moeG*moeC*moeA*moeT*moeA*moeG*moeA*moeC * moeA*moeT*moeT*moeA*moeT*moeA*moeA/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 122).
  • SNA spherical nucleic acid
  • Embodiment 396 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 256.
  • SNA spherical nucleic acid
  • Embodiment 397 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of lA*/iMe-dC/*lCA*G*lCT*G*lCT*/iMe-dC/*lTT*/iMe- dC/*lAT*G*lTA*lC/iSp 18//iSp 18//3CholTEG/ (SEQ ID NO: 256).
  • SNA spherical nucleic acid
  • Embodiment 398 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 693.
  • SNA spherical nucleic acid
  • Embodiment 399 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of lG*/7deazaG/*lGT*G*lG/iMe-dC/*/iMe- dC/*lCA*A*lAG*T*n7iMe-dC/*/iMe-dC/* 1 A*G*1 A/iSp 18//iSp 18//3 Choi TEG/ (SEQ ID NO: 693).
  • SNA spherical nucleic acid
  • Embodiment 400 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 715.
  • SNA spherical nucleic acid
  • Embodiment 401 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of lA*G*lGT*G*lGT*/iMe-dC/*lT/iMe-dC/*A*lT/iMe- dC/*T*lAG* A*lGA*lG/iSp 18/ /iSp 18//3CholTEG/ (SEQ ID NO: 715).
  • SNA spherical nucleic acid
  • Embodiment 402. A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1421.
  • SNA spherical nucleic acid
  • Embodiment 403. A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of moeC*moeCmoeCmoeAmoeA/iMe-dC/*T*G*/iMe- dC/*T*G*T*A*A*A*moeCmoeCmoeAmoeT/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 1421).
  • SNA spherical nucleic acid
  • Embodiment 404 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1422.
  • SNA spherical nucleic acid
  • Embodiment 405. A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of /CholTEG//iSpl8//iSpl8/moeCmoeAmoeAmoeGmoeG/iMe- dC/*A*T*/iMe-dC/*/iMe-dC/*G*T*/iMe-dC/*T*/iMe-dC/*moeCmoeTmoeG* moeC (SEQ ID NO: 1422).
  • Embodiment 406 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 2030.
  • SNA spherical nucleic acid
  • Embodiment 407 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of lG*lAlGT*A*/iMe-dC/*A*G*A*T*T*T*A*lClAlC /iSp 18//iSp 18//3CholTEG/ (SEQ ID NO: 2030).
  • SNA spherical nucleic acid
  • Embodiment 408 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 2031.
  • SNA spherical nucleic acid
  • Embodiment 409 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a synthetic oligonucleotide comprising a nucleic acid sequence complementary to a region of a frataxin (FXN) gene and/or an FXN gene product, wherein the synthetic oligonucleotide comprises, consist essentially of or consists of /CholTEG//iSpl8//iSpl8/lGlClAG*A*G*T*A* /iMe- dC/*A*G*A*T*lT*lT*lA (SEQ ID NO: 2031).
  • Embodiment 410 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1421 and the second nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 28.
  • SNA spherical nucleic acid
  • Embodiment 411 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first synthetic oligonucleotide comprises, consist essentially of or consists of moeC * moeCmoeCmoeAmoeA/iMe-dC/*T*G*/iMe- dC/*T*G*T*A*A*moeCmoeCmoeAmoeT/iSpl8//iSpl8//3C
  • Embodiment 412 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1421 and the second nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 122.
  • SNA spherical nucleic acid
  • Embodiment 413 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first synthetic oligonucleotide comprises, consist essentially of or consists of moeC * moeCmoeCmoeAmoeA/iMe-dC/*T*G*/iMe- dC/*T*G*T*A*A*moeCmoeCmoeAmoeT/iSpl8//iSpl8//3
  • SNA s
  • Embodiment 414 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1421 and the second nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 256.
  • SNA spherical nucleic acid
  • Embodiment 415 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first synthetic oligonucleotide comprises, consist essentially of or consists of moeC * moeCmoeCmoeAmoeA/iMe-dC/*T*G*/iMe- dC/*T*G*T*A*A*moeCmoeCmoeAmoeT/iSpl8//iSpl8//3
  • SNA s
  • Embodiment 416 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1421 and the second nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 693.
  • SNA spherical nucleic acid
  • Embodiment 417 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first synthetic oligonucleotide comprises, consist essentially of or consists of moeC * moeCmoeCmoeAmoeA/iMe-dC/*T*G*/iMe- dC/*T*G*T*A*A*moeCmoeCmoeAmoeT/iSpl8//iSpl8//3
  • SNA s
  • Embodiment 418 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1421 and the second nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 715.
  • SNA spherical nucleic acid
  • Embodiment 419 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first synthetic oligonucleotide comprises, consist essentially of or consists of moeC * moeCmoeCmoeAmoeA/iMe-dC/*T*G*/iMe- dC/*T*G*T*A*A*moeCmoeCmoeAmoeT/iSpl8//iSpl8//3
  • SNA s
  • Embodiment 420 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1422 and the second nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 28.
  • SNA spherical nucleic acid
  • Embodiment 421 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first synthetic oligonucleotide comprises, consist essentially of or consists of /CholTEG//iSpl8//iSpl8/moeCmoeAmoeAmoeGmoeG/iMe-dC/*A*T*/iMe-dC/*/iMe- dC/*G*T*/iMe-dC/*T*/
  • Embodiment 422 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1422 and the second nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 122.
  • SNA spherical nucleic acid
  • Embodiment 423 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first synthetic oligonucleotide comprises, consist essentially of or consists of /CholTEG//iSpl8//iSpl8/moeCmoeAmoeAmoeGmoeG/iMe-dC/*A*T*/iMe-dC/*/iMe- dC/*G*T*/iMe-dC/*T*/
  • Embodiment 424 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1422 and the second nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 256.
  • SNA spherical nucleic acid
  • Embodiment 425 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first synthetic oligonucleotide comprises, consist essentially of or consists of /CholTEG//iSpl8//iSpl8/moeCmoeAmoeAmoeGmoeG/iMe-dC/*A*T*/iMe-dC/*/iMe- dC/*G*T*/iMe-dC/*T*/
  • Embodiment 426 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1422 and the second nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 693.
  • SNA spherical nucleic acid
  • Embodiment 427 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first synthetic oligonucleotide comprises, consist essentially of or consists of /CholTEG//iSpl8//iSpl8/moeCmoeAmoeAmoeGmoeG/iMe-dC/*A*T*/iMe-dC/*/iMe- dC/*G*T*/iMe-dC/*T*/
  • Embodiment 428 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 1422 and the second nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 715.
  • SNA spherical nucleic acid
  • Embodiment 429 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first synthetic oligonucleotide comprises, consist essentially of or consists of /CholTEG//iSpl8//iSpl8/moeCmoeAmoeAmoeGmoeG/iMe-dC/*A*T*/iMe-dC/*/iMe- dC/*G*T*/iMe-dC/*T*/
  • Embodiment 430 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 2030 and the second nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 122.
  • SNA spherical nucleic acid
  • Embodiment 431 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first synthetic oligonucleotide comprises, consist essentially of or consists of 1G*1A1GT* A*/iMe-dC/* A*G* A*T*T* A*lClAlC/iSp 18//iSp 18//3CholTEG/ (SEQ ID NO: 2030) and the second synthetic oligonucleotide comprises, consist essentially of or consists of
  • Embodiment 432 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 2030 and the second nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 256.
  • SNA spherical nucleic acid
  • Embodiment 433 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first synthetic oligonucleotide comprises, consist essentially of or consists of 1G*1A1GT* A*/iMe-dC/* A*G* A*T*T*A*lClAlC/iSp 18//iSp 18//3CholTEG/ (SEQ ID NO: 2030) and the second synthetic oligonucleotide comprises, consist essentially of or consists of
  • Embodiment 434 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 2030 and the second nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 693.
  • SNA spherical nucleic acid
  • Embodiment 435 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first synthetic oligonucleotide comprises, consist essentially of or consists of 1G*1A1GT* A*/iMe-dC/* A*G* A*T*T* A*lClAlC/iSp 18//iSp 18//3CholTEG/ (SEQ ID NO: 2030) and the second synthetic oligonucleotide comprises, consist essentially of or consists of
  • Embodiment 436 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 2030 and the second nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 715.
  • SNA spherical nucleic acid
  • Embodiment 437 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first synthetic oligonucleotide comprises, consist essentially of or consists of 1G*1A1GT* A*/iMe-dC/* A*G* A*T*T* A*lClAlC/iSp 18//iSp 18//3CholTEG/ (SEQ ID NO: 2030) and the second synthetic oligonucleotide comprises, consist essentially of or consists of
  • Embodiment 438 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 2031 and the second nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 28.
  • SNA spherical nucleic acid
  • a spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first synthetic oligonucleotide comprises, consist essentially of or consists of /CholTEG//iSpl8//iSpl8/lGlClAG*A*G*T*A*/iMe-dC/*A*G*A*T*lT*lT*lA (SEQ ID NO: 2031) and the second synthetic oligonucleotide comprises, consist essentially of or consists of
  • Embodiment 440 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 2031 and the second nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 122.
  • SNA spherical nucleic acid
  • Embodiment 44 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first synthetic oligonucleotide comprises, consist essentially of or consists of /CholTEG//iSpl8//iSpl8/lGlClAG*A*G*T*A*/iMe-dC/*A*G*A*T*lT*lT*lA (SEQ ID
  • the second synthetic oligonucleotide comprises, consist essentially of or consists of moeA*moeT*moeA*moeG*moeG*moeC*moeA*moeT*moeA*moeA*moeG*moeA*moeC * moeA*moeT*moeT*moeA*moeA*moeA/iSpl8//iSpl8//3CholTEG/ (SEQ ID NO: 122).
  • Embodiment 442 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 2031 and the second nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 256.
  • SNA spherical nucleic acid
  • Embodiment 443 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first synthetic oligonucleotide comprises, consist essentially of or consists of /CholTEG//iSpl8//iSpl8/lGlClAG*A*G*T*A*/iMe-dC/*A*G*A*T*lT*lT*lA (SEQ ID NO: 2031) and the second synthetic oligonucleotide comprises, consist essentially
  • Embodiment 444 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 2031 and the second nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 693.
  • SNA spherical nucleic acid
  • Embodiment 445 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first synthetic oligonucleotide comprises, consist essentially of or consists of /CholTEG//iSpl8//iSpl8/lGlClAG*A*G*T*A*/iMe-dC/*A*G*A*T*lT*lT*lA (SEQ ID NO: 2031) and the second synthetic oligonucleotide comprises, consist essentially
  • Embodiment 446 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 2031 and the second nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 715.
  • SNA spherical nucleic acid
  • Embodiment 447 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first synthetic oligonucleotide comprises, consist essentially of or consists of /CholTEG//iSpl8//iSpl8/lGlClAG*A*G*T*A*/iMe-dC/*A*G*A*T*lT*lT*lA (SEQ ID NO: 2031) and the second synthetic oligonucleotide comprises, consist essentially
  • Embodiment 448 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 28 and the second nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 122.
  • SNA spherical nucleic acid
  • Embodiment 449 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first synthetic oligonucleotide comprises, consist essentially of or consists of moeC*moeA*moeG*moeA*moeA*moeC*moeT*moeT*moeG*moeG*/7deazaG/*moeG* moeG* moeG* moeG* moeC*moeA*moeA*m
  • Embodiment 450 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 28 and the second nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 256.
  • SNA spherical nucleic acid
  • Embodiment 45 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first synthetic oligonucleotide comprises, consist essentially of or consists of moeC*moeA*moeG*moeA*moeA*moeC*moeT*moeT*moeG*moeG*/7deazaG/*moeG* moeG* moeG* moeG*moeC*moeA*moeA*m
  • Embodiment 452 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 122 and the second nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 256.
  • SNA spherical nucleic acid
  • Embodiment 453 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first synthetic oligonucleotide comprises, consist essentially of or consists of moeA*moeT*moeA*moeG*moeG*moeC*moeA*moeT*moeA*moeA*moeG*moeA*moeC * moeA*moeT*moeT*moeT*moeT
  • Embodiment 454 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 693 and the second nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 28.
  • SNA spherical nucleic acid
  • Embodiment 455. A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first synthetic oligonucleotide comprises, consist essentially of or consists of lG*/7deazaG/*lGT*G*lG/iMe-dC/*/iMe-dC/*lCA*A*lAG*T*lT/iMe-dC/*/iMe- dC/*lA*G*lA/iSp 18//iSp 18//3C
  • Embodiment 456 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 693 and the second nucleic acid sequence comprises or consists of SEQ ID NO: 122.
  • SNA spherical nucleic acid
  • Embodiment 457 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first synthetic oligonucleotide comprises, consist essentially of or consists of lG*/7deazaG/*lGT*G*lG/iMe-dC/*/iMe-dC/*lCA*A*lAG*T*lT/iMe-dC/*/iMe- dC/*lA*G*lA/iSp 18//iSp 18//3C
  • Embodiment 458 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 693 and the second nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 256.
  • SNA spherical nucleic acid
  • Embodiment 45 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first synthetic oligonucleotide comprises, consist essentially of or consists of lG*/7deazaG/*lGT*G*lG/iMe-dC/*/iMe-dC/*lCA*A*lAG*T*lT/iMe-dC/*/iMe- dC/*lA*G*lA/iSp 18//iSp 18//3Chol
  • Embodiment 460 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 693 and the second nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 715.
  • SNA spherical nucleic acid
  • Embodiment 46 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first synthetic oligonucleotide comprises, consist essentially of or consists of lG*/7deazaG/*lGT*G*lG/iMe-dC/*/iMe-dC/*lCA*A*lAG*T*lT/iMe-dC/*/iMe- dC/*lA*G*lA/iSp 18//iSp 18//3Chol
  • Embodiment 462 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 715 and the second nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 28.
  • SNA spherical nucleic acid
  • Embodiment 463 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first synthetic oligonucleotide comprises, consist essentially of or consists of lA*G*lGT*G*lGT*/iMe-dC/*lT/iMe-dC/*A*lT/iMe- dC/*T*lAG* A*lGA*lG/iSp 18//iSp 18//3CholTEG/ (SEQ ID NO: 715)
  • Embodiment 464 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 715 and the second nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 122.
  • SNA spherical nucleic acid
  • Embodiment 465 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first synthetic oligonucleotide comprises, consist essentially of or consists of lA*G*lGT*G*lGT*/iMe-dC/*lT/iMe-dC/*A*lT/iMe- dC/*T*lAG* A*lGA*lG/iSp 18//iSp 18//3CholTEG/ (SEQ ID NO: 715)
  • Embodiment 466 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 715 and the second nucleic acid sequence comprises, consist essentially of or consists of SEQ ID NO: 256.
  • SNA spherical nucleic acid
  • Embodiment 467 A spherical nucleic acid (SNA) comprising a core and an oligonucleotide shell, wherein the oligonucleotide shell comprises a first synthetic oligonucleotide comprising a first nucleic acid sequence complementary to a first region of a frataxin (FXN) gene and/or an FXN gene product and a second synthetic oligonucleotide comprising a second nucleic acid sequence complementary to a second region of an FXN gene and/or an FXN gene product, wherein the first synthetic oligonucleotide comprises, consist essentially of or consists of lA*G*lGT*G*lGT*/iMe-dC/*lT/iMe-dC/*A*lT/iMe- dC/*T*lAG* A*lGA*lG/iSp 18//iSp 18//3CholTEG/ (SEQ ID NO: 715)
  • Embodiment 468 A pharmaceutical composition comprising a synthetic oligonucleotide of any one of Embodiments 1-367 or an SNA of any one of Embodiments 368-467.
  • Embodiment 469 A method of increasing frataxin (FXN) mRNA levels in a cell, the method comprising: contacting a cell comprising an FXN gene and/or an FXN gene product with a synthetic oligonucleotide of any one of Embodiments 1-367, an SNA of any one of Embodiments 368-467, or a pharmaceutical composition of Embodiment 468, to increase FXN mRNA levels in the cell relative to a reference level.
  • FXN frataxin
  • Embodiment 470 The method of Embodiment 469, wherein the increased FXN mRNA levels result in increased FXN protein levels in the cell relative to a reference level.
  • Embodiment 471 A method of treating a disease or disorder in a subject, the method comprising: administering to a subject in order to treat the disease or disorder in the subject an effective amount of a synthetic oligonucleotide of any one of Embodiments 1-367, an SNA of any one of Embodiments 368-467, or a pharmaceutical composition of Embodiment 468.
  • Embodiment 472 A method of increasing frataxin (FXN) mRNA levels in a cell, the method comprising: contacting a cell comprising an FXN gene and/or an FXN gene product with two or more synthetic oligonucleotides, two or more SNAs, or two or more pharmaceutical compositions, wherein each of the two or more synthetic oligonucleotides is a synthetic oligonucleotide of any one of Embodiments 1-367, each of the two or more SNAs is an SNA of any one of Embodiments 368-467, or each of the two or more pharmaceutical compositions is a pharmaceutical composition of Embodiment 468, to increase FXN mRNA levels in the cell relative to a reference level.
  • FXN frataxin
  • Embodiment 473 The method of Embodiment 472, wherein the increased FXN mRNA levels result in increased FXN protein levels in the cell relative to a reference level.
  • Embodiment 474 A method of treating a disease or disorder in a subject, the method comprising: administering to a subject in order to treat the disease or disorder in the subject an effective amount of two or more synthetic oligonucleotides, two or more SNAs, or two or more pharmaceutical compositions, wherein each of the two or more synthetic oligonucleotides is a synthetic oligonucleotide of any one of Embodiments 1-367, each of the two or more SNAs is an SNA of any one of Embodiments 368-467, or each of the two or more pharmaceutical compositions is a pharmaceutical composition of Embodiment 468.
  • Embodiment 475 The method of Embodiment 474, further comprising mixing the two or more synthetic oligonucleotides, the two or more SNAs, or the two or more pharmaceutical compositions prior to the administering step.
  • Embodiment 476 A method of preparing a composition for administration to a subject, the method comprising: combining two or more synthetic oligonucleotides, two or more SNAs, or two or more pharmaceutical compositions into a composition, to prepare the composition for administration to a subject, wherein the each of the two or more synthetic oligonucleotides is a synthetic oligonucleotide of any one of Embodiments 1-367, each of the two or more SNAs is an SNA of any one of Embodiments 368-467, or each of the two or more pharmaceutical compositions is a pharmaceutical composition of Embodiment 468.

Abstract

L'invention concerne des compositions et des procédés pour réguler l'expression d'un gène de frataxine (FXN) ou d'un produit génique de FXN. De telles compositions et procédés sont utiles, par exemple, pour traiter, prévenir ou soulager des maladies ou des troubles associés à une dysrégulation dans le gène de FXN ou l'expression du produit génique de FXN.
PCT/US2021/024922 2020-03-30 2021-03-30 Acides nucléiques sphériques (sna) pour la régulation de la frataxine WO2021202557A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11633503B2 (en) 2009-01-08 2023-04-25 Northwestern University Delivery of oligonucleotide-functionalized nanoparticles
US11696954B2 (en) 2017-04-28 2023-07-11 Exicure Operating Company Synthesis of spherical nucleic acids using lipophilic moieties
US11866700B2 (en) 2016-05-06 2024-01-09 Exicure Operating Company Liposomal spherical nucleic acid (SNA) constructs presenting antisense oligonucleotides (ASO) for specific knockdown of interleukin 17 receptor mRNA

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WO2012170771A1 (fr) * 2011-06-09 2012-12-13 Curna, Inc. Traitement des maladies associées à la frataxine (fxn) par inhibition de la transcription de l'anti-sens naturel de la fxn
WO2015023939A1 (fr) * 2013-08-16 2015-02-19 Rana Therapeutics, Inc. Compositions et procédés de modulation de l'expression de la frataxine
WO2018002783A1 (fr) * 2016-06-29 2018-01-04 Crispr Therapeutics Ag Matériels et méthodes de traitement de l'ataxie de friedreich et d'autres troubles associés
WO2019246409A1 (fr) * 2018-06-20 2019-12-26 Exicure, Inc. Acides nucléiques sphériques ciblant l'il-1 bêta

Patent Citations (4)

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Publication number Priority date Publication date Assignee Title
WO2012170771A1 (fr) * 2011-06-09 2012-12-13 Curna, Inc. Traitement des maladies associées à la frataxine (fxn) par inhibition de la transcription de l'anti-sens naturel de la fxn
WO2015023939A1 (fr) * 2013-08-16 2015-02-19 Rana Therapeutics, Inc. Compositions et procédés de modulation de l'expression de la frataxine
WO2018002783A1 (fr) * 2016-06-29 2018-01-04 Crispr Therapeutics Ag Matériels et méthodes de traitement de l'ataxie de friedreich et d'autres troubles associés
WO2019246409A1 (fr) * 2018-06-20 2019-12-26 Exicure, Inc. Acides nucléiques sphériques ciblant l'il-1 bêta

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11633503B2 (en) 2009-01-08 2023-04-25 Northwestern University Delivery of oligonucleotide-functionalized nanoparticles
US11866700B2 (en) 2016-05-06 2024-01-09 Exicure Operating Company Liposomal spherical nucleic acid (SNA) constructs presenting antisense oligonucleotides (ASO) for specific knockdown of interleukin 17 receptor mRNA
US11696954B2 (en) 2017-04-28 2023-07-11 Exicure Operating Company Synthesis of spherical nucleic acids using lipophilic moieties

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