Dosing regimens for antisense treatment of angelman syndrome

Abstract

Disclosed herein are methods for treating Angelman syndrome (AS) in a human subject in need thereof by administering at least one loading dose and one maintenance dose of an antisense compound (e.g., antisense compound comprising the nucleic acid sequence of SEQ ID NO: 1 or modified nucleic acid sequence of SEQ ID NO: 2). The disclosed methods achieve a concentration of the antisense compound in the brain that 1) is effective for treating or reducing symptoms of Angelman syndrome and 2) minimizes the risk of unwanted side effects (e.g., radiculopathy).

Description

DOSING REGIMENS FOR ANTISENSE TREATMENT OF ANGELMAN SYNDROME CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Application No.63 / 632,943, filed on April 11, 2024 and U.S. Provisional Application No.63 / 746,619, filed on January 17, 2025, the entire disclosures of each of which are hereby incorporated herein by reference in their entirety for all purposes. REFERENCE TO A SEQUENCE LISTING

[0002] This contains a Sequence Listing which has been submitted electronically in XML format. The Sequence Listing XML is incorporated herein by reference. Said XML file, created April 1, 2025, is named ULTA-032WO_SL, and is 11,075 bytes in size. BACKGROUND

[0003] Angelman syndrome is a neurodevelopmental disorder, resulting in delayed development, intellectual disability, severe cognitive and motor deficits, and epileptic seizures. Individuals with Angelman syndrome are often diagnosed during or near the years of infancy e.g., 1-3 years of age. To date, there remain few treatment options for individuals with Angelman syndrome, most of which involve anti-epileptic medications to treat the symptoms of Angelman syndrome. Thus, there is a need for improved treatments for Angelman syndrome. SUMMARY

[0004] Methods disclosed herein include methods for treating Angelman syndrome (AS) in a human subject in need thereof. Such methods include administering an antisense compound complementary to a UBE3A-AS transcript to a human subject suffering from Angelman syndrome. In various embodiments, methods of administration of the antisense compound include at least one loading dose and at least one maintenance dose of the antisense compound. In various embodiments, the antisense compound comprises the nucleic acid sequence of SEQ ID NO: 1. In various embodiments, the antisense compound comprises the modified nucleic acid sequence of SEQ ID NO: 2.

[0005] Altogether, the disclosed methods for treating Angelman syndrome (AS) in a human subject in need thereof achieve the following:IPTS / 128916176.1 1^ Administration of the antisense compound across the at least one loading dose and at least one maintenance dose to achieve a concentration of the antisense compound in the brain that 1) is effective for treating or reducing symptoms of Angelman syndrome and 2) minimizes the risk of unwanted side effects (e.g., radiculopathy). ^ The antisense compound is administered with a dose pause of about 20-80 days between a final loading dose and a first maintenance dose. This dose pause ensures that the concentration of the antisense compound in the brain remains at a level that achieves efficacy, while also minimizing the risk of unwanted side effects (e.g., radiculopathy). ^ One or more additional methods for reducing radiculopathy can be implemented. For example, the human subject may be positioned in an inverted position after administration of an antisense compound to reduce the occurrence of side effects (e.g., radiculopathy).

[0006] Thus, provided herein are methods of treating Angelman syndrome (AS) in a human subject in need thereof, comprising: (a) administering a first loading dose of about 5 mg to about 10 mg of an antisense compound comprising a nucleic acid sequence complementary to a UBE3A-AS transcript; (b) administering a first maintenance dose of about 6 mg to about 14 mg of the antisense compound; and (c) administering a second maintenance dose of about 8 mg to about 16 mg of the antisense compound.

[0007] Also provided are methods of treating Angelman syndrome (AS) in a plurality of human subjects of a patient population, comprising: (a) administering a first loading dose of about 5 mg to about 10 mg of an antisense compound comprising a nucleic acid sequence complementary to a UBE3A-AS transcript; (b) administering a first maintenance dose of about 6 mg to about 14 mg of the antisense compound; and (c) administering a second maintenance dose of about 8 mg to about 16 mg of the antisense compound.

[0008] The antisense compound may comprise the nucleic acid sequence of SEQ ID NO: 1.

[0009] The nucleic acid sequence of the antisense compound may comprise a modified nucleic acid sequence of AL*GL*AL*a*t*g*g*c*a*c*a*t*c*t*5mCL*TL*TL*GL(SEQ ID NO: 2), wherein: capital letters denote RNA nucleosides; lower case letters denote DNA nucleosides; 5mC denotes a 5-methylcytosine nucleoside; superscript L denotes a locked nucleic acid (LNA) nucleoside; and asterisks denote phosphorothioate internucleoside linkages.IPTS / 128916176.1 2

[0010] The first loading dose may comprise from about 6 mg to about 9 mg, about 7 mg to about 8.5 mg, or about 8 mg of the antisense compound.

[0011] The methods may further comprise administering a second loading dose.

[0012] The second loading dose may comprise from about 5 mg to about 10 mg, about 6 mg to about 9 mg, about 7 mg to about 8.5 mg, or about 8 mg of the antisense compound.

[0013] The second loading dose may be administered between about 21 days to about 35 days, about 22 days to about 34 days, about 23 days to about 33 days, about 24 days to about 32 days, about 25 days to about 31 days, about 26 days to about 30 days, about 27 days to about 29 days, or about 28 days after the first loading dose.

[0014] The methods may further comprise administering a third loading dose.

[0015] The third loading dose may comprise from about 5 mg to about 10 mg, about 6 mg to about 9 mg, about 7 mg to about 8.5 mg, or about 8 mg of the antisense compound.

[0016] The third loading dose may be administered between about 21 days to about 35 days, about 22 days to about 34 days, about 23 days to about 33 days, about 24 days to about 32 days, about 25 days to about 31 days, about 26 days to about 30 days, about 27 days to about 29 days, or about 28 days after the second loading dose.

[0017] In some embodiments, the methods do not include administering a fourth loading dose.

[0018] The methods may further comprise: positioning the human subject into an inverted position after administration of the first, second, and / or third loading dose.

[0019] Positioning the human subject into the inverted position may comprise positioning the human subject into the Trendelenburg position.

[0020] The human subject may be positioned in the inverted position for about 30 minutes to about 60 minutes, about 40 minutes to about 50 minutes, or about 45 minutes.

[0021] In some embodiments, the first maintenance dose may comprise from about 7 mg to about 13 mg, about 6 mg to about 12 mg, about 8 mg to about 11 mg, about 9 mg to about 10.5 mg, or about 10 mg of the antisense compound.

[0022] The first maintenance dose may be administered between about 50 days to about 70 days, about 51 days to about 67 days, about 52 days to about 64 days, about 53 days to aboutIPTS / 128916176.1 361 days, about 54 days to about 58 days, about 55 days to about 57 days, or about 56 days after a final loading dose.

[0023] The methods may comprise a lapse period between a final loading dose and the first maintenance dose, wherein the lapse period may be between about 28 days to about 56 days, between about 35 days to about 49 days, about 28 days, or about 56 days.

[0024] The second maintenance dose may comprise from about 9 mg to about 15 mg, about 10 mg to about 14 mg, about 11 mg to about 13 mg or about 12 mg of the antisense compound.

[0025] The second maintenance dose may comprise from about 9 mg to about 15 mg, about 11 mg to about 14 mg, about 12 mg to about 14.5 mg, or about 14 mg of the antisense compound.

[0026] The second maintenance dose may be administered between about 50 days to about 90 days, about 51 days to about 80 days, about 52 days to about 70 days, about 53 days to about 60 days, about 54 days to about 57 days, or about 56 days after administration of the first maintenance dose.

[0027] The second maintenance dose may be administered between about 50 days to about 90 days, about 60 days to about 89 days, about 70 days to about 88 days, about 80 days to about 87 days, about 82 days to about 88 days, or about 84 days after administration of the first maintenance dose.

[0028] The methods may further comprise administering one or more additional maintenance doses comprising from about 10 mg to about 16 mg of the antisense compound, wherein each of the one or more additional maintenance doses may be equal to or higher than the second maintenance dose.

[0029] Each of the one or more additional maintenance doses may comprise from about 11 mg to about 16 mg, from about 12 mg to about 15 mg, from about 13 mg to about 14.5 mg, or about 14 mg of the antisense compound.

[0030] One of the one or more additional maintenance doses may be administered between about 50 days to about 90 days, about 51 days to about 80 days, about 52 days to about 70 days, about 53 days to about 60 days, about 54 days to about 57 days, or about 56 days after administration of the second maintenance dose.

[0031] One of the one or more additional maintenance doses may be administered between about 50 days to about 90 days, about 60 days to about 89 days, about 70 days to about 88 days,IPTS / 128916176.1 4about 80 days to about 87 days, about 82 days to about 88 days, or about 84 days after administration of the second maintenance dose.

[0032] The one or more additional maintenance doses may be administered Q2M.

[0033] The one or more additional maintenance doses may be administered Q3M.

[0034] In some embodiments, the second maintenance dose may be higher than the first maintenance dose.

[0035] In some embodiments, the methods further comprise: administering a second loading dose of about 8 mg of the antisense compound about 28 days after administration of the first loading dose; administering a third loading dose of about 8 mg of the antisense compound about 56 days after administration of the first loading dose; and administering a third maintenance dose comprising a dose of about 14 mg of the antisense compound about 56 days after administration of the second maintenance dose, wherein the first loading dose comprises a dose of about 8 mg of the antisense compound, the first maintenance dose comprises a dose of about 10 mg of the antisense compound and may be administered about 56 days after administration of the third loading dose, and the second maintenance dose comprises a dose of about 12 mg of the antisense compound and may be administered about 56 days after administration of the first maintenance dose.

[0036] The methods may further comprise: administering a second loading dose of about 8 mg of the antisense compound about 28 days after administration of the first loading dose; administering a third loading dose of about 8 mg of the antisense compound about 56 days after administration of the first loading dose; administering a fourth loading dose of about 8 mg of the antisense compound about 84 days after administration of the first loading dose; and administering a third maintenance dose comprising a dose of about 14 mg of the antisense compound about 84 days after administration of the second maintenance dose, wherein the first loading dose comprises a dose of about 8 mg of the antisense compound, the first maintenance dose comprises a dose of about 10 mg of the antisense compound and may be administered about 56 days after administration of the fourth loading dose, the second maintenance dose comprises a dose of about 14 mg of the antisense compound and may be administered about 84 days after administration of the first maintenance dose.

[0037] Also provided herein are methods of treating Angelman syndrome (AS) in a human subject in need thereof, comprising: (a) administering a first loading dose of about 5 mg to about 10 mg of an antisense compound comprising a nucleic acid sequence complementary toIPTS / 128916176.1 5a UBE3A-AS transcript; (b) positioning the human subject into an inverted position after administration of the first loading dose; and (c) administering a first maintenance dose of about 6 mg to about 14 mg of the antisense compound.

[0038] Also provided are methods of treating Angelman syndrome (AS) in a plurality of human subjects of a patient population, comprising: (a) administering a first loading dose of about 5 mg to about 10 mg of an antisense compound comprising a nucleic acid sequence complementary to a UBE3A-AS transcript; (b) positioning the human subject into an inverted position after administration of the first loading dose; and (c) administering a first maintenance dose of about 6 mg to about 14 mg of the antisense compound.

[0039] Also provided herein are methods of treating Angelman syndrome (AS) in a human subject in need thereof, comprising: (a) administering a first loading dose of about 5 mg to about 10 mg of an antisense compound comprising a nucleic acid sequence complementary to a UBE3A-AS transcript; (b) positioning the human subject into an inverted position after administration of the first loading dose; (c) administering a first maintenance dose of about 6 mg to about 14 mg of the antisense compound; and (d) administering a second maintenance dose of about 8 mg to about 16 mg of the antisense compound.

[0040] Also provided are methods of treating Angelman syndrome (AS) in a plurality of human subjects in need thereof from a patient population, comprising: (a) administering a first loading dose of about 5 mg to about 10 mg of an antisense compound comprising a nucleic acid sequence complementary to a UBE3A-AS transcript; (b) positioning the human subject into an inverted position after administration of the first loading dose; (c) administering a first maintenance dose of about 6 mg to about 14 mg of the antisense compound; and (d) administering a second maintenance dose of about 8 mg to about 16 mg of the antisense compound.

[0041] The methods may further comprise: administering a second loading dose of about 8 mg of the antisense compound about 28 days after administration of the first loading dose; administering a third loading dose of about 8 mg of the antisense compound about 56 days after administration of the first loading dose; and administering a third maintenance dose comprising a dose of about 14 mg of the antisense compound about 56 days after administration of the second maintenance dose, wherein the first loading dose may comprise a dose of about 8 mg of the antisense compound, the first maintenance dose may comprise a dose of about 10 mg of the antisense compound and may be administered about 56 days after administration of theIPTS / 128916176.1 6third loading dose, and the second maintenance dose may comprise a dose of about 12 mg of the antisense compound and may be administered about 56 days after administration of the first maintenance dose.

[0042] The methods may further comprise: administering a second loading dose of about 8 mg of the antisense compound about 28 days after administration of the first loading dose; administering a third loading dose of about 8 mg of the antisense compound about 56 days after administration of the first loading dose; and administering a fourth loading dose of about 8 mg of the antisense compound about 84 days after administration of the first loading dose; and administering a third maintenance dose comprising a dose of about 14 mg of the antisense compound about 84 days after administration of the second maintenance dose, wherein the first loading dose may comprise a dose of about 8 mg of the antisense compound, the first maintenance dose may comprise a dose of about 10 mg of the antisense compound and may be administered about 56 days after administration of the fourth loading dose, the second maintenance dose may comprise a dose of about 14 mg of the antisense compound and may be administered about 84 days after administration of the first maintenance dose.

[0043] Also provided herein are methods of treating Angelman syndrome (AS) in a human subject in need thereof, comprising: administering a first loading dose of an antisense compound comprising a nucleic acid sequence complementary to a UBE3A-AS transcript; and administering a first maintenance dose of the antisense compound, wherein the improvement may comprise: administering a second maintenance dose of about 8 mg to about 16 mg of the antisense compound, wherein the first loading dose of the antisense compound may be about 5 mg to about 10 mg, wherein the first maintenance dose of the antisense compound may be about 6 mg to about 14 mg.

[0044] In the methods provided herein, each loading dose and maintenance dose may be administered to the human subject via intrathecal (IT) lumbar puncture (LP).

[0045] The methods provided herein may achieve a concentration of the antisense oligonucleotide in the brain of the subject that may be maintained between about 500 ng / g and about 8000 ng / g between the first loading dose and at least the first maintenance dose.

[0046] The methods provided herein may achieve a concentration of the antisense oligonucleotide in the brain of the subject that may be maintained between about 1000 ng / g and about 7000 ng / g between the first loading dose and at least the first maintenance dose.IPTS / 128916176.1 7

[0047] The methods provided herein may achieve a concentration of the antisense oligonucleotide in the brain of the subject that may be maintained between about 2000 ng / g and about 4000 ng / g between the first loading dose and at least the first maintenance dose.

[0048] The methods provided herein may achieve a concentration of the antisense oligonucleotide in the brain of the subject that may be maintained below about 6500 ng / g between the first loading dose and at least the first maintenance dose.

[0049] The methods provided herein may avoid causing radiculopathy in the human subject.

[0050] The methods provided herein may avoid causing elevated cerebrospinal fluid (CSF) protein levels in the human subject.

[0051] The volume of each loading dose and / or maintenance dose of the methods provided herein may be between 1 mL and 10 mL.

[0052] For the methods provided herein, the human subject may be between about 4 years of age and about 18 years of age or 4 years of age to less than 18 years of age.

[0053] The methods provided herein may further comprise administering a steroid premedication.

[0054] The steroid premedication may comprise administering the steroid prior to intrathecal (IT) lumbar puncture (LP) administration of the first loading dose.

[0055] The steroid may be a corticosteroid.

[0056] The corticosteroid may be dexamethasone.

[0057] Administering the steroid may comprise intravenous administration or oral administration of the steroid.

[0058] Intravenous administration of the steroid may comprise intravenous administration at 0.3 mg / kg of dexamethasone or dose-equivalent of an alternative corticosteroid.

[0059] Administering the steroid may comprise orally administering the steroid at 0.3 mg / kg of dexamethasone or dose-equivalent of an alternative corticosteroid one day before the first loading dose.

[0060] The steroid premedication may be administered within about 0.5 hours to about 5 hours, within about 1 hour to about 4 hours, within about 1.5 hours to about 3 hours, or within about 2 hours prior to administration of any or each loading dose.IPTS / 128916176.1 8

[0061] The methods provided herein may further comprise administering a flush of artificial cerebrospinal fluid (aCSF) after administration of any or each loading dose.

[0062] The methods provided herein may further comprise administering a flush of aCSF after administration of any or each maintenance dose.

[0063] The flush of aCSF may comprise a volume of 1 mL to 10 mL.

[0064] The flush of aCSF may be administered as a bolus injection over one to two minutes.

[0065] The flush of aCSF may be administered prior to positioning the human subject in an inverted position.

[0066] Also provided herein are methods of treating Angelman syndrome (AS) in a human subject in need thereof, comprising: (a) administering a first loading dose of about 2 mg to about 6 mg of an antisense compound comprising a nucleic acid sequence complementary to a UBE3A-AS transcript; (b) administering a first maintenance dose of about 4 mg to about 8 mg of the antisense compound; and (c) administering a second maintenance dose of about 6 mg to about 10 mg of the antisense compound.

[0067] In some embodiments, the antisense compound may comprise the nucleic acid sequence of SEQ ID NO: 1.

[0068] The nucleic acid sequence of the antisense compound may comprise a modified nucleic acid sequence of AL*GL*AL*a*t*g*g*c*a*c*a*t*c*t*5mCL*TL*TL*GL(SEQ ID NO: 2), wherein capital letters denote RNA nucleosides; lower case letters denote DNA nucleosides; 5mC denotes a 5-methylcytosine nucleoside; superscript L denotes a locked nucleic acid (LNA) nucleoside; and asterisks denote phosphorothioate internucleoside linkages.

[0069] The first loading dose may comprise from about 3 mg to about 5 mg, or about 4 mg of the antisense compound.

[0070] The method may further comprise administering a second loading dose.

[0071] The second loading dose may comprise from about 2 mg to about 6 mg, about 3 mg to about 5 mg, or about 4 mg of the antisense compound.

[0072] In some embodiments, the second loading dose may be administered between about 21 days to about 35 days, about 22 days to about 34 days, about 23 days to about 33 days, about 24 days to about 32 days, about 25 days to about 31 days, about 26 days to about 30 days, about 27 days to about 29 days, or about 28 days after the first loading dose.IPTS / 128916176.1 9

[0073] The method may further comprise administering a third loading dose.

[0074] The third loading dose may comprise from about 2 mg to about 6 mg, about 3 mg to about 5 mg, or about 4 mg of the antisense compound.

[0075] In some embodiments, the third loading dose may be administered between about 21 days to about 35 days, about 22 days to about 34 days, about 23 days to about 33 days, about 24 days to about 32 days, about 25 days to about 31 days, about 26 days to about 30 days, about 27 days to about 29 days, or about 28 days after the second loading dose.

[0076] In some embodiments, the method does not include administering a fourth loading dose.

[0077] The method may further comprise positioning the human subject into an inverted position after administration of the first, second, and / or third loading dose. For example, the method may comprise positioning the human subject into the Trendelenburg position.

[0078] The human subject may be positioned in the inverted position for about 30 minutes to about 60 minutes, about 40 minutes to about 50 minutes, or about 45 minutes.

[0079] The first maintenance dose may comprise from about 5 mg to about 7 mg, or about 6 mg of the antisense compound.

[0080] The first maintenance dose may be administered between about 50 days to about 70 days, about 51 days to about 67 days, about 52 days to about 64 days, about 53 days to about 61 days, about 54 days to about 58 days, about 55 days to about 57 days, or about 56 days after a final loading dose.

[0081] The method may comprise a lapse period between a final loading dose and the first maintenance dose, wherein the lapse period is between about 28 days to about 56 days, between about 35 days to about 49 days, about 28 days, or about 56 days.

[0082] The second maintenance dose may comprise from about 7 mg to about 9 mg, or about 8 mg of the antisense compound.

[0083] The second maintenance dose may be administered between about 50 days to about 90 days, about 51 days to about 80 days, about 52 days to about 70 days, about 53 days to about 60 days, about 54 days to about 57 days, or about 56 days after administration of the first maintenance dose.IPTS / 128916176.1 10

[0084] The second maintenance dose may be administered between about 50 days to about 90 days, about 60 days to about 89 days, about 70 days to about 88 days, about 80 days to about 87 days, about 82 days to about 88 days, or about 84 days after administration of the first maintenance dose.

[0085] The method may further comprise administering one or more additional maintenance doses comprising from about 6 mg to about 12 mg of the antisense compound, wherein each of the one or more additional maintenance doses is equal to or higher than the second maintenance dose.

[0086] In some embodiments, each of the one or more additional maintenance doses comprises from about 7 mg to about 11 mg, about 8 mg to about 10 mg, or about 10 mg of the antisense compound.

[0087] One of the one or more additional maintenance doses may be administered between about 50 days to about 90 days, about 51 days to about 80 days, about 52 days to about 70 days, about 53 days to about 60 days, about 54 days to about 57 days, or about 56 days after administration of the second maintenance dose.

[0088] One of the one or more additional maintenance doses may be administered between about 50 days to about 90 days, about 60 days to about 89 days, about 70 days to about 88 days, about 80 days to about 87 days, about 82 days to about 88 days, or about 84 days after administration of the second maintenance dose.

[0089] The one or more additional maintenance doses may be administered Q2M.

[0090] The one or more additional maintenance doses may be administered Q3M.

[0091] The second maintenance dose may be higher than the first maintenance dose.

[0092] In some embodiments, the method may further comprise: administering a second loading dose of about 4 mg of the antisense compound about 28 days after administration of the first loading dose; administering a third loading dose of about 4 mg of the antisense compound about 56 days after administration of the first loading dose; and administering a third maintenance dose comprising a dose of about 10 mg of the antisense compound about 56 days after administration of the second maintenance dose, wherein the first loading dose comprises a dose of about 4 mg of the antisense compound, the first maintenance dose comprises a dose of about 6 mg of the antisense compound and is administered about 56 days after administration of the third loading dose, and the second maintenance dose comprises aIPTS / 128916176.1 11dose of about 8 mg of the antisense compound and is administered about 56 days after administration of the first maintenance dose.

[0093] In some embodiments, the method may further comprise: administering a second loading dose of about 4 mg of the antisense compound about 28 days after administration of the first loading dose; administering a third loading dose of about 4 mg of the antisense compound about 56 days after administration of the first loading dose; and administering a fourth loading dose of about 4 mg of the antisense compound about 84 days after administration of the first loading dose; and administering a third maintenance dose comprising a dose of about 10 mg of the antisense compound about 84 days after administration of the second maintenance dose, wherein the first loading dose comprises a dose of about 4 mg of the antisense compound, the first maintenance dose comprises a dose of about 6 mg of the antisense compound and is administered about 56 days after administration of the fourth loading dose, the second maintenance dose comprises a dose of about 8 mg of the antisense compound and is administered about 84 days after administration of the first maintenance dose.

[0094] In some embodiments, the human subject is less than 4 years of age.

[0095] The human subject may be greater than 12 months of age and less than 4 years of age.

[0096] The human subject may be greater than 12 months of age and less than 4 years of age at the time of administering the first loading dose.

[0097] The method may comprise administering the second loading dose or a dose subsequent to the second loading dose after the human subject achieves the age of 4 years.

[0098] The method may comprise increasing the amount of the antisense compound administered to the human subject having achieved the age of 4 years by about 2 mg per dose of the antisense compound up to a maximum of about 12 mg to about 16 mg of the antisense compound.

[0099] The method may comprise increasing the amount of the antisense compound administered to the human subject having achieved the age of 4 years by about 2 mg per dose of the antisense compound up to a maximum of about 14 mg of the antisense compound.IPTS / 128916176.1 12BRIEF DESCRIPTION OF THE DRAWINGS

[0100] These and other features, aspects, and advantages of the present disclosure will become better understood with reference to the following description and accompanying drawings.

[0101] FIG. 1 depicts a schematic of a Structural PK Model for GTX-102 following Intrathecal (IT) Administrations.

[0102] FIG.2 shows mean Concentration-time Profiles of GTX-102 in Monkeys After the Last Dose Following the 4 Monthly Doses.

[0103] FIG.3A shows predicted Concentration-Time Profiles of GTX-102 in Monkey CSF Against the Observed Data.

[0104] FIG. 3B shows predicted Concentration-Time Profiles of GTX-102 in Monkey Plasma Against the Observed Data.

[0105] FIG.3C shows predicted Concentration-Time Profiles of GTX-102 in Monkey CNS Against the Observed Data.

[0106] FIG. 41 shows Predicted Dose-normalized Concentration-Time Profiles of GTX- 102 in Human Plasma Against the Observed Data.

[0107] FIG.5 shows simulated CNS Concentration of GTX-102 in Patients Who Developed Radiculopathy in the Original Protocol (see Cohorts 1-7 of the GTX-102-001 clinical study NCT04259281, available online at www.clinicaltrials.gov; see also Example 1 and Table 1 herein).

[0108] FIG.6 shows the simulated GTX-102 Concentrations in Human CNS in a simulated human patient receiving 10 mg QM for 2 doses, followed by 12 mg QM for 2 doses.

[0109] FIG.7A shows simulated GTX-102 Concentrations in Human CNS in Patients (10 mg QM for 4 doses, followed by 14 mg Q3M for 3 doses).

[0110] FIG. 7B shows simulated GTX-102 Concentrations in Human CNS in Patients (10 mg QM for 4 doses, followed by 12 mg Q3M for 3 doses).

[0111] FIG. 8 shows Apparent Waning of GTX-102 Clinical Effect in Some Patients Following Transition from Final Loading Dose (QM) at Day 86 to Maintenance Regimen (Q3M) Beginning at Day 170.IPTS / 128916176.1 13

[0112] FIGs. 9A and 9B show that GTX-102 treatment improved cognition by Bayley-4, which demonstrated rapid and ongoing, long-term improvement compared to Natural History.

[0113] FIGs. 10A and 10B show that GTX-102 treatment improved receptive communication by Bayley-4, which demonstrated rapid and sustained improvement compared to Natural History.

[0114] FIGs. 11A and 11B show that GTX-102 treatment improved expressive communication by Bayley-4, which displayed sustained improvement over time.

[0115] FIGs. 12A and 12B show that GTX-102 treatment improved gross motor function by Bayley-4, which demonstrated long term and ongoing improvement compared to Natural History.

[0116] FIGs.13A and 13B show that GTX-102 treatment improved fine motor function by Bayley-4, which demonstrated long term and continuous improvement compared to Natural History.

[0117] FIGs. 14A and 14B show that GTX-102 treatment improved sleep by ASA, which showed rapid and sustained improvement. Scores were as follows: 1 = Not at all impaired; 2 = Borderline, slightly impaired; 3 = Mildly impaired; 4 = Moderately impaired; 5 = Markedly impaired; 6 = Severely impaired; 7 = Among the most severely impaired.

[0118] FIG. 15 shows that GTX-102 treatment improved behavior by ASA, which demonstrated rapid and continuous improvement. Scores were as follows: 1 = Not at all impaired; 2 = Borderline, slightly impaired; 3 = Mildly impaired; 4 = Moderately impaired; 5 = Markedly impaired; 6 = Severely impaired; 7 = Among the most severely impaired.

[0119] FIG. 16 shows that GTX-102 treatment improved communication by ASA, which demonstrated sustained benefit. Scores were as follows: 1 = Not at all impaired; 2 = Borderline, slightly impaired; 3 = Mildly impaired; 4 = Moderately impaired; 5 = Markedly impaired; 6 = Severely impaired; 7 = Among the most severely impaired.

[0120] FIG. 17 shows that GTX-102 treatment improved fine motor function by ASA, which demonstrated continuous long-term improvement. Scores were as follows: 1 = Not at all impaired; 2 = Borderline, slightly impaired; 3 = Mildly impaired; 4 = Moderately impaired; 5 = Markedly impaired; 6 = Severely impaired; 7 = Among the most severely impaired.

[0121] FIG. 18 shows that GTX-102 treatment improved gross motor function by ASA, which demonstrated long-term improvement. Scores were as follows: 1 = Not at all impaired;IPTS / 128916176.1 142 = Borderline, slightly impaired; 3 = Mildly impaired; 4 = Moderately impaired; 5 = Markedly impaired; 6 = Severely impaired; 7 = Among the most severely impaired.

[0122] FIG. 19 shows that GTX-102 treatment improved ASA overall score, which demonstrated long-term improvement. Scores were as follows: 1 = Not at all impaired; 2 = Borderline, slightly impaired; 3 = Mildly impaired; 4 = Moderately impaired; 5 = Markedly impaired; 6 = Severely impaired; 7 = Among the most severely impaired.

[0123] FIGs. 20A and 20B show that GTX-102 treatment improved irritability raw score, by ABC-C, and shows a positive trend compared with Natural History.

[0124] FIGs. 21A and 21B show that GTX-102 treatment improved hyperactivity / noncompliance raw score, by ABC-C, and demonstrates rapid and continuous improvement compared with Natural History.

[0125] FIG.22 shows a study schema indicating GTX-102 dose (mg), timing of doses, and loading and maintenance periods.

[0126] FIG. 23 shows an alternative study schema indicating GTX-102 dose (mg), timing of doses, and loading and maintenance periods. DETAILED DESCRIPTION Definitions

[0127] The features and other details of the disclosure will now be more particularly described. Certain terms employed in the specification, examples and appended claims are collected here. These definitions should be read in light of the remainder of the disclosure and understood as by a person of skill in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by a person of ordinary skill in the art.

[0128] The phrases “intrathecal delivery” or “intrathecal administration” generally refer to a route of administration for drugs via an injection, e.g., an infusion, into the spinal canal, more specifically into the subarachnoid space so that it reaches the cerebrospinal fluid (CSF). Intrathecal delivery may include lumbar puncture (LP), intraventricular (including intracerebroventricular (ICV)), suboccipital / intracisternal, and / or CI-2 puncture. For example, material may be introduced for diffusion throughout the subarachnoid space by means of lumbar puncture. In another example, injection may be into the cisterna magna.IPTS / 128916176.1 15

[0129] The phrases “intracisternal magna delivery” or “intracisternal magna administration” generally refer to a route of administration for drugs directly into the cerebrospinal fluid of the cisterna magna cerebellomedularis, more specifically via a suboccipital puncture or by direct injection into the cisterna magna or via permanently positioned tube.

[0130] The term “preventing” a disease refers to inhibiting the full development of a disease. The term “treating” refers to a therapeutic intervention that ameliorates a sign or symptom of a disease or pathological condition after it has begun to develop. The term “ameliorating” refers to the reduction in the number or severity of signs or symptoms of a disease.

[0131] The terms “subject” and “patient” are used interchangeably and encompass a cell, tissue, organism, human or non-human, mammal or non-mammal, male or female, whether in vivo, ex vivo, or in vitro. In one embodiment, the subject is an adult subject, i.e., a human subject 18 years old or older. In one embodiment, the human subject is a pediatric subject, i.e., a human subject of ages 0 to less than 18 years old.

[0132] The phrase “therapeutically effective amount” refers to a quantity of a specified therapeutic (e.g., a disclosed antisense compound) sufficient to achieve a desired effect in a subject, or in a cell, being treated with the therapeutic. The effective amount of the therapeutic will be dependent on several factors, including, but not limited to the subject or cells being treated, and the manner of administration of the therapeutic.

[0133] Unless otherwise explained, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The singular terms “a,” “an,” and “the” include plural referents unless context clearly indicates otherwise. “Comprising A or B” means including A, or B, or A and B. It is further to be understood that all base sizes or amino acid sizes, and all molecular weight or molecular mass values, given for nucleic acids or polypeptides are approximate, and are provided for description. Although methods and materials similar or equivalent to those described herein can be used in the practice or testing of the present disclosure, suitable methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including explanations of terms, will control. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.IPTS / 128916176.1 16

[0134] Throughout the description, where compositions are described as having, including, or comprising specific components, or where processes and methods are described as having, including, or comprising specific steps, it is contemplated that, additionally, there are compositions of the present disclosure that consist essentially of, or consist of, the recited components, and that there are processes and methods according to the present disclosure that consist essentially of, or consist of, the recited processing steps.

[0135] In the present disclosure, where an element or component is said to be included in and / or selected from a list of recited elements or components, it should be understood that the element or component can be any one of the recited elements or components, or the element or component can be selected from a group consisting of two or more of the recited elements or components.

[0136] It should be understood that the expression “at least one of” includes individually each of the recited objects after the expression and the various combinations of two or more of the recited objects unless otherwise understood from the context and use. The expression “and / or” in connection with three or more recited objects should be understood to have the same meaning unless otherwise understood from the context.

[0137] The use of the term “comprise,” “comprises,” “include,” “includes,” “including,” “have,” “has,” “having,” “contain,” “contains,” or “containing,” including grammatical equivalents thereof, should be understood generally as open-ended and non-limiting, for example, not excluding additional unrecited elements or steps, unless otherwise specifically stated or understood from the context.

[0138] Where the use of the term “about” is before a quantitative value, the present disclosure also includes the specific quantitative value itself, unless specifically stated otherwise. As used herein, the term “about” refers to a ± 10% variation from the nominal value unless otherwise indicated or inferred.

[0139] It should be understood that the order of steps or order for performing certain actions is immaterial so long as the present disclosure remains operable. Moreover, two or more steps or actions may be conducted simultaneously.

[0140] The use of any and all examples, or exemplary language herein, for example, “such as” or “including” is intended merely to illustrate better the present disclosure and does not pose a limitation on the scope of the disclosure unless claimed. No language in the specificationIPTS / 128916176.1 17should be construed as indicating any non-claimed element as essential to the practice of the present disclosure. Methods for administering an antisense compound for treating Angelman syndrome (AS)

[0141] In various embodiments, the method of treating Angelman syndrome comprises administering one or more loading doses and one or more maintenance doses of an antisense compound. In various embodiments, the methods involve administering one or more loading doses and one or more maintenance doses of an antisense compound comprising a nucleic acid sequence complementary to a UBE3A-AS transcript. In various embodiments, the methods involve administering one or more loading doses and one or more maintenance doses of an antisense compound comprising a nucleic acid sequence complementary to one of five different host gene exons (“E-3 exons”) in Cluster 2 at the start of the UBE3A-AS transcript, such as any one of SEQ ID NOs: 3-7 herein (see Scott V. Dindot et al., An ASO therapy for Angelman syndrome that targets an evolutionarily conserved region at the start of the UBE3A-AS transcript. Sci. Transl. Med. 15, eabf4077 (2023). DOI: 10.1126 / scitranslmed.abf4077; and Scott V. Dindot, et al. Development of an ASO therapy for Angelman syndrome by targeting an evolutionarily conserved region at the start of the UBE3A-AS transcript. bioRxiv (2021): 2021-07, which are incorporated by reference in their entirety). In various embodiments, the methods involve administering one or more loading doses and one or more maintenance doses of an antisense compound comprising a nucleic acid sequence of SEQ ID NO: 1. In various embodiments, the methods involve administering one or more loading doses and one or more maintenance doses of an antisense compound comprising a modified nucleic acid sequence of SEQ ID NO: 2.

[0142] In various embodiments, the method of treating Angelman syndrome comprises administering between 1 and 10 loading doses. In various embodiments, the method of treating Angelman syndrome comprises administering at least a first loading dose. In various embodiments, the method of treating Angelman syndrome comprises administering at least a second loading dose. In various embodiments, the method of treating Angelman syndrome comprises administering at least a third loading dose. In various embodiments, the method of treating Angelman syndrome comprises administering at least a fourth loading dose. In various embodiments, the method of treating Angelman syndrome comprises administering at least a fifth loading dose. In various embodiments, methods involve administering at least a sixth loading dose. In various embodiments, the method of treating Angelman syndrome comprisesIPTS / 128916176.1 18administering at least a seventh loading dose. In various embodiments, the method of treating Angelman syndrome comprises administering at least an eighth loading dose. In various embodiments, the method of treating Angelman syndrome comprises administering at least a ninth loading dose. In various embodiments, the method of treating Angelman syndrome comprises administering at least a tenth loading dose. In various embodiments, the method of treating Angelman syndrome comprises administering three loading doses. In various embodiments, the method of treating Angelman syndrome comprises administering four loading doses. In various embodiments, the method of treating Angelman syndrome comprises administering no more than three loading doses.

[0143] In various embodiments, the method of treating Angelman syndrome comprises administering one or more maintenance doses. In various embodiments, the method of treating Angelman syndrome comprises administering at least a second maintenance dose. In various embodiments, the method of treating Angelman syndrome comprises administering at least a third maintenance dose. In various embodiments, the method of treating Angelman syndrome comprises administering at least a fourth maintenance dose. In various embodiments, methods involve administering at least a fifth maintenance dose. In various embodiments, the method of treating Angelman syndrome comprises administering at least a sixth maintenance dose. In various embodiments, the method of treating Angelman syndrome comprises administering at least a seventh maintenance dose. In various embodiments, the method of treating Angelman syndrome comprises administering at least an eighth maintenance dose. In various embodiments, the method of treating Angelman syndrome comprises administering at least a ninth maintenance dose. In various embodiments, the method of treating Angelman syndrome comprises administering at least a tenth maintenance dose.

[0144] In various embodiments, the method of treating Angelman syndrome comprises administering at least 1, at least 2, 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 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 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 31, at least 32, at least 33, at least 34, at least 35, at least 36, at least 37, at least 38, at least 39, at least 40, at least 41, at least 42, at least 43, at least 44, at least 45, at least 46, at least 47, at least 48, at least 49, at least 50, at least 51, at least 52, at least 53, at least 54, at least 55, at least 56, at least 57, at least 58, at least 59, or at least 60 maintenance doses. In various embodiments, the method of treatingIPTS / 128916176.1 19Angelman syndrome comprises administering one or more maintenance doses for as long as the subject’s symptoms improve or until the subject’s symptoms have resolved.

[0145] In various embodiments, the maintenance doses are administered subsequent to administration of a loading dose. In various embodiments, the maintenance doses are administered subsequent to administration of a second loading dose. In various embodiments, the maintenance doses are administered subsequent to administration of a third loading dose. In various embodiments, the maintenance doses are administered subsequent to administration of a fourth loading dose. In various embodiments, the maintenance doses are administered subsequent to administration of a final loading dose, which, in various embodiments, is a third loading dose. In various embodiments, the maintenance doses are administered subsequent to administration of a final loading dose, which, in various embodiments, is a fourth loading dose.

[0146] In various embodiments, the method of treating Angelman syndrome comprises administering three loading doses and one or more maintenance doses. In various embodiments, the method of treating Angelman syndrome comprises administering three loading doses and two or more maintenance doses. In various embodiments, the method of treating Angelman syndrome comprises administering three loading doses and three or more maintenance doses. In various embodiments, the method of treating Angelman syndrome comprises administering three loading doses and four or more maintenance doses. For example, the method of treating Angelman syndrome comprises administering three loading doses and at least 1, at least 2, 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 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 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 31, at least 32, at least 33, at least 34, at least 35, at least 36, at least 37, at least 38, at least 39, at least 40, at least 41, at least 42, at least 43, at least 44, at least 45, at least 46, at least 47, at least 48, at least 49, at least 50, at least 51, at least 52, at least 53, at least 54, at least 55, at least 56, at least 57, at least 58, at least 59, or at least 60 maintenance doses.

[0147] In various embodiments, the method of treating Angelman syndrome comprises administering four loading doses and one or more maintenance doses. In various embodiments, the method of treating Angelman syndrome comprises administering four loading doses and two or more maintenance doses. In various embodiments, the method of treating Angelman syndrome comprises administering four loading doses and three or more maintenance doses. In various embodiments, the method of treating Angelman syndrome comprises administeringIPTS / 128916176.1 20four loading doses and four or more maintenance doses. For example, the method of treating Angelman syndrome comprises administering four loading doses and at least 1, at least 2, 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 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 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 31, at least 32, at least 33, at least 34, at least 35, at least 36, at least 37, at least 38, at least 39, at least 40, at least 41, at least 42, at least 43, at least 44, at least 45, at least 46, at least 47, at least 48, at least 49, at least 50, at least 51, at least 52, at least 53, at least 54, at least 55, at least 56, at least 57, at least 58, at least 59, or at least 60 maintenance doses. Loading and Maintenance Doses

[0148] In some embodiments, the method of treating Angelman syndrome comprises administering a first loading dose of an antisense compound (e.g., an antisense compound having a nucleic acid sequence SEQ ID NO: 1 or a modified nucleic acid sequence of SEQ ID NO: 2). In some embodiments, the first loading dose comprises about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg of an antisense compound. In various embodiments, the first loading dose comprises about 5 mg to about 10 mg of the antisense compound. In some embodiments, the first loading dose comprises about 6 mg to about 9 mg of an antisense compound. In some embodiments, the first loading dose comprises about 7 mg to about 8.5 mg of an antisense compound. In some embodiments, the first loading dose comprises about 8 mg of an antisense compound.

[0149] In some embodiments, the method of treating Angelman syndrome comprises administering a second loading dose of an antisense compound (e.g., an antisense compound having a nucleic acid sequence SEQ ID NO: 1 or a modified nucleic acid sequence of SEQ ID NO: 2). In some embodiments, the second loading dose comprises about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg of an antisense compound. In various embodiments, the second loading dose comprises about 5 mg to about 10 mg of the antisense compound. In some embodiments, the second loading dose comprises about 6 mg to about 9 mg of an antisense compound. In some embodiments, the second loading dose comprises about 7 mg to about 8.5 mg of an antisense compound. In some embodiments, the second loading dose comprises about 8 mg of an antisense compound.IPTS / 128916176.1 21

[0150] In some embodiments, the method of treating Angelman syndrome comprises administering a second loading dose about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days, about 31 days, about 32 days, about 33 days, about 34 days, or about 35 days after a first loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a second loading dose about 21 days to about 35 days after a first loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a second loading dose about 22 days to about 34 days after a first loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a second loading dose about 23 days to about 33 days after a first loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a second loading dose about 24 days to about 32 days after a first loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a second loading dose about 25 days to about 31 days after a first loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a second loading dose about 26 days to about 30 days after a first loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a second loading dose about 27 days to about 29 days after a first loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a second loading dose about 28 days after a first loading dose.

[0151] In some embodiments, the method of treating Angelman syndrome comprises administering a third loading dose of an antisense compound (e.g., an antisense compound having a nucleic acid sequence SEQ ID NO: 1 or a modified nucleic acid sequence of SEQ ID NO: 2). In some embodiments, the third loading dose comprises about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg of an antisense compound. In various embodiments, the third loading dose comprises about 5 mg to about 10 mg of the antisense compound. In some embodiments, the third loading dose comprises about 6 mg to about 9 mg of an antisense compound. In some embodiments, the third loading dose comprises about 7 mg to about 8.5 mg of an antisense compound. In some embodiments, the third loading dose comprises about 8 mg of an antisense compound.

[0152] In some embodiments, the method of treating Angelman syndrome comprises administering a third loading dose about 20 days, about 21 days, about 22 days, about 23 days,IPTS / 128916176.1 22about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days, about 31 days, about 32 days, about 33 days, about 34 days, or about 35 days after a second loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a third loading dose about 21 days to about 35 days after a second loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a third loading dose about 22 days to about 34 days after a second loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a third loading dose about 23 days to about 33 days after a second loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a third loading dose about 24 days to about 32 days after a second loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a third loading dose about 25 days to about 31 days after a second loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a third loading dose about 26 days to about 30 days after a second loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a third loading dose about 27 days to about 29 days after a second loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a third loading dose about 28 days after a second loading dose.

[0153] In some embodiments, the method of treating Angelman syndrome comprises administering a fourth loading dose of an antisense compound (e.g., an antisense compound having a nucleic acid sequence SEQ ID NO: 1 or a modified nucleic acid sequence of SEQ ID NO: 2). In some embodiments, the fourth loading dose comprises about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg of an antisense compound. In various embodiments, the fourth loading dose comprises about 5 mg to about 10 mg of the antisense compound. In some embodiments, the fourth loading dose comprises about 6 mg to about 9 mg of an antisense compound. In some embodiments, the fourth loading dose comprises about 7 mg to about 8.5 mg of an antisense compound. In some embodiments, the fourth loading dose comprises about 8 mg of an antisense compound.

[0154] In some embodiments, the method of treating Angelman syndrome comprises administering a fourth loading dose about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days, about 31 days, about 32 days, about 33 days, about 34 days, or about 35 daysIPTS / 128916176.1 23after a third loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a fourth loading dose about 21 days to about 35 days after a third loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a fourth loading dose about 22 days to about 34 days after a third loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a fourth loading dose about 23 days to about 33 days after a third loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a fourth loading dose about 24 days to about 32 days after a third loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a fourth loading dose about 25 days to about 31 days after a third loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a fourth loading dose about 26 days to about 30 days after a third loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a fourth loading dose about 27 days to about 29 days after a third loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a fourth loading dose about 28 days after a third loading dose.

[0155] In some embodiments, the method of treating Angelman syndrome comprises administering a further loading dose of an antisense compound (e.g., an antisense compound having a nucleic acid sequence SEQ ID NO: 1 or a modified nucleic acid sequence of SEQ ID NO: 2). In some embodiments, the further loading dose comprises about 5 mg, about 5.5 mg, about 6 mg, about 6.5 mg, about 7 mg, about 7.5 mg, about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, or about 10 mg of an antisense compound. In various embodiments, the further loading dose comprises about 5 mg to about 10 mg of the antisense compound. In some embodiments, the further loading dose comprises about 6 mg to about 9 mg of an antisense compound. In some embodiments, the further loading dose comprises about 7 mg to about 8.5 mg of an antisense compound. In some embodiments, the further loading dose comprises about 8 mg of an antisense compound.

[0156] In some embodiments, the method of treating Angelman syndrome comprises administering a further loading dose about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, about 28 days, about 29 days, about 30 days, about 31 days, about 32 days, about 33 days, about 34 days, or about 35 days after a fourth loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a further loading dose about 21 days to about 35 days after a fourthIPTS / 128916176.1 24loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a further loading dose about 22 days to about 34 days after a fourth loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a further loading dose about 23 days to about 33 days after a fourth loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a further loading dose about 24 days to about 32 days after a fourth loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a further loading dose about 25 days to about 31 days after a fourth loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a further loading dose about 26 days to about 30 days after a fourth loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a further loading dose about 27 days to about 29 days after a fourth loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a further loading dose about 28 days after a fourth loading dose.

[0157] In various embodiments, each of the loading doses include an equal dose of an antisense compound. For example, each of the loading doses include an 8 mg dose of an antisense compound. In various embodiments, each of the first loading dose, second loading dose, and third loading dose include an equal dose (e.g., an 8 mg dose) of an antisense compound. In various embodiments, each of the first loading dose, second loading dose, third loading dose, and fourth loading dose include an equal dose (e.g., an 8 mg dose) of an antisense compound.

[0158] In some embodiments, the method of treating Angelman syndrome comprises administering a first maintenance dose of an antisense compound (e.g., an antisense compound having a nucleic acid sequence SEQ ID NO: 1 or a modified nucleic acid sequence of SEQ ID NO: 2). In some embodiments, the first maintenance dose comprises about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 13.5 mg, about 14 mg, about 14.5 mg, about 15 mg, about 15.5 mg, or about 16 mg of an antisense compound. In various embodiments, the first maintenance dose comprises about 9 mg to about 15 mg of an antisense compound. In various embodiments, the first maintenance dose comprises about 10 mg to about 14 mg of an antisense compound. In various embodiments, the first maintenance dose comprises about 11 mg to about 13 mg of an antisense compound. In various embodiments, the first maintenance dose comprises about 10 mg of an antisense compound.IPTS / 128916176.1 25

[0159] In some embodiments, the method of treating Angelman syndrome comprises administering a first maintenance dose about 86 days, about 87 days, about 88 days, about 89 days, about 90 days, about 91 days, about 92 days, about 93 days, about 94 days, about 95 days, about 96 days, about 97 days, about 98 days, about 99 days, about 100 days, about 101 days, about 102 days, about 103 days, about 104 days, about 105 days, about 106 days, about 107 days, about 108 days, about 109 days, about 110 days, about 111 days, about 112 days, about 113 days, about 114 days, about 115 days, about 116 days, about 117 days, about 118 days, about 119 days, about 120 days, about 121 days, about 122 days, about 123 days, about 124 days, about 125 days, about 126 days, about 127 days, about 128 days, about 129 days, about 130 days, about 131 days, about 132 days, about 133 days, about 134 days, about 135 days, about 136 days, about 137 days, about 138 days, about 139 days, about 140 days, about 141 days, or about 142 days after a first loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a first maintenance dose about 86 days to about 142 days after a first loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a first maintenance dose about 90 days to about 135 days after a first loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a first maintenance dose about 95 days to about 130 days after a first loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a first maintenance dose about 100 days to about 125 days after a first loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a first maintenance dose about 105 days to about 120 days after a first loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a first maintenance dose about 110 days to about 115 days after a first loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a first maintenance dose about 114 days after a first loading dose.

[0160] In some embodiments, the method of treating Angelman syndrome comprises administering a first maintenance dose about 28 days, about 29 days, about 30 days, about 31 days, about 32 days, about 33 days, about 34 days, about 35 days, about 36 days, about 37 days, about 38 days, about 39 days, about 40 days, about 41 days, about 42 days, about 43 days, about 44 days, about 45 days, about 46 days, about 47 days, about 48 days, about 49 days, about 50 days, about 51 days, about 52 days, about 53 days, about 54 days, about 55 days, about 56 days, about 57 days, about 58 days, about 59 days, about 60 days, about 61 days, about 62 days, about 63 days, about 64 days, about 65 days, about 66 days, about 67 days,IPTS / 128916176.1 26about 68 days, about 69 days, about 70 days, about 71 days, about 72 days, about 73 days, about 74 days, about 75 days, about 76 days, about 77 days, about 78 days, about 79 days, about 80 days, about 81 days, about 82 days, about 83 days, or about 84 days after a final loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a first maintenance dose about 28 days to about 84 days after a final loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a first maintenance dose about 35 days to about 75 days after a final loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a first maintenance dose about 45 days to about 65 days after a final loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a first maintenance dose about 56 days after a final loading dose.

[0161] In some embodiments, the method of treating Angelman syndrome comprises a lapse period between about 28 days to about 84 days between a final loading dose and a first maintenance dose. A lapse period refers to a period of time in which no doses are administered to a subject. The lapse period can be long enough to avoid side effects (e.g., radiculopathy) arising from multiple dosings while also short enough to ensure that the concentration of the antisense compound in the brain does not fall below efficacious levels. In various embodiments, the lapse period is about 28 days, about 29 days, about 30 days, about 31 days, about 32 days, about 33 days, about 34 days, about 35 days, about 36 days, about 37 days, about 38 days, about 39 days, about 40 days, about 41 days, about 42 days, about 43 days, about 44 days, about 45 days, about 46 days, about 47 days, about 48 days, about 49 days, about 50 days, about 51 days, about 52 days, about 53 days, about 54 days, about 55 days, or about 56 days. In various embodiments, the lapse period is between about 28 days to about 56 days, or between about 35 days to about 49 days. In some embodiments, the lapse period is about 28 days. In some embodiments, the lapse period is about 56 days.

[0162] In some embodiments, the method of treating Angelman syndrome comprises administering a second maintenance dose of an antisense compound (e.g., an antisense compound having a nucleic acid sequence SEQ ID NO: 1 or a modified nucleic acid sequence of SEQ ID NO: 2). In various embodiments, the second maintenance dose comprises an equal dose of the antisense compound in comparison to the first maintenance dose. In various embodiments, the second maintenance dose comprises a higher dose of the antisense compound in comparison to the first maintenance dose. For example, the first maintenance dose may comprise about 10 mg of the antisense compound and the second maintenance dose mayIPTS / 128916176.1 27comprise about 12 mg of the antisense compound. As another example, the first maintenance dose may comprise about 10 mg of the antisense compound and the second maintenance dose may comprise about 14 mg of the antisense compound.

[0163] In some embodiments, the second maintenance dose comprises about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 13.5 mg, about 14 mg, about 14.5 mg, about 15 mg, about 15.5 mg, or about 16 mg of an antisense compound. In some embodiments, the second maintenance dose comprises about 8 mg to about 16 mg of an antisense compound. In some embodiments, the second maintenance dose comprises about 9 mg to about 15 mg of an antisense compound. In some embodiments, the second maintenance dose comprises about 10 mg to about 14 mg of an antisense compound. In some embodiments, the second maintenance dose comprises about 11 mg to about 13 mg of an antisense compound. In some embodiments, the second maintenance dose comprises about 12 mg of an antisense compound. In some embodiments, the second maintenance dose comprises about 10 mg to about 16 mg of an antisense compound. In some embodiments, the second maintenance dose comprises about 11 mg to about 15.5 mg of an antisense compound. In some embodiments, the second maintenance dose comprises about 12 mg to about 15 mg of an antisense compound. In some embodiments, the second maintenance dose comprises about 13 mg to about 14.5 mg of an antisense compound. In some embodiments, the second maintenance dose comprises about 14 mg of an antisense compound.

[0164] In some embodiments, the method of treating Angelman syndrome comprises administering a second maintenance dose about 142 days, about 143 days, about 144 days, about 145 days, about 146 days, about 147 days, about 148 days, about 149 days, about 150 days, about 151 days, about 152 days, about 153 days, about 154 days, about 155 days, about 156 days, about 157 days, about 158 days, about 159 days, about 160 days, about 161 days, about 162 days, about 163 days, about 164 days, about 165 days, about 166 days, about 167 days, about 168 days, about 169 days, about 170 days, about 171 days, about 172 days, about 173 days, about 174 days, about 175 days, about 176 days, about 177 days, about 178 days, about 179 days, about 180 days, about 181 days, about 182 days, about 183 days, about 184 days, about 185 days, about 186 days, about 187 days, about 188 days, about 189 days, about 190 days, about 191 days, about 192 days, about 193 days, about 194 days, about 195 days, about 196 days, about 197 days, about 198 days, about 199 days, about 200 days, about 201 days, about 202 days, about 203 days, about 204 days, about 205 days, about 206 days, aboutIPTS / 128916176.1 28207 days, about 208 days, about 209 days, about 210 days, about 211 days, about 212 days, about 213 days, about 214 days, about 215 days, about 216 days, about 217 days, about 218 days, about 219 days, about 220 days, about 221 days, about 222 days, about 223 days, about 224 days, about 225 days, about 226 days, about 227 days, about 228 days, about 229 days, about 230 days, about 231 days, about 232 days, about 233 days, about 234 days, about 235 days, about 236 days, about 237 days, about 238 days, about 239 days, about 240 days, about 241 days, about 242 days, about 243 days, about 244 days, about 245 days, about 246 days, about 247 days, about 248 days, about 249 days, about 250 days, about 251 days, about 252 days, about 253 days, or about 254 days after a first loading dose. In various embodiments, the method of treating Angelman syndrome comprises administering a second maintenance dose about 142 days to about 254 days after a first loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a second maintenance dose about 150 days to about 240 days after a first loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a second maintenance dose about 160 days to about 230 days after a first loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a second maintenance dose about 168 days after a first loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a second maintenance dose about 224 days after a first loading dose.

[0165] In some embodiments, the method of treating Angelman syndrome comprises administering a second maintenance dose about 28 days, about 29 days, about 30 days, about 31 days, about 32 days, about 33 days, about 34 days, about 35 days, about 36 days, about 37 days, about 38 days, about 39 days, about 40 days, about 41 days, about 42 days, about 43 days, about 44 days, about 45 days, about 46 days, about 47 days, about 48 days, about 49 days, about 50 days, about 51 days, about 52 days, about 53 days, about 54 days, about 55 days, about 56 days, about 57 days, about 58 days, about 59 days, about 60 days, about 61 days, about 62 days, about 63 days, or about 64 days, about 65 days, about 66 days, about 67 days, about 68 days, about 69 days, about 70 days, about 71 days, about 72 days, about 73 days, about 74 days, about 75 days, about 76 days, about 77 days, about 78 days, about 79 days, about 80 days, about 81 days, about 82 days, about 83 days, or about 84 days after a first maintenance dose. In some embodiments, the method of treating Angelman syndrome comprises administering a second maintenance dose about 28 days to about 84 days after a first maintenance dose. In some embodiments, the method of treating Angelman syndrome comprises administering a second maintenance dose about 35 days to about 75 days after a firstIPTS / 128916176.1 29maintenance dose. In some embodiments, the method of treating Angelman syndrome comprises administering a second maintenance dose about 45 days to about 65 days after a first maintenance dose. In some embodiments, the method of treating Angelman syndrome comprises administering a second maintenance dose about 28 days after a first maintenance dose. In some embodiments, the method of treating Angelman syndrome comprises administering a second maintenance dose about 56 days after a first maintenance dose. In some embodiments, the method of treating Angelman syndrome comprises administering a second maintenance dose about 84 days after a first maintenance dose.

[0166] In some embodiments, the method of treating Angelman syndrome comprises administering a third maintenance dose of an antisense compound (e.g., an antisense compound having a nucleic acid sequence SEQ ID NO: 1 or a modified nucleic acid sequence of SEQ ID NO: 2). In various embodiments, the third maintenance dose comprises an equal dose of the antisense compound in comparison to one or both of the first maintenance dose and the second maintenance dose. In various embodiments, the third maintenance dose comprises a higher dose of the antisense compound in comparison to one or both of the first maintenance dose and the second maintenance dose. In various embodiments, the third maintenance dose comprises an equal dose of the antisense compound in comparison to one of the first maintenance dose and the second maintenance dose and further comprises a higher dose of the antisense compound in comparison to the other of the first maintenance dose and the second maintenance dose. For example, the first maintenance dose may comprise about 10 mg of the antisense compound, the second maintenance dose may comprise about 12 mg of the antisense compound, and the third maintenance dose may comprise about 14 mg of the antisense compound. As another example, the first maintenance dose may comprise about 10 mg of the antisense compound, the second maintenance dose may comprise about 14 mg of the antisense compound, and the third maintenance dose may comprise about 14 mg of the antisense compound.

[0167] In some embodiments, the third maintenance dose comprises about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 13.5 mg, about 14 mg, about 14.5 mg, about 15 mg, about 15.5 mg, or about 16 mg of an antisense compound. In some embodiments, the third maintenance dose comprises about 8 mg to about 16 mg of an antisense compound. In some embodiments, the third maintenance dose comprises about 9 mg to about 15 mg of an antisense compound. In some embodiments, the third maintenance dose comprises about 10 mg to aboutIPTS / 128916176.1 3014 mg of an antisense compound. In some embodiments, the third maintenance dose comprises about 11 mg to about 13 mg of an antisense compound. In some embodiments, the third maintenance dose comprises about 12 mg of an antisense compound. In some embodiments, the third maintenance dose comprises about 10 mg to about 16 mg of an antisense compound. In some embodiments, the third maintenance dose comprises about 11 mg to about 15.5 mg of an antisense compound. In some embodiments, the third maintenance dose comprises about 12 mg to about 15 mg of an antisense compound. In some embodiments, the third maintenance dose comprises about 13 mg to about 14.5 mg of an antisense compound. In some embodiments, the third maintenance dose comprises about 14 mg of an antisense compound.

[0168] In some embodiments, the method of treating Angelman syndrome comprises administering a third maintenance dose about 198 days, about 199 days, about 200 days, about 201 days, about 202 days, about 203 days, about 204 days, about 205 days, about 206 days, about 207 days, about 208 days, about 209 days, about 210 days, about 211 days, about 212 days, about 213 days, about 214 days, about 215 days, about 216 days, about 217 days, about 218 days, about 219 days, about 220 days, about 221 days, about 222 days, about 223 days, about 224 days, about 225 days, about 226 days, about 227 days, about 228 days, about 229 days, about 230 days, about 231 days, about 232 days, about 233 days, about 234 days, about 235 days, about 236 days, about 237 days, about 238 days, about 239 days, about 240 days, about 241 days, about 242 days, about 243 days, about 244 days, about 245 days, about 246 days, about 247 days, about 248 days, about 249 days, about 250 days, about 251 days, about 252 days, about 253 days, about 254 days, about 255 days, about 256 days, about 257 days, about 258 days, about 259 days, about 260 days, about 261 days, about 262 days, about 263 days, about 264 days, about 265 days, about 266 days, about 267 days, about 268 days, about 269 days, about 270 days, about 271 days, about 272 days, about 273 days, about 274 days, about 275 days, about 276 days, about 277 days, about 278 days, about 279 days, about 280 days, about 281 days, about 282 days, about 283 days, about 284 days, about 285 days, about 286 days, about 287 days, about 288 days, about 289 days, about 290 days, about 291 days, about 292 days, about 293 days, about 294 days, about 295 days, about 296 days, about 297 days, about 298 days, about 299 days, about 300 days, about 301 days, about 302 days, about 303 days, about 304 days, about 305 days, about 306 days, about 307 days, about 308 days, about 309 days, about 310 days, about 311 days, about 312 days, about 313 days, about 314 days, about 315 days, about 316 days, about 317 days, about 318 days, about 319 days, about 320 days, about 321 days, about 322 days, about 323 days, about 324 days, about 325 days,IPTS / 128916176.1 31about 326 days, about 327 days, about 328 days, about 329 days, about 330 days, about 331 days, about 332 days, about 333 days, about 334 days, about 335 days, about 336 days, about 337 days, or about 338 days after a first loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a third maintenance dose about 198 days to about 338 days after a first loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a third maintenance dose about 200 days to about 320 days after a first loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a third maintenance dose about 210 days to about 310 days after a first loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a third maintenance dose about 226 days after a first loading dose. In some embodiments, the method of treating Angelman syndrome comprises administering a third maintenance dose about 310 days after a first loading dose.

[0169] In some embodiments, the method of treating Angelman syndrome comprises administering a third maintenance dose about 28 days, about 29 days, about 30 days, about 31 days, about 32 days, about 33 days, about 34 days, about 35 days, about 36 days, about 37 days, about 38 days, about 39 days, about 40 days, about 41 days, about 42 days, about 43 days, about 44 days, about 45 days, about 46 days, about 47 days, about 48 days, about 49 days, about 50 days, about 51 days, about 52 days, about 53 days, about 54 days, about 55 days, about 56 days, about 57 days, about 58 days, about 59 days, about 60 days, about 61 days, about 62 days, about 63 days, about 64 days, about 65 days, about 66 days, about 67 days, about 68 days, about 69 days, about 70 days, about 71 days, about 72 days, about 73 days, about 74 days, about 75 days, about 76 days, about 77 days, about 78 days, about 79 days, about 80 days, about 81 days, about 82 days, about 83 days, about 84 days, about 85 days, about 86 days, about 87 days, about 88 days, about 89 days, about 90 days, about 91 days, about 92 days, about 93 days, about 94 days, about 95 days, about 96 days, about 97 days, about 98 days, about 99 days, about 100 days, about 101 days, about 102 days, about 103 days, about 104 days, about 105 days, about 106 days, about 107 days, about 108 days, about 109 days, about 110 days, about 111 days, about 112 days, about 113 days, about 114 days, about 115 days, about 116 days, about 117 days, about 118 days, about 119 days, about 120 days, about 121 days, about 122 days, about 123 days, about 124 days, about 125 days, about 126 days, about 127 days, about 128 days, about 129 days, about 130 days, about 131 days, or about 132 days after a second maintenance dose. In some embodiments, the method of treating Angelman syndrome comprises administering a third maintenance dose about 28 days to aboutIPTS / 128916176.1 3284 days after a second maintenance dose. In some embodiments, the method of treating Angelman syndrome comprises administering a third maintenance dose about 35 days to about 75 days after a second maintenance dose. In some embodiments, the method of treating Angelman syndrome comprises administering a third maintenance dose about 45 days to about 65 days after a second maintenance dose. In some embodiments, the method of treating Angelman syndrome comprises administering a third maintenance dose about 56 days after a second maintenance dose. In some embodiments, the method of treating Angelman syndrome comprises administering a third maintenance dose about 56 days to about 132 days after a second maintenance dose. In some embodiments, the method of treating Angelman syndrome comprises administering a third maintenance dose about 70 days to about 100 days after a second maintenance dose. In some embodiments, the method of treating Angelman syndrome comprises administering a third maintenance dose about 75 days to about 90 days after a second maintenance dose. In some embodiments, the method of treating Angelman syndrome comprises administering a third maintenance dose about 84 days after a second maintenance dose.

[0170] In some embodiments, the method of treating Angelman syndrome comprises administering one or more additional maintenance doses of an antisense compound (e.g., an antisense compound having a nucleic acid sequence SEQ ID NO: 1 or a modified nucleic acid sequence of SEQ ID NO: 2). In various embodiments, an additional maintenance dose comprises an equal dose of the antisense compound in comparison to a third maintenance dose. For example, the third maintenance dose may comprise about 14 mg of an antisense compound and the additional maintenance dose may comprise about 14 mg of an antisense compound. In various embodiments, the additional maintenance dose comprises a higher dose of the antisense compound in comparison to the third maintenance dose.

[0171] In some embodiments, the method of treating Angelman syndrome comprises administering one or more additional maintenance doses each comprising about 8 mg, about 8.5 mg, about 9 mg, about 9.5 mg, about 10 mg, about 10.5 mg, about 11 mg, about 11.5 mg, about 12 mg, about 12.5 mg, about 13 mg, about 13.5 mg, about 14 mg, about 14.5 mg, about 15 mg, about 15.5 mg, or about 16 mg of an antisense compound. In some embodiments, an additional maintenance dose comprises about 10 mg to about 16 mg of an antisense compound. In some embodiments, an additional maintenance dose comprises about 11 mg to about 15.5 mg of an antisense compound. In some embodiments, an additional maintenance dose comprises about 12 mg to about 15 mg of an antisense compound. In some embodiments, anIPTS / 128916176.1 33additional maintenance dose comprises about 13 mg to about 14.5 mg of an antisense compound. In some embodiments, an additional maintenance dose comprises about 14 mg of an antisense compound.

[0172] In some embodiments, the method of treating Angelman syndrome comprises administering additional maintenance doses Q2M or Q3M. As used herein, “Q2M” refers to a bimonthly administration (e.g., once every two months). In some embodiments, the method of treating Angelman syndrome comprises administering further maintenance doses Q2M. In some embodiments, the method of treating Angelman syndrome comprises administering further maintenance doses Q3M. In various embodiments, a monthly administration refers to an administration every 28 days, every 29 days, every 30 days, or every 31 days. In particular embodiments, a monthly administration refers to an administration every 28 days and therefore, Q2M refers to a bimonthly administration of every 56 days. As used herein, “Q3M” refers to a trimonthly administration (e.g., once every three months). In particular embodiments, a monthly administration refers to an administration every 28 days and therefore, Q3M refers to a trimonthly or quarterly administration of every 84 days.

[0173] In various embodiments, the method of treating Angelman syndrome comprises (a) administering a first loading dose of about 5 mg to about 10 mg of an antisense compound comprising a nucleic acid sequence complementary to a UBE3A-AS transcript (e.g., an antisense compound comprising the nucleic acid sequence of SEQ ID NO 1 or 2); (b) administering a first maintenance dose of about 6 mg to about 14 mg of the antisense compound; and (c) administering a second maintenance dose of about 8 mg to about 16 mg of the antisense compound.

[0174] In various embodiments, the method of treating Angelman syndrome comprises (a) administering a first loading dose of about 6 mg to about 9 mg, about 7 mg to about 8.5 mg, or about 8 mg of an antisense compound comprising a nucleic acid sequence complementary to a UBE3A-AS transcript (e.g., an antisense compound comprising the nucleic acid sequence of SEQ ID NO 1 or 2); (b) administering a first maintenance dose of about 8.5 mg to about 15 mg, about 9 mg to about 14 mg, about 9.5 mg to about 12 mg, or about 10 mg of the antisense compound; and (c) administering a second maintenance dose of about 9 mg to about 15 mg, about 10 mg to about 14 mg, about 11 mg to about 13 mg, about 12 mg, or about 14 mg of the antisense compound. In some embodiments, the method of treating Angelman syndrome further comprises administering a second loading dose of about 6 mg to about 9 mg, about 7 mg to about 8.5 mg, or about 8 mg of an antisense compound; administering a third loadingIPTS / 128916176.1 34dose of about 6 mg to about 9 mg, about 7 mg to about 8.5 mg, or about 8 mg of an antisense compound. In some embodiments, the method of treating Angelman syndrome further comprises administering a fourth loading dose of about 6 mg to about 9 mg, about 7 mg to about 8.5 mg, or about 8 mg of an antisense compound. In some embodiments, the method of treating Angelman syndrome does not comprise administering a fourth loading dose. In some embodiments, the method of treating Angelman syndrome further comprises administering a third maintenance dose of about 9 mg to about 15 mg, about 10 mg to about 14 mg, about 11 mg to about 13 mg, or about 14 mg of the antisense compound. In some embodiments, the method of treating Angelman syndrome further comprises administering a fourth maintenance dose of about 9 mg to about 15 mg, about 10 mg to about 14 mg, about 11 mg to about 13 mg, about 12 mg, or about 14 mg of the antisense compound. In some embodiments, the method of treating Angelman syndrome further comprises administering additional maintenance doses of about 9 mg to about 15 mg, about 10 mg to about 14 mg, about 11 mg to about 13 mg, about 12 mg, or about 14 mg of the antisense compound.

[0175] In various embodiments, the method of treating Angelman syndrome comprises administering a first loading dose on about day 1, subsequently administering a first maintenance dose between about 28 to about 84 days, about 35 to about 75, about 45 to about 65, or about 56 days after the last loading dose, and subsequently administering a second loading dose between about 28 to about 84 days, about 35 to about 75, about 45 to about 65, or about 56 days after the first maintenance dose.

[0176] In various embodiments, methods of treating Angelman syndrome (AS) in a human subject in need thereof comprise administering a first loading dose of about 5 mg to about 10 mg of an antisense compound comprising a nucleic acid sequence complementary to a UBE3A- AS transcript, administering a second loading dose of about 8 mg of the antisense compound about 28 days after administration of the first loading dose; administering a third loading dose of about 8 mg of the antisense compound about 56 days after administration of the first loading dose; administering a first maintenance dose of about 6 mg to about 14 mg of the antisense compound; administering a second maintenance dose of about 8 mg to about 16 mg of the antisense compound, and administering a third maintenance dose comprising a dose of about 14 mg of the antisense compound about 56 days after administration of the second maintenance dose.

[0177] In various embodiments, methods of treating Angelman syndrome (AS) in a human subject in need thereof comprise administering a first loading dose of about 8 mg of anIPTS / 128916176.1 35antisense compound comprising a nucleic acid sequence complementary to a UBE3A-AS transcript, administering a second loading dose of about 8 mg of the antisense compound about 28 days after administration of the first loading dose; administering a third loading dose of about 8 mg of the antisense compound about 56 days after administration of the first loading dose; administering a first maintenance dose of about 10 mg of the antisense compound about 57 days after administration of the third loading dose; administering a second maintenance dose of about 12 mg of the antisense compound about 56 days after administration of the first maintenance dose, and administering a third maintenance dose comprising a dose of about 14 mg of the antisense compound about 56 days after administration of the second maintenance dose.

[0178] In various embodiments, methods of treating Angelman syndrome (AS) in a human subject in need thereof comprise administering a first loading dose of about 5 mg to about 10 mg of an antisense compound comprising a nucleic acid sequence complementary to a UBE3A- AS transcript; administering a second loading dose of about 8 mg of the antisense compound about 28 days after administration of the first loading dose; administering a third loading dose of about 8 mg of the antisense compound about 56 days after administration of the first loading dose; and administering a fourth loading dose of about 8 mg of the antisense compound about 84 days after administration of the first loading dose; administering a first maintenance dose of about 6 mg to about 14 mg of the antisense compound; administering a second maintenance dose of about 8 mg to about 16 mg of the antisense compound, and administering a third maintenance dose comprising a dose of about 14 mg of the antisense compound about 84 days after administration of the second maintenance dose.

[0179] In various embodiments, methods of treating Angelman syndrome (AS) in a human subject in need thereof comprise administering a first loading dose of about 8 mg of an antisense compound comprising a nucleic acid sequence complementary to a UBE3A-AS transcript; administering a second loading dose of about 8 mg of the antisense compound about 28 days after administration of the first loading dose; administering a third loading dose of about 8 mg of the antisense compound about 56 days after administration of the first loading dose; and administering a fourth loading dose of about 8 mg of the antisense compound about 84 days after administration of the first loading dose; administering a first maintenance dose of about 10 mg of the antisense compound about 56 days after administration of the fourth loading dose; administering a second maintenance dose of about 14 mg of the antisense compound about 84 days after administration of the first maintenance dose, and administeringIPTS / 128916176.1 36a third maintenance dose comprising a dose of about 14 mg of the antisense compound about 84 days after administration of the second maintenance dose.

[0180] In some embodiments, methods of treating Angelman syndrome (AS) in a human subject in need thereof comprise administering a first loading dose of about 2 mg to about 6 mg of an antisense compound, wherein the antisense compound comprises a nucleic acid sequence complementary to a UBE3A-AS transcript; administering a first maintenance dose of about 4 mg to about 8 mg of the antisense compound; and administering a second maintenance dose of about 6 mg to about 10 mg of the antisense compound to the human subject. The first loading dose may comprise from about 3 mg to about 5 mg, or about 4 mg of the antisense compound. The method may further comprise administering a second loading dose. The second loading dose may comprise from about 2 mg to about 6 mg, about 3 mg to about 5 mg, or about 4 mg of the antisense compound.

[0181] In some embodiments, the methods involve administering one or more loading doses and one or more maintenance doses of an antisense compound comprising a nucleic acid sequence of SEQ ID NO: 1. In various embodiments, the methods involve administering one or more loading doses and one or more maintenance doses of an antisense compound comprising a modified nucleic acid sequence of SEQ ID NO: 2.

[0182] In some embodiments, the second loading dose may be administered between about 21 days to about 35 days, about 22 days to about 34 days, about 23 days to about 33 days, about 24 days to about 32 days, about 25 days to about 31 days, about 26 days to about 30 days, about 27 days to about 29 days, or about 28 days after the first loading dose.

[0183] In some embodiments, the methods may further comprise administering a third loading dose. The third loading dose may comprise from about 2 mg to about 6 mg, about 3 mg to about 5 mg, or about 4 mg of the antisense compound. In some embodiments, the third loading dose may be administered between about 21 days to about 35 days, about 22 days to about 34 days, about 23 days to about 33 days, about 24 days to about 32 days, about 25 days to about 31 days, about 26 days to about 30 days, about 27 days to about 29 days, or about 28 days after the second loading dose. In some embodiments, the method does not include administering a fourth loading dose.

[0184] Some embodiments of the method may further comprise positioning the human subject into an inverted position after administration of the first, second, and / or third loading dose. For example, the method may comprise positioning the human subject into theIPTS / 128916176.1 37Trendelenburg position. The human subject may be positioned in the inverted position for about 30 minutes to about 60 minutes, about 40 minutes to about 50 minutes, or about 45 minutes.

[0185] In some embodiments, the first maintenance dose may comprise from about 5 mg to about 7 mg, or about 6 mg of the antisense compound. The first maintenance dose may be administered between about 50 days to about 70 days, about 51 days to about 67 days, about 52 days to about 64 days, about 53 days to about 61 days, about 54 days to about 58 days, about 55 days to about 57 days, or about 56 days after a final loading dose. The method may comprise a lapse period between a final loading dose and the first maintenance dose, wherein the lapse period is between about 28 days to about 56 days, between about 35 days to about 49 days, about 28 days, or about 56 days.

[0186] In some embodiments, the second maintenance dose may comprise from about 7 mg to about 9 mg, or about 8 mg of the antisense compound. The second maintenance dose may be administered between about 50 days to about 90 days, about 51 days to about 80 days, about 52 days to about 70 days, about 53 days to about 60 days, about 54 days to about 57 days, or about 56 days after administration of the first maintenance dose. The second maintenance dose may be administered between about 50 days to about 90 days, about 60 days to about 89 days, about 70 days to about 88 days, about 80 days to about 87 days, about 82 days to about 88 days, or about 84 days after administration of the first maintenance dose.

[0187] In some embodiments, the methods may further comprise administering one or more additional maintenance doses comprising from about 6 mg to about 12 mg of the antisense compound, wherein each of the one or more additional maintenance doses is equal to or higher than the second maintenance dose. Each of the one or more additional maintenance doses may comprise from about 7 to about 11 mg, or about 10 mg of the antisense compound. One of the one or more additional maintenance doses may be administered between about 50 days to about 90 days, about 51 days to about 80 days, about 52 days to about 70 days, about 53 days to about 60 days, about 54 days to about 57 days, or about 56 days after administration of the second maintenance dose. One of the one or more additional maintenance doses may be administered between about 50 days to about 90 days, about 60 days to about 89 days, about 70 days to about 88 days, about 80 days to about 87 days, about 82 days to about 88 days, or about 84 days after administration of the second maintenance dose. The one or more additional maintenance doses may be administered Q2M. The one or more additional maintenance doses may be administered Q3M. In some cases, the second maintenance dose is higher than the firstIPTS / 128916176.1 38maintenance dose. In some cases, a subsequent maintenance dose is higher than the preceding maintenance dose.

[0188] In some embodiments, the method may further comprise: administering a second loading dose of about 4 mg of the antisense compound about 28 days after administration of the first loading dose; administering a third loading dose of about 4 mg of the antisense compound about 56 days after administration of the first loading dose; and administering a third maintenance dose comprising a dose of about 10 mg of the antisense compound about 56 days after administration of the second maintenance dose, wherein the first loading dose comprises a dose of about 4 mg of the antisense compound, the first maintenance dose comprises a dose of about 6 mg of the antisense compound and is administered about 56 days after administration of the third loading dose, and the second maintenance dose comprises a dose of about 8 mg of the antisense compound and is administered about 56 days after administration of the first maintenance dose.

[0189] In some embodiments, the method may further comprise: administering a second loading dose of about 4 mg of the antisense compound about 28 days after administration of the first loading dose; administering a third loading dose of about 4 mg of the antisense compound about 56 days after administration of the first loading dose; and administering a fourth loading dose of about 4 mg of the antisense compound about 84 days after administration of the first loading dose; and administering a third maintenance dose comprising a dose of about 10 mg of the antisense compound about 84 days after administration of the second maintenance dose, wherein the first loading dose comprises a dose of about 4 mg of the antisense compound, the first maintenance dose comprises a dose of about 6 mg of the antisense compound and is administered about 56 days after administration of the fourth loading dose, the second maintenance dose comprises a dose of about 8 mg of the antisense compound and is administered about 84 days after administration of the first maintenance dose.

[0190] In some embodiments, the methods of treating Angelman syndrome comprise administering a first loading dose of an antisense compound to a human subject who is less than 4 years of age. The human subject may be greater than 12 months of age and less than 4 years of age. The human subject may be greater than 12 months of age and less than 4 years of age at the time of administering the first loading dose. The method may comprise administering the second loading dose or a dose subsequent to the second loading dose after the human subject achieves the age of 4 years. The method may comprise increasing the amount of the antisense compound administered to the human subject having achieved the age of 4 years by about 2IPTS / 128916176.1 39mg per dose of the antisense compound up to a maximum of about 12 mg to about 16 mg of the antisense compound. The method may comprise increasing the amount of the antisense compound administered to the human subject having achieved the age of 4 years by about 2 mg per dose of the antisense compound up to a maximum of about 14 mg of the antisense compound. Example Antisense Compound

[0191] Disclosed herein are methods for treating Angelman syndrome (AS) in a human subject in need thereof by administering an antisense compound. In various embodiments, an antisense compound comprises an antisense oligonucleotide (ASO) designed to target exons at the 5′-end of the SNORD115 host-gene transcript (AF400500), which encompasses SNORD115-46, SNORD115-47, SNORD115-48, and SNORD109B snoRNAs and is thought to represent the 5′-end of the UBE3A antisense transcript (UBE3A-AS). Additional antisense oligonucleotides (ASOs) are described in WO2019109001, which is incorporated by reference in its entirety.

[0192] In various embodiments, the antisense compound comprises a nucleic acid sequence complementary to a UBE3A-AS transcript. In various embodiments, an antisense compound comprises a contiguous nucleotide sequence of 10 to 30 nucleotides in length with at least 90% complementary, such as at least 91%, such as at least 92%, such as at least 93%, such as at least 94%, such as at least 95%, such as at least 96%, such as at least 97%, such as at least 98%, or 100% complementarity to one of five E-3 exons located in the 5′-end of UBE3A-AS disclosed herein. In particular the target nucleic acid can be the 5′-end of UBE3A-AS, corresponding to position 25,511,577 to 25,516,681 on human chromosome 15 human genome assembly hg19. In some embodiments, the target nucleic acid is one of five E-3 exons located in the 5′-end of UBE3A-AS, which can correspond to positions 25,511,577 to 25,511,761 (exon E-3.1), 25,512,059 to 25,512,191 (exon E-3.2), 25,513,476 to 25,513,600 (exon E-3.3), 25,514,752 to 25,514,880 (exon E-3.4), and 25,516,565 to 25,516,681 (exon E-3.5). Therefore, in some embodiments, the target nucleic acid comprises a nucleic acid sequence of one or more of exon E-3.1 (SEQ ID NO: 3), exon E-3.2 (SEQ ID NO.4), exon E-3.3 (SEQ ID NO.5), exon E-3.4 (SEQ ID NO: 6), or exon E-3.5 (SEQ ID NO: 7). In some embodiments, the target nucleic acid comprises a nucleic acid sequence of exon E-3.1 (SEQ ID NO: 3). In some embodiments, the target nucleic acid comprises a nucleic acid sequence of exon E-3.2 (SEQ ID NO: 4). In some embodiments, the target nucleic acid comprises a nucleic acid sequence of exon E-3.3 (SEQ ID NO: 5). In some embodiments, the target nucleic acid comprises a nucleic acidIPTS / 128916176.1 40sequence of exon E-3.4 (SEQ ID NO: 6). In some embodiments, the target nucleic acid comprises a nucleic acid sequence of exon E-3.5 (SEQ ID NO: 7).

[0193] In various embodiments, the antisense compound is capable of modulating expression of paternal UBE3A, in particular induction or up-regulation of paternally expressed UBE3A in neuronal cells. The modulation is achieved by hybridizing to the 5′-end of UBE3A- AS. In certain embodiments the antisense compound disclosed herein hybridizes to a sub- sequence of the target nucleic acid of SEQ ID NO: 4 with a ΔG° below −10 kcal, such as with a ΔG° between −10 to −60 kcal, such as −12 to −40, such as from −15 to −30 kcal or −16 to −27 kcal such as −18 to −25 kcal.

[0194] In some embodiments the disclosed antisense compound is capable of increasing the expression of UBE3A by least 20% compared to the expression level of UBE3A in a neuronal cell treated with saline or a non-targeting oligonucleotide, more preferably by at least 30%, 35%, 40%, 45%, 50%, 55%, 60%, 80%, 100%, 120%, 150%, 160%, 170%, 180%, 190%, 200%, 210%, 220%, 230%, 240% or 250% compared to the expression level of UBE3A in a neuronal cell treated with saline or a non-targeting oligonucleotide.

[0195] Target modulation by the disclosed antisense compound is triggered by hybridization between a contiguous nucleotide sequence of the antisense compound and the target nucleic acid. In some embodiments the disclosed antisense compound comprises mismatches between the antisense compound and the target nucleic acid. Despite mismatches hybridization to the target nucleic acid may still be sufficient to show a desired modulation of UBE3A expression. Reduced binding affinity resulting from mismatches may advantageously be compensated by increased number of nucleotides in the antisense compound and / or an increased number of modified nucleosides capable of increasing the binding affinity to the target, such as 2′ modified nucleosides, including LNA, present within the antisense compound sequence.

[0196] Oligonucleotide design refers to the pattern of nucleoside sugar modifications in the oligonucleotide sequence of the disclosed antisense compounds. Modifications of the antisense oligonucleotide sequence are described in WO2019109001, which is incorporated by reference in its entirety. In some embodiments, the disclosed antisense compound comprises DNA and RNA nucleosides. In some embodiments, the antisense compound comprises at least one modified internucleoside linkage. In some embodiments, the internucleoside linkages within the contiguous nucleotide sequence are phosphorothioate linkages. In some embodiments, theIPTS / 128916176.1 41disclosed antisense compound comprises one or more sugar modified nucleosides, such as 2′ sugar modified nucleosides. In some embodiments, the disclosed antisense compound comprises one or more locked nucleic acid (LNA) nucleosides.

[0197] In some embodiments, the disclosed antisense compound comprises at least one LNA unit, such as 1, 2, 3, 4, 5, 6, 7, or 8 LNA units, such as from 2 to 6 LNA units, such as from 3 to 7 LNA units, 4 to 8 LNA units or 3, 4, 5, 6 or 7 LNA units. In some embodiments, all the modified nucleosides are LNA nucleosides. In some embodiments, LNA comprises a 2′-4′ biradical bridge of -L-, wherein -L- is —OCH2—, wherein —CH2— is optionally substituted. In some embodiments, LNA comprises a 2′-4′ biradical bridge of -L-, wherein -L- is —O—CH2—. In some embodiments, LNA comprises a 2′-4′ biradical bridge of -L-, wherein -L- is —O—CH(Et)-. In a further embodiment, the antisense compound may comprise both beta-D-oxy-LNA, and one or more of the following LNA units: thio-LNA, amino-LNA, oxy- LNA, and / or ENA in either the beta-D or alpha-L configurations or combinations thereof. In a further embodiment, all LNA cytosine units are 5-methyl-cytosine. In some embodiments, the antisense compound or contiguous nucleotide sequence has at least 1 LNA unit at the 5′ end and at least 2 LNA units at the 3′ end of the nucleotide sequence.

[0198] In some embodiments, the disclosed antisense compound comprises a backbone nucleic acid sequence AGAATGGCACATCTCTTG (SEQ ID NO.1). In some embodiments, the disclosed antisense compound comprises the modified nucleotide sequence AL*GL*AL*a*t*g*g*c*a*c*a*t*c*t*5mCL*TL*TL*GL(SEQ ID NO: 2) wherein capital letters denote RNA nucleosides; lower case letters denote DNA nucleosides; 5mC denotes a 5- methylcytosine nucleoside; superscript L denotes a locked nucleic acid (LNA) nucleoside; and asterisks denote phosphorothioate internucleoside linkages.

[0199] Methods for manufacturing the disclosed antisense compound are known. In some cases, the method uses phosphoramidite chemistry (see for example Caruthers et al, 1987, Methods in Enzymology vol.154, pages 287-313). In a further embodiment the method further comprises reacting the contiguous nucleotide sequence with a conjugating moiety (ligand).

[0200] In some embodiments, oligonucleotide synthesis methodologies are utilized that provide control of stereochemistry at one or more modified internucleoside linkages that include(s) a chiral atom. See, for example, WO2010 / 064146, WO2014 / 012081, WO2015 / 107425, WO2016 / 079183, WO2016 / 079181, WO2016 / 096938, WO2017 / 194498, and WO2018 / 177825, which are incorporated by reference for these methodologies.IPTS / 128916176.1 42

[0201] Those skilled in the art will appreciate that the useful nucleic acids provided by the present disclosure include those that store and / or express sequences of oligonucleotides described herein. In some embodiments, such nucleic acids may be or comprise vectors appropriate for delivery into and / or replication and / or expression in a cell (e.g., a microbial cell, for example for production and / or a mammalian cell, for example for treatment). Those skilled in the art are aware of a variety of technologies (e.g., recombinant nucleic acid technologies such as, for instance, that utilize one or more of amplification such as by polymerase chain reaction, cleavage such as by restriction digestion, linkage such as by ligation—whether in vitro or in vivo e.g., by gap repair, etc.). Target concentration of antisense compound in brain of a patient administered the antisense compound

[0202] In various embodiments, methods disclosed herein for administering an antisense compound for treating Angelman syndrome (AS) achieve a target concentration of about 6500 ng / g of the antisense compound in the brain of a patient. In various embodiments, methods disclosed herein for administering an antisense compound for treating Angelman syndrome (AS) achieve a target concentration under about 6500 ng / g of the antisense compound in the brain of a patient. In various embodiments, methods disclosed herein for administering an antisense compound for treating Angelman syndrome (AS) achieve a target concentration between 500 ng / g and 8000 ng / g. In various embodiments, methods disclosed herein for administering an antisense compound for treating Angelman syndrome (AS) achieve a target concentration between 1500 ng / g and 7500 ng / g. In various embodiments, methods disclosed herein for administering an antisense compound for treating Angelman syndrome (AS) achieve a target concentration between 3000 ng / g and 7000 ng / g. In various embodiments, methods disclosed herein for administering an antisense compound for treating Angelman syndrome (AS) achieve a target concentration between 5000 ng / g and 6750 ng / g. In various embodiments, methods disclosed herein for administering an antisense compound for treating Angelman syndrome (AS) achieve a target concentration of about 6500 ng / g. In some embodiments, methods disclosed herein for administering an antisense compound for treating Angelman syndrome (AS) that achieve the target concentration in the brain have reduced risk of radiculopathy in the subject being treated for Angelman syndrome (AS).

[0203] In various embodiments, the method of treating Angelman syndrome disclosed herein maintains the target concentration between the first loading dose and a first maintenance dose. In various embodiments, the method of treating Angelman syndrome disclosed hereinIPTS / 128916176.1 43maintains the target concentration between the first loading dose and a second maintenance dose. In various embodiments, the method of treating Angelman syndrome disclosed herein maintains the target concentration between the first loading dose and a third maintenance dose. In various embodiments, the method of treating Angelman syndrome disclosed herein maintains the target concentration between the first loading dose and a fourth maintenance dose. In various embodiments, the method of treating Angelman syndrome disclosed herein maintains the target concentration between the first loading dose and a fifth maintenance dose. In various embodiments, the method of treating Angelman syndrome disclosed herein maintains the target concentration between the first loading dose and a tenth maintenance dose. In various embodiments, the method of treating Angelman syndrome disclosed herein maintains the target concentration between the first loading dose and a 20thmaintenance dose. In various embodiments, the method of treating Angelman syndrome disclosed herein maintains the target concentration between the first loading dose and a 30thmaintenance dose. In various embodiments, the method of treating Angelman syndrome disclosed herein maintains the target concentration between the first loading dose and a 40thmaintenance dose. In various embodiments, the method of treating Angelman syndrome disclosed herein maintains the target concentration between the first loading dose and a 50thmaintenance dose. In various embodiments, the method of treating Angelman syndrome disclosed herein maintains the target concentration between the first loading dose and a 60thmaintenance dose. In various embodiments, the method of treating Angelman syndrome disclosed herein maintains the target concentration between the first loading dose and any number of maintenance doses. Methods for reducing radiculopathy in a subject administered an antisense compound

[0204] In some embodiments, methods disclosed herein for treating Angelman syndrome in a human subject in need thereof reduces the risk of radiculopathy in the subject. Radiculopathy refers to a nerve injury that may result in numbness, weakness, pain, or tingling. In various embodiments, the risk of radiculopathy may arise from an injury or response in the spine at or near the location where the antisense compound is administered to the subject.

[0205] In various embodiments, reducing radiculopathy in a subject administered an antisense compound involves maintaining below a maximum concentration of the antisense compound in the brain. By ensuring that the concentration of the antisense compound in the subject’s brain does not exceed above a maximum concentration, this can reduce the risk ofIPTS / 128916176.1 44developing radiculopathy, e.g., at or near the location where the antisense compound is administered to the subject. Example maximum concentrations of the antisense compound in the brain are further disclosed herein and may be referred to as a target concentration. For example, reducing radiculopathy in a subject administered an antisense compound involves maintaining below a maximum concentration of about 6500 ng / g of the antisense compound in the subject’s brain.

[0206] In some embodiments, reducing radiculopathy in a subject administered an antisense compound involves positioning the subject in an inverted position. Generally, an inverted position refers to a position in which the subject’s feet are elevated above the subject’s head. This may enable the improved distribution of the administered antisense compound away from the site of administration, thereby reducing the risk of radiculopathy. In some embodiments, the inverted position is the Trendelenburg position. The Trendelenburg position refers to a position where the subject’s body is lain supine on a 15-30 degree incline with the subject’s feet elevated above the subject’s head.

[0207] In various embodiments, the subject is positioned in an inverted position after a loading dose. In various embodiments, the subject is positioned in an inverted position after a maintenance dose. In various embodiments, the subject is positioned in an inverted position after a loading dose and is further positioned in an inverted position after a maintenance dose. In various embodiments, the subject is positioned in an inverted position after every loading dose and is further positioned in an inverted position after every maintenance dose.

[0208] In some embodiments the subject is maintained in the inverted position for about 15 minutes to about 60 minutes after administration of the antisense compound. In some embodiments the subject is maintained in the inverted position for about 30 minutes to about 50 minutes after administration of the antisense compound. In some embodiments the subject is maintained in the inverted position for about 35 minutes to about 48 minutes after administration of the antisense compound. In some embodiments the subject is maintained in the inverted position for about 40 minutes to about 46 minutes after administration of the antisense compound.

[0209] In some embodiments the subject is maintained in the inverted position for about 10 minutes, 11 minutes, for about 12 minutes, for about 13 minutes, for about 14 minutes, for about 15 minutes, for about 16 minutes, for about 17 minutes, for about 18 minutes, for about 19 minutes, for about 20 minutes, for about 21 minutes, for about 22 minutes, for about 23IPTS / 128916176.1 45minutes, for about 24 minutes, for about 25 minutes, for about 26 minutes, for about 27 minutes, for about 28 minutes, for about 29 minutes, for about 30 minutes, for about 31 minutes, for about 32 minutes, for about 33 minutes, for about 34 minutes, for about 35 minutes, for about 36 minutes, for about 37 minutes, for about 38 minutes, for about 39 minutes, for about 40 minutes, for about 41 minutes, for about 42 minutes, for about 43 minutes, for about 44 minutes, for about 45 minutes, for about 46 minutes, for about 47 minutes, for about 48 minutes, for about 49 minutes, for about 50 minutes, for about 51 minutes, for about 52 minutes, for about 53 minutes, for about 54 minutes, for about 55 minutes, for about 56 minutes, for about 57 minutes, for about 58 minutes, for about 59 minutes, or for about 60 minutes after administration of the antisense compound. In particular embodiments the subject is maintained in the inverted position for about 30 minutes after administration of the antisense compound. In particular embodiments the subject is maintained in the inverted position for about 45 minutes after administration of the antisense compound.

[0210] In some embodiments, reducing radiculopathy in a subject administered an antisense compound involves administering a flush of artificial cerebrospinal fluid (aCSF). In various embodiments, the subject is administered an aCSF flush after a loading dose. In various embodiments, the subject is administered an aCSF flush after a maintenance dose. In various embodiments, the subject is administered an aCSF flush after a loading dose and is further administered an aCSF flush after a maintenance dose. In various embodiments, the subject is administered an aCSF flush after every loading dose and is further administered an aCSF flush after every maintenance dose.

[0211] In some embodiments, the subject is administered an aCSF flush of about 1 mL to about 10 mL of aCSF. In some embodiments, the subject administered about 2 mL to about 9 mL, about 3 mL to 8 mL, about 4 mL to 7 mL, or about 5 mL to 6 mL of aCSF. In various embodiments, the subject is administered at least 0.5 mL, at least 1 mL, at least 2 mL, at least 3 mL, at least 4 mL, at least 5 mL, at least 6 mL, at least 7 mL, at least 8 mL, at least 9 mL, at least 10 mL, at least 11 mL, at least 12 mL, at least 13 mL, at least 14 mL, at least 15 mL, at least 16 mL, at least 17 mL, at least 18 mL, at least 19 mL, or at least 20 mL or aCSF. In some embodiments, the subject is administered an aCSF flush of equivalent volume as the antisense compound administered, such that a patient receiving, e.g., 10 mL of a composition comprising the antisense compound also received a 10 mL aCSF flush following the administration of the antisense compound. In some embodiments, the aCSF flush is administered using the same needle that was used for administration of the antisense compound.IPTS / 128916176.1 46

[0212] In some embodiments, the subject is administered a bolus injection of the aCSF. For example, a bolus injection of aCSF can refer to an injection of aCSF that takes place over less than a threshold amount of time. In various embodiments, the threshold amount of time is less than 3 minutes, less than 2.9 minutes, less than 2.8 minutes, less than 2.7 minutes, less than 2.6 minutes, less than 2.5 minutes, less than 2.4 minutes, less than 2.3 minutes, less than 2.2 minutes, less than 2.1 minutes, less than 2.0 minutes, less than 1.9 minutes, less than 1.8 minutes, less than 1.7 minutes, less than 1.6 minutes, less than 1.5 minutes, less than 1.4 minutes, less than 1.3 minutes, less than 1.2 minutes, less than 1.1 minutes, less than 1.0 minutes, less than 0.9 minutes, less than 0.8 minutes, less than 0.7 minutes, less than 0.6 minutes, less than 0.5 minutes, less than 0.4 minutes, less than 0.3 minutes, less than 0.2 minutes, or less than 0.1 minutes. In various embodiments, the subject is administered a bolus injection of the aCSF over between 1 to 2 minutes.

[0213] In various embodiments, the subject is administered a continuous infusion of aCSF. A continuous infusion of aCSF can refer to a constant flow rate or the aCSF infused over at least 3 minutes. In various embodiments, the aCSF is continuously infused over at least 3 minutes, at least 4 minutes, at least 5 minutes, at least 6 minutes, at least 7 minutes, at least 8 minutes, at least 9 minutes, at least 10 minutes, at least 11 minutes, at least 12 minutes, at least 13 minutes, at least 14 minutes, at least 15 minutes, at least 16 minutes, at least 17 minutes, at least 18 minutes, at least 19 minutes, at least 20 minutes, at least 21 minutes, at least 22 minutes, at least 23 minutes, at least 24 minutes, at least 25 minutes, at least 26 minutes, at least 27 minutes, at least 28 minutes, at least 29 minutes, or at least 30 minutes.

[0214] In some embodiments, reducing radiculopathy in a subject administered an antisense compound involves pre-administering a steroid medication. In some embodiments a steroid premedication is administered prior to intrathecal (IT) lumbar puncture (LP) administration of a dose of the antisense compound. In various embodiments, the subject is administered a steroid premedication prior to a loading dose. In various embodiments, the subject is administered a steroid premedication prior to a maintenance dose. In various embodiments, the subject is administered a steroid premedication prior to a loading dose and is further administered a steroid premedication prior to a maintenance dose. In various embodiments, the subject is administered a steroid premedication prior to every loading dose and is further administered a steroid premedication prior to every maintenance dose.

[0215] In some embodiments, the steroid premedication comprises a corticosteroid. In some embodiments, the corticosteroid is dexamethasone. In some embodiments, administering theIPTS / 128916176.1 47steroid premedication comprises intravenously administering the steroid premedication. In some embodiments, administering the steroid premedication comprises orally administering the steroid premedication.

[0216] In some embodiments, intravenous administration of the steroid premedication comprises administering between about 0.1 mg / kg to about 1.0 mg / kg of the steroid. In some embodiments, administering the steroid premedication comprises administering between about 0.2 mg / kg to about 0.9 mg / kg, between about 0.3 mg / kg to about 0.8 mg / kg, between about 0.4 mg / kg to about 0.7 mg / kg, or between about 0.5 to about 0.6 mg / kg of the steroid. In particular embodiments, administering the steroid premedication comprises administering about 0.3 mg / kg of the steroid.

[0217] In various embodiments, administering the steroid premedication comprises intravenously administering about 0.3 mg / kg of dexamethasone, or a dose-equivalent of an alternative corticosteroid. In some embodiments, the steroid premedication is administered within about 0.5 hours to about 5 hours, within about 1 hour to about 4 hours, within about 1.5 hours to about 3 hours, or within about 2 hours prior to administration of the antisense compound.

[0218] In some embodiments, administering the steroid premedication comprises orally administering about 0.3 mg / kg of dexamethasone, or dose-equivalent of an alternative corticosteroid. In various embodiments, administering the steroid premedication comprises orally administering the steroid between about 8 hours and 48 hours prior to administering the antisense compound. In various embodiments, administering the steroid premedication comprises orally administering the steroid between about 12 hours and 36 hours prior to administering the antisense compound. In various embodiments, administering the steroid premedication comprises orally administering the steroid between about 18 hours and 30 hours prior to administering the antisense compound. In various embodiments, administering the steroid premedication comprises orally administering the steroid between about 20 hours and 28 hours prior to administering the antisense compound. In various embodiments, administering the steroid premedication comprises orally administering the steroid between about 22 hours and 26 hours prior to administering the antisense compound. In various embodiments, administering the steroid premedication comprises orally administering the steroid about 24 hours prior to administering the antisense compound.IPTS / 128916176.1 48Routes of Administration

[0219] The antisense compound, or pharmaceutical compositions thereof, may be administered to a subject via one or a variety of different routes of administration. In various embodiments, the antisense compound, or pharmaceutical compositions thereof, may be administered by topical (such as, to the skin, inhalation, ophthalmic or otic) or enteral (such as, orally or through the gastrointestinal tract) or parenteral (such as, intravenous, subcutaneous, intra-muscular, intracerebral, intracerebroventricular or intrathecal) administration. In some embodiments, the antisense compound, or pharmaceutical compositions thereof, are administered by a parenteral route including intravenous, intraarterial, subcutaneous, intraperitoneal or intramuscular injection or infusion, intrathecal or intracranial, e.g., intracerebral or intraventricular, administration. In some embodiments, the antisense compound, or pharmaceutical compositions thereof, is administered by intracerebral or intracerebroventricular injection. In some embodiments, the antisense compound, or pharmaceutical compositions thereof, is administered intrathecally. In some embodiments, the antisense compound, or pharmaceutical compositions thereof, is administered via a lumbar puncture (LP). In some embodiments, the antisense compound, or pharmaceutical compositions thereof, is administered by intracisterna magna injection.

[0220] In various embodiments, the steroid premedication and / or artificial cerebrospinal fluid (aCSF), as described herein, may be administered to a subject by one of a variety of routes, such as orally, intravenously, subcutaneously, intramuscularly, parenterally or by intrathecal (IT) lumbar puncture (LP). The most suitable route for administration in any given case will depend on the particular agent administered, the patient, pharmaceutical formulation methods, administration methods (e.g., administration time and administration route), the patient's age, body weight, sex, severity of the diseases being treated, the patient’s diet, and the patient’s excretion rate.

[0221] In some embodiments, the antisense compound is administered by intrathecal (IT) lumbar puncture (LP). In some embodiments, artificial cerebrospinal fluid (aCSF) is administered by intrathecal (IT) lumbar puncture (LP). In some embodiments, artificial cerebrospinal fluid (aCSF) is administered after each loading or maintenance dose of the antisense compound. In some embodiments, artificial cerebrospinal fluid (aCSF) is administered using the same needle used to administer the antisense compound. In some embodiments, the human subject is positioned into an inverted position after administration ofIPTS / 128916176.1 49the antisense compound. In some embodiments, the human subject is positioned into the Trendelenburg position.

[0222] In some embodiments, the steroid premedication is administered intravenously. In some embodiments, the steroid premedication is administered orally. Angelman syndrome in a human subject

[0223] Angelman syndrome (AS) is a neurodevelopmental disorder caused by genetic abnormalities in a region of human chromosome 15 harboring the ubiquitin protein ligase E3A (UBE3A) gene. The UBE3A gene is subject to genomic imprinting which is a naturally occurring phenomenon that turns off or suppresses expression of an allele of a gene. In most cell types of the body, both the maternal and paternal UBE3A alleles are expressed. In central nervous system neurons, the paternal UBE3A allele is turned-off by expression of the maternal UBE3A antisense transcript (UBE3A-AS), which is a component of a long RNA transcript that expresses several protein coding and noncoding transcripts. Thus, in neurons of the CNS, UBE3A-AS is expressed from the maternal allele and turns off expression of the paternal UBE3A allele. In patients harboring a deletion of or within the maternal UBE3A allele, natural imprinting of the paternal allele by maternal UBE3A-AS results in a deficiency of UBE3A expression, which is believed to underlie the disease state in Angelman syndrome. In addition to this Angelman syndrome maternal “deletion positive” genotype, AS can be caused by other genetic mechanisms, such as mutations affecting expression or function of the maternal UBE3A allele, imprinting center defects in the maternal allele, and paternal uniparental disomy (UPD).

[0224] As described herein, methods involve administering an antisense compound to a subject suffering from or susceptible to AS. In some embodiments, the subject is between about 0.5 years old (i.e., 0.5 years or 6 months of age) and about 18 years old (i.e., 18 years of age). In some embodiments, the subject is between about 1 year old and about 15 years old, between about 2 years old and about 14 years old, between about 3 years old and about 13 years old, between about 4 years old and about 12 years old, between about 5 years old and about 11 years old, between about 6 years old and about 10 years old, between about 7 years old and about 9 years old. In some embodiments, the subject is about 0.5 years old, about 1 year old, about 2 years old, about 3 years old, about 4 years old, about 5 years old, about 6 years old, about 7 years old, about 8 years old, about 9 years old, about 10 years old, about 11 years old,IPTS / 128916176.1 50about 12 years old, about 13 years old, about 14 years old, about 15 years old, about 16 years old, about 17 years old, about 18 years old, about 19 years old, or about 20 years old.

[0225] In some embodiments, a subject has been determined to have a deletion of or within the maternal UBE3A gene (referred to as the maternal deletion, or simply, deletion genotype). In some embodiments, a subject has been determined to have a different AS disease-causing genotype such as mutations affecting expression or function of the maternal UBE3A allele, imprinting center defects in the maternal allele, and paternal uniparental disomy (UPD).

[0226] In some embodiments, a subject has been determined to have one or more developmental history and / or laboratory finding characteristics that have been associated with AS such as, for example, one or more of: (i) normal prenatal and birth history with normal head circumference and absence of major birth defects; (ii) feeding difficulties as a neonate and / or as an infant; (iii) developmental delay evident by 6-12 months of age, sometimes associated with truncal hypotonus; (iv) unsteady limb movements and / or increased smiling; (v) delayed but forward progression of development (no loss of skills); (vi) normal metabolic, hematologic and chemical laboratory profiles; and (vii) structurally normal brain when assessed using MRI or CT (may have mild cortical atrophy or dysmyelination).

[0227] Alternatively or additionally, in some embodiments, a subject has been determined to display one or more clinical features that are consistently associated with AS such as, for example, one or more of: (i) developmental delay, functionally severe; (ii) movement or balance disorder, usually ataxia of gait and / or tremulous movement of limbs. In some embodiments, such movement disorder can be mild. In some embodiments, such movement disorder may not appear as frank ataxia but can be or involve, for example, forward lurching, unsteadiness, clumsiness, or quick, jerky motion;IPTS / 128916176.1 51(iii) behavioral uniqueness: any combination of frequent laughter / smiling; apparent happy demeanor; easily excitable personality, often with uplifted hand-flapping or waving movements; hypermotoric behavior; and (iv) speech impairment, such as for example absent or minimal use of words; alternatively or additionally, receptive and non-verbal communication skills higher than verbal ones.

[0228] Alternatively or additionally, in some embodiments, a subject has been determined to display one or more clinical features that are frequently (e.g., about 80% of the time) associated with AS such as, for example, one or more of: (i) delayed, disproportionate growth in head circumference, usually resulting in microcephaly (≤2 S.D. of normal OFC) by age 2 years. In some embodiments, microcephaly is more pronounced in those with 15q11.2-q13 deletions; (ii) seizures, onset usually <3 yrs. of age. In some embodiments, seizure severity may decrease with age but regardless, in some embodiments, the seizure disorder lasts throughout adulthood; and (iii) abnormal EEG, with a characteristic pattern, as is known in the art. In some embodiments, EEG abnormalities can occur in the first 2 years of life and can precede clinical features, and may not be correlated to clinical seizure events.

[0229] Alternatively or additionally, in some embodiments, a subject has been determined to display one or more clinical features that are sometimes (e.g., about 20-80% of the time) associated with AS such as, for example, one or more of: (i) flat occiput; (ii) occipital groove; (iii) protruding tongue; (iv) tongue thrusting; suck / swallowing disorders; (v) feeding problems and / or truncal hypotonia during infancy; (vi) prognathia; (vii) wide mouth, wide-spaced teeth; (viii) frequent drooling; (ix) excessive chewing / mouthing behaviors;IPTS / 128916176.1 52(x) strabismus; (xi) hypopigmented skin, light hair and eye color, in some embodiments determined as compared to family, and typically seen only in deletion cases; (xii) hyperactive lower extremity deep tendon reflexes; (xiii) uplifted, flexed arm position especially during ambulation; (xiv) wide-based gait with pronated or valgus-positioned ankles; (xv) increased sensitivity to heat; (xvi) abnormal sleep wake cycles and diminished need for sleep; (xvii) attraction to / fascination with water; fascination with crinkly items such as certain papers and plastics; (xviii) abnormal food related behaviors; (xix) obesity (in the older child); (xx) scoliosis; and (xxi) constipation.

[0230] In some embodiments, a subject who is administered an antisense compound has suffered or is suffering from one or more seizures and / or is receiving or has received anti- seizure therapy. In some embodiments, a subject may have received or be receiving one or more of valproic acid, clonazepam, phenobarbital, topiramate, carbamazepine, lamotrigine, leveltiracetam, phenytoin, zonisamide, ethosuxaminde, gabapentin, felbatame, oxcarbazepine, tranxene, ACTS, nitrazapam, pregabalin, mysoline, vigabatrin, etc. In some particular embodiments, a subject may have received or be receiving one or more of valproic acid, clonazepam, phenobarbital, topiramate, carbamazepine, lamotrigine, and / or levetiracetam. Alternatively or additionally, in some embodiments, a subject may have received or be receiving dietary therapy such as, for example, a ketogenic diet, low glycemic index therapy, etc. Still further alternatively or additionally, in some embodiments, a subject may have received or be receiving treatment with a vagal nerve stimulator. Patient Population

[0231] As disclosed herein, methods involve treating Angelman syndrome in a human subject in need thereof. In various embodiments, a human subject suffering from Angelman syndrome may be part of a patient population. In various embodiments, the subjects of theIPTS / 128916176.1 53patient population are diagnosed or suspected of having Angelman syndrome. In various embodiments, a human subject is suspected of having Angelman syndrome due to one or more of developmental history, laboratory finding characteristics, and / or exhibiting one or more clinical features of Angelman syndrome.

[0232] In various embodiments, a subject suffering from Angelman syndrome is part of a patient population of individuals affected by Angelman syndrome. In some embodiments, treating subjects of the patient population with the antisense compound disclosed herein is useful for evaluation of the efficacy of the antisense compound for treatment of Angelman syndrome across the patient population. In some embodiments, subjects of the patient population are treated with the antisense compound as part of a clinical trial. In some embodiments, treatment of the subjects of the patient population as part of a clinical trial is useful for evaluation of safety of treatment with the antisense compound, efficacy of treatment with the antisense compound, and side effects caused by treatment with the antisense compound.

[0233] In various embodiments, one or more subjects of the patient population are characterized by the presence of genetic defects associated with Angelman syndrome. In some embodiments, the patient population consists of patients having a maternal deletion genotype. In some embodiments, one or more subjects of the patient population include a UBE3A loss- of-function mutation. In some embodiments, one or more subjects of the patient population include a copy of the UBE3A gene (e.g., a maternal copy of the UBE3A gene) that is partially or completely deleted. In some embodiments, one or more subjects of the patient population include a loss-of-function of UBE3A gene on chromosome 15a11.2-q13. In some embodiments, one or more subjects of the patient population are characterized by a copy of the UBE3A gene that contains a missense mutation. In some embodiments, one or more subjects of the patient population exhibit an aberrant imprinting of the copy of the UBE3A allele, thereby turning expression of the gene off. In some embodiments, one or more subjects of the patient population have paternal uniparental disomy (UPD).

[0234] In various embodiments, one or more subjects may be analyzed for their genotypes to determine whether the one or more subjects are to be included in a patient population (e.g., for undergoing evaluation of an antisense compound). Thus, the patient population may include a proportion of subjects with a genetic defect associated with Angelman syndrome. In various embodiments, at least 5% of subjects in a patient population have a known genetic defect associated with Angelman syndrome. In some embodiments, at least 10% of subjects in aIPTS / 128916176.1 54patient population have a known genetic defect associated with Angelman syndrome. In some embodiments, at least 20% of subjects in a patient population have a known genetic defect associated with Angelman syndrome. In some embodiments, at least 30% of subjects in a patient population have a known genetic defect associated with Angelman syndrome. In some embodiments, at least 40% of subjects in a patient population have a known genetic defect associated with Angelman syndrome. In some embodiments, at least 50% of subjects in a patient population have a known genetic defect associated with Angelman syndrome. In some embodiments, at least 60% of subjects in a patient population have a known genetic defect associated with Angelman syndrome. In some embodiments, at least 70% of subjects in a patient population have a known genetic defect associated with Angelman syndrome. In some embodiments, at least 80% of subjects in a patient population have a known genetic defect associated with Angelman syndrome. In some embodiments, at least 90% of subjects in a patient population have a known genetic defect associated with Angelman syndrome. In some embodiments, at least 91% of subjects in a patient population have a known genetic defect associated with Angelman syndrome. In some embodiments, at least 92% of subjects in a patient population have a known genetic defect associated with Angelman syndrome. In some embodiments, at least 93% of subjects in a patient population have a known genetic defect associated with Angelman syndrome. In some embodiments, at least 94% of subjects in a patient population have a known genetic defect associated with Angelman syndrome. In some embodiments, at least 95% of subjects in a patient population have a known genetic defect associated with Angelman syndrome. In some embodiments, at least 96% of subjects in a patient population have a known genetic defect associated with Angelman syndrome. In some embodiments, at least 97% of subjects in a patient population have a known genetic defect associated with Angelman syndrome. In some embodiments, at least 98% of subjects in a patient population have a known genetic defect associated with Angelman syndrome. In some embodiments, at least 99% of subjects in a patient population have a known genetic defect associated with Angelman syndrome. In some embodiments, 100% of subjects in a patient population have a known genetic defect associated with Angelman syndrome.

[0235] In some embodiments, administration of an antisense compound or pharmaceutical compositions thereof as described herein may have a beneficial treatment effect in patients with Angelman syndrome caused by non-deletion genotypes. Non-deletion genotypes that may give rise to Angelman syndrome in a patient include, e.g., point mutation, uniparental disomy (UPD), and imprinting center defects (ICD), such as maternal allele ICD. Patients with theseIPTS / 128916176.1 55and potentially other non-deletion genotypes have a different phenotype than deletion-type Angelman syndrome. Molecular differences in the different subtypes of Angelman syndrome merit additional dose considerations for these particular populations.

[0236] In some embodiments, administration of an antisense compound or pharmaceutical compositions thereof as described herein may also have a beneficial treatment effect in younger patients with deletion-type Angelman syndrome. Younger deletion-type Angelman syndrome patients (1 to 3 years of age) may require lower loading doses due to their age and size.

[0237] In some embodiments, administration of an antisense compound or pharmaceutical compositions thereof as described herein may also have beneficial treatment effect in adults with Angelman syndrome (18 years of age and older), regardless of genotype (i.e., either deletion-type Angelman syndrome or nondeletion-type Angelman syndrome, such as Angelman syndrome caused by, e.g., point mutation, UPD, or ICD).

[0238] In some embodiments, administration of an antisense compound or pharmaceutical compositions thereof as described herein may also have beneficial treatment effect in patients with Angelman syndrome having reduced cerebrospinal fluid (CSF) volume. For instance, antisense compounds or pharmaceutical compositions thereof described herein may have beneficial treatment effect in AS patients with reduced estimated body size and / or thoracolumbosacral (TLS) CSF volume. In some embodiments, reduced estimated body size and / or TLS CSF volume is less than that of, e.g., a typical 4 year-old Angelman syndrome patient. In patients with such reduced CSF volume, it may be necessary or beneficial to reduce the total volume of drug and / or flush solutions administered to the patient. As an example, TLS CSF volume in a 12-month-old is estimated to be approximately 60% of the TLS CSF volume of a 48-month-old (Jang YE, Lee JH, Seo YS, et al. (2019) Lumbosacral and thoracolumbosacral cerebrospinal fluid volume changes in neonates, infants, children, and adolescents: A retrospective magnetic resonance imaging study. Paediatr Anaesth 29(1): 92- 97.), when considering factors of age, weight, and height in the 50th percentile using CDC growth charts.

[0239] Accordingly, a single-arm, open-label, Phase 2 / 3 clinical study (see Example 8 herein) is proposed evaluating the safety and exploratory efficacy of GTX-102 in the following patient populations: Pediatric patients 4 to 17 years of age (inclusive) with nondeletion-type Angelman syndrome (e.g., point mutation, UPD, and ICD); Pediatric patients 1 to 3 years of age (inclusive) with deletion-type Angelman syndrome; and Adults with Angelman syndromeIPTS / 128916176.1 56(18 years of age and older, inclusive), regardless of genotype (i.e., either deletion-type Angelman syndrome or nondeletion-type Angelman syndrome as defined above).

[0240] The proposed populations to be evaluated will include patients with the most severe phenotype of Angelman syndrome (deletion-type) from 3 years of age down to 1 year of age and over 17 years of age, and will include less severe and rarer forms of Angelman (non- deletion type) ages 4 and above (see Dagli et al., 2012; Sell and Margolis, 2015; Keute et al., 2021). The study design will include a Loading Period (i.e., monthly dosing) and a Maintenance Period with less frequent dosing. Pharmaceutical Compositions

[0241] The antisense compounds described herein may each be formulated into a pharmaceutical composition for administration to a subject (e.g., a human subject suffering from Angelman syndrome). In some embodiments the pharmaceutical composition comprises an antisense compound comprising a nucleic acid sequence of SEQ ID NO: 1. In some embodiments the pharmaceutical composition comprises an antisense compound comprising a modified nucleic acid sequence of SEQ ID NO: 2. For instance, contemplated herein are pharmaceutical compositions comprising an antisense compound, in a mixture with one or more pharmaceutically acceptable diluents, carriers, salts and / or adjuvants. A pharmaceutically acceptable diluent includes phosphate-buffered saline (PBS) and pharmaceutically acceptable salts include, but are not limited to, sodium and potassium salts. In some embodiments, the diluent is artificial cerebrospinal fluid (aCSF).

[0242] Pharmaceutical compositions may include sterile aqueous suspensions. Those skilled in the art are aware of a variety of formulation strategies useful for storage and / or administration of nucleic acid therapeutics such as oligonucleotide therapeutics, e.g., “antisense compounds.” See, for example, Remington: The Science and Practice of Pharmacy (2012, 22nded.) The United States Pharmacopeia: The National Formulary (2015, USP 38 NF 33), Pushpendra et al "Nucleic Acids as Therapeutics" in From Nucleic Acid Sequences to Molecular Medicines, ed., and Erdmann and Barciszewski, Springer- Verlag, 2012; Juliano "The Delivery of Therapeutic Oligonucleotides" Nuc. Acids. Res. 44:6518, 2016, the disclosure of each of which is incorporated herein by reference in its entirety.

[0243] A pharmaceutical composition may be administered to a subject, such as a human subject, alone or in combination with pharmaceutically acceptable carriers, the proportion of which may be determined by the quantity of active pharmaceutical ingredient (i.e., an antisenseIPTS / 128916176.1 57compound), chosen route of administration, and standard pharmaceutical practice. In some embodiments the pharmaceutical composition is administered with a pharmaceutically acceptable carrier for administration by intrathecal (IT) lumbar puncture (LP). EXAMPLES

[0244] The disclosure now being generally described, will be more readily understood by reference to the following examples, which are included merely for purposes of illustration of certain aspects and embodiments of the present disclosure, and are not intended to limit the scope of the disclosure in any way. Example 1. Summary of Phase 1 and 2 dosing regimens used to evaluate the safety and efficacy of GTX-102 in the treatment of Angelman syndrome Phase 1 dose-finding study

[0245] Cohorts 1-2: Patients aged 4 to less than 18 years old received escalating monthly (QM) doses of GTX-102 (SEQ ID NO: 2) ranging from 3.3 mg to 36 mg. After initial occurrences of radiculopathy in Cohorts 1-3, the trial was paused and patients were later re- dosed according to an initial loading regimen of 5 mg to 7.5 mg administered monthly (QM) and a maintenance regimen of less than or equal to 10 mg administered quarterly (Q3M) in US patients or less than or equal to 14 mg administered quarterly (Q3M) in ex-US patients. The Cohort 3 patient was re-dosed with GTX-102 under a compassionate use protocol, separate from Study GTX-102-001.

[0246] Cohorts 4 & 6: Patients aged 4 to less than 8 years old received monthly (QM) loading doses of GTX-102 ranging from 3.3 mg to 10 mg followed by a maintenance regimen of 7.5 mg to 14 mg administered monthly (QM).

[0247] Cohorts 5 & 7: Patients aged 8 to less than 18 years old received monthly (QM) loading doses of GTX-102 ranging from 5 mg to 12 mg followed by a maintenance regimen of 7.5 mg to less than or equal to 14 mg administered quarterly (Q3M).

[0248] 2 mg Cohort: Patients aged 4 years old to less than 18 years old received monthly (QM) loading doses of GTX-102 at 2 mg followed by a 2-month dosing pause at day 114 followed by a maintenance regimen of 2 mg administered quarterly (Q3M). Phase 2 expansion cohorts

[0249] Cohort A: Patients ex-US aged 4 years old to less than 8 years old received four monthly (QM) loading doses of GTX-102 of 7.5 mg followed by a stepwise approach to doseIPTS / 128916176.1 58escalation during the Maintenance phase, starting at 7.5 mg to 10 mg and escalating to 12 mg and then less than or equal to 14 mg, provided no safety issues arise in an individual patient that would preclude an escalation.

[0250] Cohort B: Patients ex-US aged 8 to less than 18 years old received four monthly (QM) loading doses of GTX-102 of 7.5 mg followed by a stepwise approach to dose escalation during the Maintenance phase, starting at 7.5 mg to 10 mg and escalating to 12 mg and then less than or equal to 14 mg, provided no safety issues arise in an individual patient that would preclude an escalation.

[0251] Cohort C: Patients aged 4 years old to less than 8 years old received three monthly (QM) loading doses of GTX-102 ranging from 5 mg to 7.5 mg followed by a 1-month dosing pause at day 86 before a fourth loading dose ranging from 5 mg to 7.5 mg, then a maintenance regimen of less than or equal to 10 mg administered quarterly (Q3M).

[0252] Cohort D: Patients aged 8 years old to less than 18 years old received three monthly (QM) loading doses of GTX-102 ranging from 5 mg to 7.5 mg followed by a 1-month dosing pause at day 86 before a fourth loading dose ranging from 5 mg to 7.5 mg, then a maintenance regimen of less than or equal to 10 mg administered quarterly (Q3M).

[0253] Cohort E: Patients aged 4 years old to less than 8 years old received 3 monthly (QM) loading doses of GTX-102 ranging from 5 mg to 7.5 mg followed by a 1-month dosing pause at day 86 before a fourth loading dose ranging from 5 mg to 7.5 mg, then a maintenance regimen of less than or equal to 7.5 mg administered bi-monthly (Q2M).

[0254] In Cohorts A-E, subjects were, at the discretion of the investigator, treated with dexamethasone prior to GTX-102 treatment. If used, dexamethasone was administered either IV (0.3 mg / kg as a slow IV push over several minutes with a maximum dose of 6 mg) within 2 hours prior to GTX-102 dosing, or orally the day before the dosing visit (0.3 mg / kg with a maximum dose of 6 mg). If dexamethasone was unavailable, a different corticosteroid at a dose of equivalent activity was used. Immediately following GTX-102 administration in Cohorts 4- 7 and A-E, a 10 mL flush of artificial CSF (aCSF) was administered as a slow bolus injection over 1 to 2 minutes through the same spinal needle as GTX-102. Following the flush, subjects were placed into the Trendelenburg position, which was recommended to be maintained for at least 45 minutes. The flush and Trendelenburg positioning were implemented to minimize local contact in the lumbosacral region and to aid in drug distribution to the cranial area and cisterna magna where rapid mixing can occur.IPTS / 128916176.1 59

[0255] The aforementioned dosing regimens of Cohorts 1-7 and A-E are summarized in Table 1, which also illustrates three potential dosing regimens under consideration for Phase 3 clinical trials (see Example 7 herein), based on Phase 1 and Phase 2 clinical data through Cohorts A and B to-date. Example 2. Pharmacokinetic model to predict maximum GTX-102 concentration in human central nervous system

[0256] Following an intrathecal (IT) administration in monkeys, GTX-102 was quickly eliminated from CSF and plasma with a terminal half-life less than ~10 hours but sustained longer in CNS with a terminal half-life ranging from ~20 to ~30 days (data not shown). These results suggest that the plasma PK does not reflect the target tissue distribution and drug accumulation after repeat dosing. Thus, plasma PK cannot be used to inform the dose levels and frequencies. Therefore, it was determined CNS PK of GTX-102 in humans should be based on predictions from a PK model built with monkey data and translated to humans accounting for physiological differences between humans and monkeys.

[0257] A modeling and simulation paradigm was developed to build a quantitative relationship of GTX-102 among monkey plasma, CSF, and CNS and translate those results to human patients to guide dose selections in pediatric patients with Angelman syndrome (AS). Methodology Nonclinical Data Used in Modeling

[0258] The monkey PK data used in the current modeling were obtained from a PK / PD repeat dose study of GTX-102 in cynomolgus monkey. PK data were obtained from 27 animals receiving GTX-102 in this study and each animal received 4 monthly doses either at 2 or 3 mg following IT administrations. Blood and CSF samples were collected up to 96 hours post-dose after each administration of GTX-102 on Days 1, 29, 57, and 85. Brain samples were collected on Days 92, 113, 141, 169, and 197 after the last dose (Day 85), encompassing from 7 days up to ~4 months post-dose. The plasma and CSF samples were analyzed for concentrations of GTX-102 using a validated method with a lower limit of quantitation (LLOQ) of 1.00 ng / mL for plasma and 2.00 ng / mL for CSF. Brain samples were analyzed for concentration of GTX- 102 using a qualified method with a LLOQ of 40.0 ng / g. Refer to nonclinical study report for detailed methods and results.IPTS / 128916176.1 60Model Development

[0259] Considering a relatively complicated model structure, model development followed a sequential approach. Initially, the model was developed to describe concentration-time profiles of GTX-102 in CSF following IT administrations. Both 1 and 2 compartmental models were tested to identify the structural model to describe the concentration-time data in CSF. After a best model was identified to describe the PK data in CSF, the simulated concentrations of GTX-102 in CSF were linked to subsequent plasma and CNS compartments to optimize model parameters against observed plasma or brain concentration data. For each step, at least 2 models (1 or 2 compartmental models) were tested to select the better model describing concentration-time profiles. Except for CSF, a one-compartmental model described the observed concentration-time profiles adequately. In monkeys, PK data were collected from 11 subsections in brain regions. Thus, it was not feasible to incorporate 11 sub-compartments in the current model. PK data in the frontal cortex were chosen to represent the entire CNS considering that this region is physiologically important in brain function and the observed data in this region were close to the median range among different subsections.

[0260] A schematic of the final structural model describing time-concentration profiles of GTX-102 in CSF, plasma, and CNS is presented in FIG. 1. The following notations are included in FIG.1: V1 = volume of distribution in CSF; V2 = volume of distribution in lumped compartment depicting reversible transfer between CSF and brain; V3 = volume of distribution in plasma; V4 = volume of distribution in CNS compartment depicting directional transfer from CSF to brain; K12 = intercompartmental transfer rate from CSF to brain; K21 = intercompartmental transfer rate from brain to CSF; K14 = transfer rate from CSF to brain; K13 = transfer rate from CSF to plasma; K30 = elimination rate from plasma; K40 = elimination rate from brain.

[0261] Once the model parameters were optimized with observed PK data in monkeys, the PK model was further evaluated to determine whether the model could be used to predict the concentration-time profiles of GTX-102 in humans. It was assumed that the rate constants describing transfer among CSF, plasma, and brain are the same between monkeys and humans, but the physiological parameters represented by volume of distribution in the respective compartments are different. Differences in volume of distribution parameters were adjusted by applying physiological differences in the respective compartments between monkeys and humans. The revised model in humans was evaluated with the observed concentration-timeIPTS / 128916176.1 61profiles in human plasma. Plasma PK data in humans were the only available data to compare with the predicted concentration-time profiles from the PK model. Model Application

[0262] The predicted brain concentrations of GTX-102 in humans were correlated with a selected safety endpoint (i.e., radiculopathy). The analyses were intended to investigate whether there was a positive or negative relationship between drug exposure and clinical findings. Results Exploratory Analyses of Observed PK data in Monkeys

[0263] The mean observed concentration-time profiles after the last dose in monkeys following 4 monthly doses are presented in FIG. 2. As indicated in FIG. 2, GTX-102 was eliminated from CSF and plasma with a terminal half-life less than ~10 hours but sustained longer in brain with a terminal half-life ranging from ~20 to ~30 days. This result reiterates that plasma PK cannot be used in determination of the dosing rationale for GTX-102; thus, supporting the use of a PK model to predict brain concentrations of GTX-102. Model Development and Verification

[0264] The final PK model includes 4 compartments (CSF, plasma, brain, lumped tissue) describing the transfer of GTX-102 from CSF to plasma and brain following IT administrations. After optimization of model parameters, it appears that the model described the observed data in the respective compartments adequately as presented in FIG.3A, FIG.3B, and FIG. 3C, respectively. Note, in each of FIGs. 3A-3C, the line represents the predicted concentration-time profiles and the dots represent the observed concentration-time data.

[0265] The optimized final model parameters in monkeys are presented in Table 2. Notably, the optimized parameters representing volume of distribution (V1, V3, and V4) were close to the physiological volumes of CSF, plasma, and CNS in monkeys, respectively. These results may suggest that the current PK model can adequately capture the transfer rate of GTX-102 across multiple tissues reflected by rate constants and the concentration in the respective tissues would be mostly dependent upon the physiological volumes of the tissues. Additionally, these results may suggest that GTX-102 concentrations in human CSF, plasma, and CNS can be predicted from the current model by replacing physiological volumes from monkeys to humans.IPTS / 128916176.1 62Revised PK Model in Humans and Partial Validation

[0266] Based on the results in the previous section, the following assumptions were made to predict the concentrations of GTX-102 in humans.

[0267] The rate constants describing the transfer of GTX-102 across tissues are the same between monkeys and humans. The model parameters representing volume of distribution in the respective tissues should reflect the physiological volumes of tissues. Therefore, these parameters in monkeys should be replaced by physiological volumes in the human tissues. Based on the above assumptions, the final model parameters in humans were revised as presented in Table 3.

[0268] The revised PK model in humans was used to predict GTX-102 concentrations in CSF, plasma, and CNS. The predicted plasma concentration-time profiles in humans were compared with the observed data obtained from the 5 patients receiving a single dose of GTX- 102 from 3.3 to 20 mg. Due to a small sample size, the appropriate comparison cannot be made at the respective dose levels. Thus, dose-normalized concentration-time data were used for comparisons assuming human PK is linear as presented in FIG.4. Note the line shown in FIG. 4 represents the predicted dose-normalized concentration-time profiles of GTX-102 in human plasma. Dots represent the observed dose-normalized concentration-time data in human plasma.

[0269] As indicated in FIG. 4, the predicted data appear to describe the observed dose- normalized concentration-time profiles of GTX-102 adequately in human plasma. These results suggest that GTX-102 concentrations can be predicted in human tissues (CSF, plasma, and CNS) with the revised PK model replacing physiological parameters from monkeys to humans. Therefore, it was concluded that the current PK model was partially validated to predict GTX-102 concentrations in humans. Model Application

[0270] To identify the potential concentration range in human CNS associated with radiculopathy, the PK model was applied to predict GTX-102 concentrations with the actual dosing regimen in the 5 patients who developed radiculopathy in the original protocol. It should be noted that the onset of radiculopathy differed among the 5 patients. Thus, the simulation was individualized to reflect the actual dose and frequencies until the time when the respective patients developed radiculopathy and stopped the treatment. FIG.5 presents the predicted CNS concentrations between the maximum concentration (Cmax) and the concentration whenIPTS / 128916176.1 63radiculopathy was observed. It appears that the predicted concentration in Patient 102-005 was much lower than those in other patients. This patient received only a single dose (20 mg) and stopped further treatment due to radiculopathy, whereas the other 4 patients received multiple monthly doses at higher doses. Based on the simulation results, concentrations in the range for this patient were explored to determine potential GTX-102 concentrations linked to radiculopathy. FIG. 5 shows simulated CNS Concentration of GTX-102 in Patients Who Developed Radiculopathy in the Original Protocol (see Cohorts 1-7 of the GTX-102-001 clinical study NCT04259281, available online at www.clinicaltrials.gov; see also Example 1 and Table 1 herein). Note. Each bar represents the range of CNS concentration between the concentration when radiculopathy starts to appear (left side of bar) and Cmax after the last dose (right side of bar). Patient 102-005 showed the lowest concentration range compared with 4 other patients.

[0271] To understand whether radiculopathy was associated better with predicted Cmax or the concentration at the time when radiculopathy started, the predicted GTX-102 concentrations in patients without radiculopathy were compared with those in Patient 102-005 as a potential threshold. The simulation results suggest that radiculopathy would be more closely associated with Cmax in human CNS after the most recent dose rather than the predicted level at the time of the event. The occurrence of radiculopathy in Patient 109-001 appeared to confirm this result. This patient received 10 mg QM for 2 doses, followed by 12 mg QM for 2 doses. As presented in FIG.6, the simulated Cmax in this patient would exceed the hypothetical Cmax associated with radiculopathy (~6500 ng / g) at the fourth dose. This patient developed radiculopathy after receiving the fourth dose. Note, the line represents the simulated GTX-102 concentrations over time in CNS in Patient 109-001(10 mg QM for 2 doses, followed by 12 mg QM for 2 doses). The horizontal bar represents Cmax in Patient 102- 005.

[0272] Overall, simulation results suggest that the radiculopathy was associated with the predicted Cmax of GTX-102 in CNS. The predicted Cmax of GTX-102 associated with radiculopathy was ~6500 ng / g. It is recommended that the dosing regimen in clinical studies consider not exceeding the predicted Cmax associated with radiculopathy in the human CNS.

[0273] The dosing regimen proposed in the US population (Cohorts C, D, and E) was supported by simulation results that do not exceed predicted Cmax levels associated with radiculopathy at any timepoints for both loading and maintenance phase.IPTS / 128916176.1 64

[0274] Under the circumstance that the highest dose in the loading dose may be 10 mg QM, further simulations were conducted to investigate whether 12 or 14 mg Q3M may be administered during the maintenance phase. As indicated in the following figures (FIG.7A and FIG. 7B), the administration of GTX-102 may be administered either at 12 or 14 mg Q3M without exceeding the predicted Cmax associated with radiculopathy (~6500 ng / g) during the maintenance phase. In FIG.7A, the line represents the simulated GTX-102 concentrations over time in CNS in patients receiving 10 mg QM for 4 doses, followed by 14 mg QM for 3 doses during the maintenance phase. Horizontal bar represents Cmax in Patient 102-005. In FIG.7B, the line represents the simulated GTX-102 concentrations over time in the CNS in patients receiving 10 mg QM for 4 doses, followed by 12 mg QM for 3 doses during the maintenance phase. Horizontal bar represents Cmax in Patient 102-005. Discussion

[0275] Modeling and simulation results suggest that the predicted Cmax in human CNS may be associated with radiculopathy observed in the 5 patients receiving high dose levels. Further simulations indicate that the predicted Cmax in patients without radiculopathy receiving low dose levels were lower than that in patients with radiculopathy. Based on these evaluations, the predicted Cmax (~6500 ng / g) in human CNS avoiding radiculopathy was proposed. The further modeling and simulation exercises focused on identifying appropriate dosing regimen to increase GTX-102 levels in the brain without exceeding the predicted Cmax, to avoid radiculopathy. Overall simulation results support the proposed dosing regimen. PK Model Conclusion

[0276] To predict GTX-102 concentrations in human CNS, a PK model was developed combining PK data in monkey plasma, CSF, and brain regions. The predicted CNS concentrations in humans were correlated with corresponding safety endpoints. Exposure- response (E-R) analysis for the safety identifies a possible Cmax in the human CNS associated with the radiculopathy. Overall E-R analysis supports the proposed dosing regimen in the ongoing Phase 1 / 2 study.

[0277] In the ex-US Global protocol, no patient developed radiculopathy in the maintenance phase, including at the maximum dose of 14 mg. The doses proposed are currently being explored outside the US and are expected to provide clinical benefit, based on available data that show a dose response and greater benefit in receptive communication and sleep outcome measures for ex-US patients compared to the lower dose cohorts in the US.IPTS / 128916176.1 65

[0278] The proposed doses and regimens were supported by PK modeling, translated from the PK model developed to describe concentration-time profiles of GTX-102 in monkeys (CNS, CSF, and plasma). Simulation results suggest that a predicted Cmax in the CNS may be associated with radiculopathy. The proposed doses and regimen in the loading and maintenance phases are expected to result in simulated Cmax in the CNS below the hypothetical Cmax associated with radiculopathy at all time points based on current data and modeling. Example 3. Therapeutic measures to mitigate the potential risk of radiculopathy

[0279] Based on treatment emergent cases of radiculopathy in Cohorts 1-3 receiving GTX- 102, it was important to identify a highly optimized dosing strategy to minimize the risk of radiculopathy while ensuring sustained efficacy.

[0280] Per the original study design, subjects in US Cohorts 1, 2, and 3 received intrathecal (IT) GTX-102 via lumbar puncture (LP) at starting doses of 3.3 mg, 10 mg, and 20 mg, respectively, with rapid monthly dose-escalation per protocol. All 5 patients in these cohorts were hospitalized for mild (Grade 1; 1 patient) or moderate (Grade 2; 4 patients) treatment- emergent SAEs of radiculopathy, characterized by significant lower extremity weakness with signs of inflammation on magnetic resonance imaging (MRI) in the lumbosacral region and limited to the cauda equina. In all 5 subjects, the CSF protein was elevated.

[0281] Time to onset ranged from 6 to 26 days following the last and highest doses of 20 mg or 36 mg (and 26 to 132 days following their first dose of GTX-102). Total doses of GTX- 102 at the time of SAE onset ranged from 20 mg to 105.3 mg for these 5 subjects. All subjects recovered following treatment with intravenous immunoglobulin (IVIG) and corticosteroids (e.g., dexamethasone) with majority of symptoms resolving within 2 to 4 weeks after onset and full recovery from all symptoms 19 to 126 days after onset; the longest time to recovery was confounded by a concurrent sprained ankle.

[0282] Based on this experience, dosing and enrolment were paused and the study design was modified. The following risk minimization strategies were implemented in amended protocols to mitigate the potential risk of radiculopathy: ^ Evaluation of dose levels by age where subjects < 8 years and ≥ 8 years were allocated to different dose cohorts to account for differences in CSF volume and CNS compartment size. ^ Regimented use of a post-GTX-102 administration flush with aCSF followed by Trendelenburg positioning to minimize local contact in the lumbosacral regionIPTS / 128916176.1 66and to aid in drug distribution to the cranial area and cisterna magna where rapid mixing can occur. ^ Initiation of dosing at lower levels than Cohorts 1 to 3, with incremental escalation to higher levels based on defined lack of effect, as indicated for a given cohort. ^ Implementation of a maximum dose of 14 mg. ^ Protocol-defined criteria to withhold dosing in subjects with signs / symptoms of radiculopathy (e.g., prior to dosing, gross motor function is evaluated, and CSF protein results reviewed). ^ In Cohorts 4 to 7, individualized dosing decisions were made based on safety and efficacy, to identify the lowest possible effective dose for each subject. ^ Dexamethasone administration prior to all GTX-102 loading doses (implemented in later protocol amendments).

[0283] In all clinical study protocols for GTX-102, CSF laboratory results from the prior dosing visit were reviewed prior to administration of GTX-102. Dosing was held when the subjects exhibited elevated CSF protein, as defined in each protocol.

[0284] Since the time the risk mitigation strategies were implemented in amended protocols, 69 additional subjects were enrolled and treated with GTX-102 at doses ranging from 2 to 14 mg; of these, only 2 subjects experienced radiculopathy – an incidence of 3% (2 / 69) compared with the 100% incidence (5 / 5) in the original 5 subjects in Cohorts 1 to 3 (9% [7 / 74] incidence overall). Example 4. Dose pause after 3 loading doses reduces risk of elevated CSF protein and radiculopathy

[0285] CSF protein elevation events were compared across Cohorts 1-7 and A-E. Most asymptomatic CSF protein elevations were observed during loading phase. Lower incidences of elevated CSF protein were observed among Cohorts C, D, and E compared to Cohorts 1-7 (Table 4). Similar to CSF protein elevation, radiculopathy onset was confined to loading phase. No incidents of radiculopathy were observed among Cohorts C, D, and E, each of which had a dosing pause of 1 month beginning after the third loading dose. That is, each of Phase 2 expansion Cohorts C, D, and E received 3 monthly loading doses between 5 to 7.5 mg, then at day 86 had a dosing pause of 1 month before resuming a fourth loading dose. After the fourth loading dose (i.e., at day 114), Cohorts C, D, and E received maintenance doses at either 10 mg Q3M (Cohorts C and D) or 7.5 mg Q2M (Cohort E).

[0286] These data suggest a correlation between incidence of elevated CSF protein and likelihood of onset of radiculopathy, though they do not establish a causal relationship. TheyIPTS / 128916176.1 67also show that the risk of elevated CSF protein levels and the risk of radiculopathy onset both decrease markedly upon introducing a dose pause (a 1-month pause, for example) after the third loading dose prior to either a fourth loading dose or initiation of a maintenance regimen. This unexpected observation suggests that a pause in dosing (e.g., a pause of 56 days) after three loading doses (e.g., after a day 58 dose) can be used to mitigate risk of elevated CSF protein and radiculopathy.

[0287] In addition to a 1-month dosing pause after the third loading dose (e.g., at day 86), dexamethasone pretreatment was implemented for Cohorts A, B, C, D, and E. Overall, markedly lower incidence of radiculopathy (<5%) was observed in patients after implementing these risk mitigation measures. Example 5. Transition to bi-monthly administration in maintenance phase avoids waning of GTX-102 clinical effect

[0288] Following observations of apparent waning of clinical efficacy in some subjects of Cohorts 4-7 following the transition from monthly loading doses to quarterly maintenance dosing, a decision was made to implement bi-monthly (Q2M) in the first phase (e.g., the first 1 or 2 doses) of the maintenance regimen. For example, apparent waning in Cohorts 4-7 EEG findings (for some patients) during the initial part of the maintenance regimen is demonstrated in FIG.8. Example 6. Sustained efficacy of GTX-102 in Cohorts 4-7 and Cohorts A & B

[0289] Clinical outcome measures were selected to assess the effect of GTX-102 on the broad and complex clinical manifestations of Angelman syndrome. These clinical outcome measures were implemented for Cohorts 4-7 and Cohorts A & B. Specifically, the clinical outcome measures included: ^ Communication: Observer-Reported Communication Ability Measure (ORCA), Bayley Scales of Infant and Toddler Development 4thEdition (Bayley-4), Vineland Adaptive Behavior Scales-3 (Vineland-3) ^ Cognition: Bayley-4 ^ Motor Function: Bayley-4, Vineland-3, ActiMyo wearable device ^ Seizure frequency: Seizure diary, video electroencephalogram (EEG) ^ Sleep: Sleep diary, overnight video EEG, Children’s Sleep Habits Questionnaire (CSHQ)IPTS / 128916176.1 68^ Behavioral assessments: Vineland-3, Aberrant Behavior Checklist-Community (ABC- C) ^ AS-specific assessments: Angelman Severity Assessment (ASA), Angelman Change Assessment (ACA) (also known as Clinical Global Impression of Change in Angelman syndrome (CGI-C-AS)

[0290] Baseline clinical outcome measures for subjects in Cohorts 4-7 and Cohorts A & B are shown in Table 5. Baseline characteristics of Natural History (NHS) studies 1 and 2 are shown in Table 6.

[0291] As of the interim Phase 1 / 2 data analysis provided herein, among Cohorts 4-7 (N=15), average age was 8.4 years (SD 3.9) with 8 (53.3%) of the patients being female. Of these, 12 (80%) were aged 4 to 11 years and 3 (20%) were 12 to 17 years of age. Among Cohorts A & B (N=34), average age was 7.8 years (SD 3.8) with 21 (61.8%) of patients being female. Of these, 27 (79.4%) were aged 4 to 11 years and 7 (20.6%) were 12 to 17 years of age.

[0292] Generally, treatment of GTX-102 in Cohorts 4-7 and Cohorts A & B resulted in improvement over time. FIGs. 9A and 9B show that GTX-102 treatment improved cognition by Bayley-4, which demonstrated rapid and ongoing, long-term improvement compared to Natural History. Cognition by Bayley-4 in Cohorts A & B shows rapid improvement consistent with Cohorts 4-7. Cognition by Bayley-4 in Cohorts 4-7 showed continuous long-term improvement through Day 758.

[0293] FIGs. 10A and 10B show that GTX-102 treatment improved receptive communication by Bayley-4, which demonstrated rapid and sustained improvement compared to Natural History. Receptive communication by Bayley-4 in Cohorts A & B shows rapid improvement consistent with what was observed in Cohorts 4-7. Long-term improvement in Receptive Communication by Bayley-4 was sustained in Cohorts 4-7.

[0294] FIGs. 11A and 11B show that GTX-102 treatment improved expressive communication by Bayley-4, which displayed sustained improvement over time. Expressive Communication by Bayley-4 in Cohorts A & B showed improvement similar to that previously observed in Cohorts 4-7. Expressive Communication by Bayley-4 in Cohorts 4-7 displays a positive long-term trend through Day 758; although no clear separation from Natural History observed at Day 365.IPTS / 128916176.1 69

[0295] FIGs.12A and 12B show that GTX-102 treatment improved gross motor by Bayley- 4, which demonstrated long term and ongoing improvement compared to Natural History. Gross Motor by Bayley-4 in Cohorts 4-7 persistently displayed positive long-term trend, demonstrating a steady and continuous improvement through Day 758.

[0296] FIGs.13A and 13B show that GTX-102 treatment improved fine motor by Bayley- 4, which demonstrated long term and continuous improvement compared to Natural History. Fine Motor by Bayley-4 in Cohorts 4-7 persistently displayed positive long-term trend, demonstrating steady & continuous improvement through Day 758.

[0297] FIGs. 14A and 14B show that GTX-102 treatment improved sleep by ASA, which showed rapid and sustained improvement. FIG. 15 shows that GTX-102 treatment improved behavior by ASA, which demonstrated rapid and continuous improvement. FIG.16 shows that GTX-102 treatment improved communication by ASA, which demonstrated sustained benefit. FIG. 17 shows that GTX-102 treatment improved fine motor by ASA, which demonstrated continuous long-term improvement. FIG. 18 shows that GTX-102 treatment improved gross motor by ASA, which demonstrated long-term improvement. FIG. 19 shows that GTX-102 treatment improved gross motor by ASA, which demonstrated long-term improvement. For FIGs. 14A-14B and 15-19, scores were as follows: 1 = Not at all impaired; 2 = Borderline, slightly impaired; 3 = Mildly impaired; 4 = Moderately impaired; 5 = Markedly impaired; 6 = Severely impaired; 7 = Among the most severely impaired.

[0298] FIGs. 20A and 20B show that GTX-102 treatment improved irritability raw score, by ABC-C, and shows a positive trend compared with Natural History. FIGs. 21A and 21B show that GTX-102 treatment improved hyperactivity / noncompliance raw score, by ABC-C, and demonstrates rapid and continuous improvement compared with Natural History.

[0299] Generally, broad clinical benefit was achieved across domains in patients treated with GTX-102. For the clinical outcomes, the changes to baseline are shown in Table 7 (clinical outcomes for Cohorts 4-7 at Day 338) and Table 8 (Clinical outcomes for Cohorts A & B at Day 170).

[0300] The Phase 1 / 2 interim data analysis provided herein reflect Cohorts A & B data to Day 170 on 24 patients and long-term dose-escalation Cohorts 4–7 data to Day 758 on 15 patients.

[0301] For Cohorts A & B at Day 170: Cognition assessed by Bayley-4 showed rapid and clinically significant improvement compared with Natural History data. Day 170 data wereIPTS / 128916176.1 70consistent with the treatment benefit observed in the Dose-escalation Cohorts at a similar timepoint. Behavior assessed by the Angelman Severity Assessment (ASA) showed rapid improvement exceeding the treatment benefit observed in the Dose-escalation Cohorts at Day 170. Hyperactivity and noncompliance assessed by the Aberrant Behavior Checklist- Community (ABC-C) showed rapid and clinically significant improvement at Day 170 compared with Natural History data, providing further insight into one of the most commonly reported behavioral issues. Sleep assessed by ASA showed rapid and clinically meaningful improvement exceeding treatment benefit observed in the Dose-escalation Cohorts at Day 170. Receptive communication assessed by Bayley-4 showed rapid improvement compared with Natural History data. Day 170 data were consistent with the treatment benefit observed in the Dose-escalation Cohorts at a similar timepoint. Gross Motor function assessed by ASA showed rapid improvement exceeding the treatment benefit observed in the Dose-escalation Cohorts at Day 170. Multi-domain Responder Index (MDRI) analysis across the four domains of Cognition, Receptive Communication, Behavior and Sleep resulted in a total net response of +2.0 (p-value <0.0001). The majority of patients had already achieved a total net response of +2 to +4 domains, demonstrating improvement exceeding the minimally important difference (MID) threshold in several domains even at this early Day 170 timepoint.

[0302] For dose-escalation Cohorts 4-7 up to Day 758: Cognition assessed by Bayley-4 showed continuing long-term improvement compared with Natural History data and exceeded the threshold of clinical significance by many-fold in many patients. Behavior assessed by ASA showed continuing clinically meaningful improvement. Sleep assessed by ASA showed sustained clinically meaningful improvement. Receptive communication measured by Bayley- 4 showed sustained and clinically significant improvement compared with Natural History data. Gross motor function assessed by Bayley-4 showed continued and clinically significant improvement compared with previously reported Natural History data. MDRI analysis across the four domains of Cognition, Receptive Communication, Behavior and Sleep resulted in a total net response of +2.0 (p-value = 0.0007) at Day 338. The majority of patients had a total net response of +2 to +4, as well as a 2- to 5-fold improvement over the MID threshold in several domains.

[0303] Surprisingly, comparable clinically meaningful therapeutic benefits were observed among older and younger patients. That is, patients in Cohorts 4-7 and Cohort A & B demonstrated clinically meaningful gains for all ages across all measures. Specifically, amongIPTS / 128916176.1 71Cohorts 4-7 and A & B, patients aged 4 to 11 years and showed comparable gains across therapeutic measures described herein versus patients aged 12 to 17 years of age.

[0304] Further, no unexpected serious adverse events were observed among Cohorts 4-7 and A & B as of an interim Phase 1 / 2 data analysis. Three patients had serious adverse events (mild to moderate) of lower extremity weakness assessed as related to study treatment (one in Cohort 7 and two in Cohorts A & B). All cases resolved rapidly without sequelae and these patients remained in the study without ongoing safety concerns. These patients were re-dosed with multiple doses following resolution of lower extremity weakness. In addition, the five original patients from Cohorts 1–3 were also safely re-dosed multiple times and initiated maintenance treatment without recurrence. The Cohort 7 patient was also re-dosed safely multiple times and entered maintenance treatment without recurrence. Two patients in Cohorts A & B remained in the study and were expected to continue dosing.

[0305] Also, as of the interim Phase 1 / 2 data analysis provided herein, feedback from physicians of patients in Cohorts A & B was highly positive, recognizing observed gains in cognition, behavior, sleep, language, and motor skills. Individual patients receiving GTX-102 were recognized as following directions for the first time, learning new routines, having improved memory, and demonstrating understanding of serial processes, all meaningful cognitive gains. Patients also exhibited milder excitability, improved focus at school, improved attention, improved situational awareness, less impulsivity, and more readiness to be in public, all meaningful behavioral gains. In terms of sleep, physicians reported patients on GTX-102 now sleeping 7 to 10 hours consistently at night, taking less time to fall asleep, waking less frequently, having improved sleep quality, and having reduced need for melatonin. Language skills were observed to improve, with some patients gaining their first words, being more attentive to speech, exhibiting new sounds and word approximations, and exhibiting pointing and more precise use of devices. Physicians also reported more independence, self-feeding, utensil-use, first instances of running, dancing, jumping and swimming, improved stability, walking on uneven ground, and less tremor and ataxia, representing significant and meaningful gains in motor skills among patients receiving GTX-102 therapy.

[0306] Importantly, the above-described beneficial effects of GTX-102 therapy in Cohorts A & B patients show positive, rapid, and sustained clinically meaningful improvements at treatment day 170 which is consistent with or an improvement over prior Phase 1 / 2 data analyses. Thus, the changes implemented in the dosing regimen over the course of Phase 1 and Phase 2 studies, including, e.g., Trendelenburg positioning, aCSF flush, maximum dose of 14IPTS / 128916176.1 72mg, and optimized loading and maintenance regimens, enabled the discovery of safe and efficacious methods for administering GTX-102 to AS patients.

[0307] In conclusion, broad GTX-102 exposure at doses ranging from 3.3 mg to 14 mg across Phase 1 / 2 Cohorts 4-7 for up to about 2.4 years of treatment and Cohorts A & B for up to about 1 year of treatment (totaling 74 patients) demonstrated broad and meaningful clinical gains that were sustained throughout treatment and exhibited acceptable tolerability and safety risk profile. Example 7: Phase 3 clinical trial to evaluate GTX-102 treatment Study Design

[0308] All subjects will undergo assessments at Screening / Month 0 and throughout the study. Subjects will receive treatment with GTX-102 via intrathecal (IT) lumbar puncture (LP). Upon study entry, subjects receive 3 loading does of 8 mg of GTX-102 and at least 4 maintenance doses of increasing concentration until reaching 14 mg GTX-102 on the days indicated in the study schema depicted in FIG. 22. Alternatively, subjects may receive four loading doses of 8 mg of GTX-102 and at least three maintenance doses of increasing concentration until reaching 14 mg GTX-102 on the days indicated in the alternative study schema depicted in FIG. 23. Maintenance doses of 14 mg of GTX-102 may continue to be administered either every 2 months (Q2M) or every three months (Q3M) for long term treatment of the subject. For the purposes of this study, a month is defined as 28 days. Clinical outcome assessments (e.g., Vineland Adaptive Behavior Scales-3 [Vineland-3]) and specific laboratory tests will be assessed approximately every 6 or 12 months, coinciding with the subject’s nearest Dosing Visit. Anesthesia, Trendelenburg Positioning, and Optional Premedication

[0309] Radiculopathy is an identified risk and adverse event of special interest (AESI) for GTX-102. The administration technique inclusive of optional premedication with IV steroids, aCSF flush post study drug administration and Trendelenburg positioning described here are measures to mitigate the potential risk of radiculopathy.

[0310] As GTX-102 is administered via LP, anesthesia may be administered by an experienced anesthesiologist with a focus on subject comfort and minimization of risk. Immediately following study drug administration, a 10 mL flush of aCSF (Elliotts B solution or GTX / UX Diluent and Flush Solution) is administered as a slow bolus injection over 1 to 2 minutes through the same spinal needle. Following the flush, the subject is placed into theIPTS / 128916176.1 73Trendelenburg position. The Trendelenburg position is recommended to be maintained for at least 45 minutes. The flush and Trendelenburg positioning help to maximize distribution of GTX-102 across the CNS. The parent / legal guardian or caregiver may lie with the child in the recovery area per Investigator discretion.

[0311] Per Investigator discretion, the subject may be treated with dexamethasone prior to GTX-102 treatment. Dexamethasone may be administered either IV (0.3 mg / kg as a slow IV push over several minutes with a maximum dose of 6 mg) within 2 hours prior to GTX-102 dosing, or orally the day before the dosing visit (0.3 mg / kg as a single dose with maximum dose of 6 mg). If dexamethasone is unavailable at the site, the Investigator may use a different corticosteroid at a dose of equivalent activity.

[0312] Subjects will be monitored for clinical signs and symptoms of radiculopathy throughout the study. Primary and Other Clinical Endpoints

[0313] The primary objective of the study is to evaluate efficacy of GTX-102 in subjects with AS. In the proposed Phase 3 study, the primary endpoint is Bayley-4 Cognitive raw score. Specific Cognitive subtest items measure sensorimotor development, exploration and manipulation, object relatedness, concept formation, memory, precursors to executive function, and other aspects of cognitive processing. MDRI may also be used as a key secondary, an analytical strategy that combines an individual patient-level analysis in cognition, behavior, sleep, receptive communication and motor function. Phase 3 secondary endpoints adjusted for multiplicity include the ABC-C Hyperactivity / Noncompliance subscale, the Bayley-4 Receptive Communication raw score, the ORCA Expressive Communication subscale, and the ASA sleep rating. Analyses may be descriptive in nature, with point and 95% confidence interval estimates provided for the following parameters of interest: • Change from Month 0 in Bayley-4: − Cognition Raw Score − Receptive Communication Raw Score − Expressive Communication Raw Score − Gross Motor Raw Score − Fine Motor Raw Score

[0314] Efficacy endpoints of changes from Month 0 to each follow-up time point will be analyzed using a generalized estimating equation (GEE), baseline age as a covariate, withIPTS / 128916176.1 74exchangeable correlation structure. Baseline is defined as the last non-missing value prior to the first dose of GTX-102.

[0315] Additional efficacy endpoints of interest may include the following: • Change from Month 0 in: − ORCA Total Score − Bayley-4 Receptive Communication Growth Scale Value (GSV) − Bayley-4 Expressive Communication GSV − Vineland-3 Receptive Communication Raw Score and GSV − Vineland-3 Expressive Communication Raw Score and GSV − ASA Communication − ASA Sleep − CSHQ Total Sleep Disturbance Score and Subscales − ABC-C Hyperactivity / Noncompliance − ABC-C Irritability − Vineland-3 Socialization Raw Score and GSV − ASA Behavior − Vineland-3 Gross Motor Raw Score and GSV − Vineland-3 Fine Motor Raw Score and GSV − ASA Gross Motor Function − ASA Fine Motor Function − Bayley-4 Gross Motor GSV − Bayley-4 Fine Motor GSV − Seizure Questionnaire − Use of rescue medication − Bayley-4 Cognition GSV − EEG, sleep spindle duration and rate − EEG relative delta power (1 to 4 hertz) − Vineland-3 Daily Living Skills Raw Score and GSV − WPAI

[0316] Efficacy endpoints of changes from Month 0 to each follow-up time point will be analyzed using a generalized estimating equation (GEE), baseline age as a covariate, withIPTS / 128916176.1 75exchangeable correlation structure. Baseline is defined as the last non-missing value prior to the first dose of GTX-102. Example 8. Phase 2 / 3 Open-label study investigating the safety and efficacy of GTX-102 in subjects with Angelman syndrome

[0317] A phase 2 / 3, open-label study investigating the safety and efficacy of GTX-102 in subjects with Angelman syndrome will be initiated. Subjects will include genotypes and age groups not included in the Phase 1 / 2 or Phase 3 studies, namely: deletion-type Angelman syndrome patients aged 1-3 years of age; non-deletion-type Angelman syndrome patients 4-17 years of age; and adult Angelman syndrome patients irrespective of genotype 18-64 years of age.

[0318] The dosing regimen for non-deletion patients 4-17 years of age and adult patients 18-64 years of age will be identical to the dosing regimen described in Example 7 herein. A reduced dosing regimen for deletion-type patients 1-3 years of age will be implemented due to factors including, e.g., CSF volume, age, and body size of these patients.

[0319] The primary endpoints are TEAEs and SAEs, frequency, severity, and relationship to investigational product, procedure, and premedication throughout the study, by cohort and overall, and SAE reporting. Secondary endpoints may include: − Bayley-4 select subtests for deletion-type patients 1-3 years of age − MDRI and, separately, component assessments of the MDRI for non-deletion-type 4-17 year old patients − Vineland-3, ASA, and ABC-C select subtests for adult 18-64 years of age

[0320] Entry criteria, including age and genotype alignment, will include: − Males and females of the following ages at time of informed consent: − For the Deletion 1-3 years of age cohort: ≥ 12 to < 48 months of age − For the Nondeletion 4-17 years of age cohort: ≥ 4 to < 18 years of age − For the Adult 18-64 years of age cohort: ≥ 18 to < 65 years of age − Confirmed diagnosis of AS with genetic confirmation of the genotype causing AS in the region of 15q11.2 q13 − Weight of at least 8 kg at Screening

[0321] The total volume of drug and flush solutions for deletion-type Angelman syndrome patients aged 1-3 years will be reduced based on estimated body size and thoracolumbosacralIPTS / 128916176.1 76CSF volume calculations relative to a typical Angelman syndrome patient 4 years of age. In particular, the total volume of drug and flush solutions administered will be reduced from 20 mL (10 mL dose + 10 mL flush) to 12 mL (6 mL dose + 6 mL flush) based on the smaller thoracolumbosacral (TLS) CSF volume in a 12-month-old, estimated to be approximately 60% of the TLS CSF volume of a 48-month-old (Jang et al., 2019), when considering factors of age, weight, and height in the 50th percentile using CDC growth charts.

[0322] The loading dose for deletion-type Angelman syndrome patients aged 1-3 years will be reduced by 50% from 8 mg to 4 mg, with subsequent Q2M doses increasing by 2mg increments, after initial tolerability is established at 4 mg.

[0323] After reaching 4 years of age, participants may escalate by 2 mg per dose to a maximum of 14 mg Q3M. INCORPORATION BY REFERENCE

[0324] The entire disclosure of each of the patent documents and scientific articles referred to herein is incorporated by reference for all purposes. EQUIVALENTS

[0325] The disclosure may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting the disclosure described herein. Various structural elements of the different embodiments and various disclosed method steps may be utilized in various combinations and permutations, and all such variants are to be considered forms of the disclosure. Scope of the disclosure is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.IPTS / 128916176.1 77SEQUENCES Sequences of the disclosure. Sequence SEQ Sequence Description ID NO. Ati1A AAT A AT T TTIPTS / 128916176.1 78g2 g 2 g 2mg g2 2 g 2mg g01 452DmDmA0 m2m22 g 2m2mM0M01N D M1- D D D M1-21- Dm2D21D01X X 1≤ 50M1M5M M≤M≤S E L B A Tod238 / 5Dm5L.Dm5Am.N D5- Dm50g. D1- Dm2DmDm5.Dm5.Dmg5.Dm17- L7L3.L7L5L1L2L7L L L8e5 3.7 7 7sahP2202Dg 2 gA2 gm2 g 2 gm2 gm2 g 2 gm2 g 2 g 2 g013m- L5D Lm5N D L3.D 3 Lm5D L5.D 7 L0D 1 Lm2D L5.D 7 Lm5D Lm5D Lm8X T Gfo 1 2 1Dgm1Dgm A1 gDm1Dgm1 gDm1 gDm1Dgm1 gDm1Dgm1Dg 1DgyraL5L5N L3.3L5L5.7L01L2L5.7L5Lm5Lm8m m t uS 1.1 h111 ret e tr121etr13 etr1 4e tr1 5e tr1 6 o 2e tr1 7e tr1heoC2e tr2 tr2Et1r3nlnboy sosososososososaa ahho ahho ahho ahho ahho ahho ahho ahgsma ohhBeso&a ohhDeso&a ohhesoo aihtp T M D P C P C P C P C P C P C P C P2P C A P C C P C P OIPTS / 128916176.1 79Xylp2w1 1 13 g gddDm24Dmne4as1odM1M1gnittr -eraolh sao a51 49A 3 X X N X X es cC wX Xahs .Pgne dtnde eieics estno vuapad ie acp 3nesa t2 g et MDmn 2r r) wo2 XiaQdllh 46A oai o 163X X N X X M1MsrrtCaeeehyht,T y.l1 g 81 htoX Dmaco0 na p to3g g gM1htol rp.18 3 gD3DmA3Dm2 3m D41gDm M01X 3 DgLm8n, eig ed ouci 2tam p6 nucotdae3o 20orrf2g 2 g sht t1 poD Lm8D Lm e8sa ,hn gm- Xesuksirg gPgisge3.Ten3Gta lai2 g 2 g 2m2t04m5DmDmA D01D21 g 1 giedhdsao stodehtyndm uoi no n1 2t rf wisetM01M01≤N M-51.M-0dsaop7 1D Lm8D Lm8Lesoeclb os ge po dd naacmla nigsodmoteeugnneilpxynig na -eca udnit32 3 idtanipaa rteevs ioror2rrere tun 1 1 1en3ooc1 2 34 5soaiht ensoioMoe=d epa tLh01t==n=Mot -al dn d,h1e tr1e tr1e tr1 tr1 trNrXe u el 1etn y soh soh soheso esoP hp DDA P O L M Nx=eTrQ X1Ge 2 u l ow12 a aho aho aho ahho ahhO P0Rba oT M D P C P C P C P C P CIPTS / 128916176.1 804 gDmM41≤X Xnegt M 1 ht cn 2a ot3 g 3iQ DmDm34Dg 3DaM41M1 m≤ M2MM≤ M≤M≤ seld d -oatruts 204fo 1 1des0 -X gec 0-2T G 4g g a(ner 01 yX X X X X X X Dm3Dm3 ru -XduM41M41otct1coT GSstrloaitdm iedorfhonin eCre tea y3g 3 gnitfma rnahptapX X X X X Dm5Dm Xe stA. a es olM.7≤M4Xs1ahnPg eigre,loucienicstam 6dnucotdarno pade3htot20o1rp fognet M ,g -es k2 g 2m2 g 2 g 2 g ni3 nsa QgimXuirs 3.TetlDmD21D Dm2Dm0X Xe3GaaitM21M-5.Mm2X X M17≤M1M ≤es dho stnhydmoiro nwisetedsoec eltbnouts fsgdeaopptd naacmla nigsomoterB D o & &g neil xnid2ni tnpp yr e ginrar-oec ur adt16e t 1 71ho 2A2C2E313233da iaat evsod o2r r0eted uos re treCe tre tre treno eno eno oMon e=o eht1-aln daoh sa oh sa gsa oh soh soh s its its itL===MNrXe u elh Pohoh 2 h Po ah C Po ah C Po ah papap DA C P O P O P O L M Nx=eTr2 uC P C Pmh h D Q X1P Gew012RIPTS / 128916176.1 81Table 2: Optimized Final Model Parameters in Monkeys Parameters Estimates RSE (%) V1 (mL) 11.7 8.46 entp g ; p ; 4= volume of distribution in brain compartment depicting directional transfer from CSF to brain; K12= intercompartmental transfer rate from CSF to brain; K21= intercompartmental transfer rate from brain to CSF; K14 = transfer rate from CSF to brain; K13 = transfer rate from CSF to plasma; K30 = elimination rate from plasma; K40 = elimination rate from brain; RSE=relative standard error.IPTS / 128916176.1 82Table 3: Final Model Parameters in Humans Parameters Estimates V1 (mL) 120 entp g ; p ; 4= volume of distribution in brain compartment depicting directional transfer from CSF to brain; K12= intercompartmental transfer rate from CSF to brain; K21= intercompartmental transfer rate from brain to CSF; K14 = transfer rate from CSF to brain; K13 = transfer rate from CSF to plasma; K30 = elimination rate from plasma; K40 = elimination rate from brain; RSE was not presented as the human model was only used to predict the concentration of GTX-102 in humans without further estimation process.IPTS / 128916176.1 83Table 4. Incidence of CSF Protein Elevation in Phase 1 / 2 Cohorts Cohort Total Patients CSF Protein Elevation post-Baseline Timepoint (n) (% of patients) (n)IPTS / 128916176.1 84)xa)0 )2)9) )1)84s d . 9 840te 1 4 4 5 4roM ho )S) ) ) ) ) ) ) ) )C D (9.46. 2.1.9.8 1.6.9.9.(9(9(6 3n3( 0( 1(1( 3 3 ( (D D ae 4.872.0.4 0. . .2.9.5.N N 519788 9 8M1 4 4849494n515151515151515151escenrauislaeVpV S m m SG V oceVGSVSnomoS mGct Gmm roG nr / yun moo o oCto ottivlitC saci)sMo ytiits rinpeerssMlicanil ) rao g c p oec sreaeiyvo e x rnibarti ep( peeahC R E G Frr yne 4-4-4-4 4I Hielye( sislS Byesl yel y-ey-eye C-C-aeg onBAgASASyaylaylaylayaC C B B B 5eaiA e A e B B B B A A :nidtnineineineine e e eininininellbea lelel l l l l lilasTaeBgsAaseBaseBaseBase e e eBasBasBasBasBaBIPTS / 128916176.1 85,)ni 9.)72)20)20)04)202)M(,4 .(47.1 .6. .6785 ,0 ,(0(nai 1.4(544(46(4(4711d7e2(6.24. 4278.59.9.S M0 9298 6H5 4 40594N sc ))i) 3 ) ) )tsD) 735.988823)irS e(7.3.t (7( 11.(7.(7.(9()67(.9(c n aare426.7. 1 6aM8 3 4.3. 92. 72.2.02 3 7 9 68.759 940 91h 4 5 4C eniln4848484848489 97e 7saB V 2 V S SV&1V s SG GmSG VS eGi Gmmdu ntomorot ro ecioCCsotStinpse Mo yti narsMli ilyrgeot oc psor en ba pm s)isrCeRxE GiFtiHa 4r ol e -4-4-4 4 rIcnary(yel yel y-el y-el yelCo-Cu C - CN / teagyNAayBayBayBay ytBaB B BiA Avit: e6neil neil neine e e eininininicarel ebselelelelelele ea asBasBasBasasasasapyT B B B B B HIPTS / 128916176.1 86Table 7: Clinical outcomes for Cohorts 4-7 at Day 338 Participant ASA ASA Bayley-4 Bayley-4 Bayley-4 Total Net Sleep Behavior Receptive Gross Cognition Response* C i ti M tASA: Sleep = + / - 1; Behavior = + / - 1 Bayley-4: Receptive Communication GSV = + / - 6; Gross Motor GSV = + / - 5; Cognition GSV = + / - 5 A negative change from baseline in ASA indicates an improvement A positive change from baseline in Bayley-4 indicates an improvement *Median=2.0 and p value=0.001; **Median=2.0 and p value≤0.001IPTS / 128916176.1 87Table 8: Clinical outcomes for Cohorts A & B at Day 170 Participant ASA ASA Bayley-4 Receptive Bayley-4 Total Net Sleep Behavior Communication Cognition Response**nma mporan d erence ( ) or response app cabeo cange rom ase ne: ASA: Sleep = + / - 1; Behavior = + / - 1 Bayley-4: Receptive Communication GSV = + / - 6; Gross Motor GSV = + / - 5; Cognition GSV = + / - 5 A negative change from baseline in ASA indicates an improvement A positive change from baseline in Bayley-4 indicates an improvement *Median=2.0 and p value=0.001; **Median=2.0 and p value≤0.001IPTS / 128916176.1 88

Claims

CLAIMS WHAT IS CLAIMED IS:

1. A method of treating Angelman syndrome (AS) in a human subject in need thereof, the method comprising: (a) administering a first loading dose of about 5 mg to about 10 mg of an antisense compound comprising a nucleic acid sequence complementary to a UBE3A-AS transcript; (b) administering a first maintenance dose of about 6 mg to about 14 mg of the antisense compound; and (c) administering a second maintenance dose of about 8 mg to about 16 mg of the antisense compound.

2. A method of treating Angelman syndrome (AS) in a plurality of human subjects of a patient population, the method comprising: (a) administering a first loading dose of about 5 mg to about 10 mg of an antisense compound comprising a nucleic acid sequence complementary to a UBE3A-AS transcript; (b) administering a first maintenance dose of about 6 mg to about 14 mg of the antisense compound; and (c) administering a second maintenance dose of about 8 mg to about 16 mg of the antisense compound.

3. The method of claim 1 or 2, wherein the antisense compound comprises the nucleic acid sequence of SEQ ID NO:

1.

4. The method of any one of claims 1-3, wherein the nucleic acid sequence of the antisense compound comprises a modified nucleic acid sequence of AL*GL*AL*a*t*g*g*c*a*c*a*t*c*t*5mCL*TL*TL*GL(SEQ ID NO: 2), wherein:lower case letters denote DNA nucleosides; 5mC denotes a 5-methylcytosine nucleoside; superscript L denotes a locked nucleic acid (LNA) nucleoside; and asterisks denote phosphorothioate internucleoside linkages.IPTS / 128916176.1 895. The method of any one of claims 1-4, wherein the first loading dose comprises from about 6 mg to about 9 mg, about 7 mg to about 8.5 mg, or about 8 mg of the antisense compound.

6. The method of any one of claims 1-5, further comprising administering a second loading dose.

7. The method of claim 6, wherein the second loading dose comprises from about 5 mg to about 10 mg, about 6 mg to about 9 mg, about 7 mg to about 8.5 mg, or about 8 mg of the antisense compound.

8. The method of claim 6, wherein the second loading dose is administered between about 21 days to about 35 days, about 22 days to about 34 days, about 23 days to about 33 days, about 24 days to about 32 days, about 25 days to about 31 days, about 26 days to about 30 days, about 27 days to about 29 days, or about 28 days after the first loading dose.

9. The method of any one of claims 1-8, further comprising administering a third loading dose.

10. The method of claim 9, wherein the third loading dose comprises from about 5 mg to about 10 mg, about 6 mg to about 9 mg, about 7 mg to about 8.5 mg, or about 8 mg of the antisense compound.

11. The method of claim 9, wherein the third loading dose is administered between about 21 days to about 35 days, about 22 days to about 34 days, about 23 days to about 33 days, about 24 days to about 32 days, about 25 days to about 31 days, about 26 days to about 30 days, about 27 days to about 29 days, or about 28 days after the second loading dose.

12. The method of any one of claims 1-11, wherein the method does not include administering a fourth loading dose.

13. The method of any one of claims 1-12, further comprising: positioning the human subject into an inverted position after administration of the first, second, and / or third loading dose.IPTS / 128916176.1 9014. The method of claim 13, wherein positioning the human subject into the inverted position comprises positioning the human subject into the Trendelenburg position.

15. The method of any one of claims 13 or 14, wherein the human subject is positioned in the inverted position for about 30 minutes to about 60 minutes, about 40 minutes to about 50 minutes, or about 45 minutes.

16. The method of any one of claims 1-15, wherein the first maintenance dose comprises from about 7 mg to about 13 mg, about 6 mg to about 12 mg, about 8 mg to about 11 mg, about 9 mg to about 10.5 mg, or about 10 mg of the antisense compound.

17. The method of claim 16, wherein the first maintenance dose is administered between about 50 days to about 70 days, about 51 days to about 67 days, about 52 days to about 64 days, about 53 days to about 61 days, about 54 days to about 58 days, about 55 days to about 57 days, or about 56 days after a final loading dose.

18. The method of claim 16 or 17, wherein the method comprises a lapse period between a final loading dose and the first maintenance dose, wherein the lapse period is between about 28 days to about 56 days, between about 35 days to about 49 days, about 28 days, or about 56 days.

19. The method of any one of claims 1-17, wherein the second maintenance dose comprises from about 9 mg to about 15 mg, about 10 mg to about 14 mg, about 11 mg to about 13 mg or about 12 mg of the antisense compound.

20. The method of any one of claims 1-17, wherein the second maintenance dose comprises from about 9 mg to about 15 mg, about 11 mg to about 14 mg, about 12 mg to about 14.5 mg, or about 14 mg of the antisense compound.

21. The method of any one of claims 1-20, wherein the second maintenance dose is administered between about 50 days to about 90 days, about 51 days to about 80 days, about 52 days to about 70 days, about 53 days to about 60 days, about 54 days to about 57 days, or about 56 days after administration of the first maintenance dose.

22. The method of any one of claims 1-20, wherein the second maintenance dose is administered between about 50 days to about 90 days, about 60 days to about 89 days,IPTS / 128916176.1 91about 70 days to about 88 days, about 80 days to about 87 days, about 82 days to about 88 days, or about 84 days after administration of the first maintenance dose.

23. The method of any one of claims 1-22, further comprising administering one or more additional maintenance doses comprising from about 10 mg to about 16 mg of the antisense compound, wherein each of the one or more additional maintenance doses is equal to or higher than the second maintenance dose.

24. The method of claim 23, wherein each of the one or more additional maintenance doses comprises from about 11 mg to about 16 mg, from about 12 mg to about 15 mg, from about 13 mg to about 14.5 mg, or about 14 mg of the antisense compound.

25. The method of claim 23 or 24, wherein one of the one or more additional maintenance doses is administered between about 50 days to about 90 days, about 51 days to about 80 days, about 52 days to about 70 days, about 53 days to about 60 days, about 54 days to about 57 days, or about 56 days after administration of the second maintenance dose.

26. The method of claim 23 or 24, wherein one of the one or more additional maintenance doses is administered between about 50 days to about 90 days, about 60 days to about 89 days, about 70 days to about 88 days, about 80 days to about 87 days, about 82 days to about 88 days, or about 84 days after administration of the second maintenance dose.

27. The method of claim 23 or 24, wherein the one or more additional maintenance doses are administered Q2M.

28. The method of claim 23 or 24, wherein the one or more additional maintenance doses are administered Q3M.

29. The method of any one of claims 1-28, wherein the second maintenance dose is higher than the first maintenance dose.

30. The method of claim 1, further comprising: administering a second loading dose of about 8 mg of the antisense compound about 28 days after administration of the first loading dose;IPTS / 128916176.1 92administering a third loading dose of about 8 mg of the antisense compound about 56 days after administration of the first loading dose; and administering a third maintenance dose comprising a dose of about 14 mg of the antisense compound about 56 days after administration of the second maintenance dose, wherein the first loading dose comprises a dose of about 8 mg of the antisense compound, the first maintenance dose comprises a dose of about 10 mg of the antisense compound and is administered about 56 days after administration of the third loading dose, and the second maintenance dose comprises a dose of about 12 mg of the antisense compound and is administered about 56 days after administration of the first maintenance dose.

31. The method of claim 1, further comprising: administering a second loading dose of about 8 mg of the antisense compound about 28 days after administration of the first loading dose; administering a third loading dose of about 8 mg of the antisense compound about 56 days after administration of the first loading dose; and administering a fourth loading dose of about 8 mg of the antisense compound about 84 days after administration of the first loading dose; and administering a third maintenance dose comprising a dose of about 14 mg of the antisense compound about 84 days after administration of the second maintenance dose, wherein the first loading dose comprises a dose of about 8 mg of the antisense compound, the first maintenance dose comprises a dose of about 10 mg of the antisense compound and is administered about 56 days after administration of the fourth loading dose, the second maintenance dose comprises a dose of about 14 mg of the antisense compound and is administered about 84 days after administration of the first maintenance dose.

32. A method of treating Angelman syndrome (AS) in a human subject in need thereof, the method comprising:IPTS / 128916176.1 93(a) administering a first loading dose of about 5 mg to about 10 mg of an antisense compound comprising a nucleic acid sequence complementary to a UBE3A-AS transcript; (b) positioning the human subject into an inverted position after administration of the first loading dose; and (c) administering a first maintenance dose of about 6 mg to about 14 mg of the antisense compound.

33. A method of treating Angelman syndrome (AS) in a plurality of human subjects of a patient population, the method comprising: (a) administering a first loading dose of about 5 mg to about 10 mg of an antisense compound comprising a nucleic acid sequence complementary to a UBE3A-AS transcript; (b) positioning the human subject into an inverted position after administration of the first loading dose; and (c) administering a first maintenance dose of about 6 mg to about 14 mg of the antisense compound.

34. The method of claim 32 or 33, wherein positioning the human subject into the inverted position comprises positioning the human subject into the Trendelenburg position.

35. The method of any one of claims 32-34, wherein the human subject is positioned in the inverted position for about 30 minutes to about 60 minutes, about 40 minutes to about 50 minutes, or about 45 minutes.

36. The method of any one of claims 32-35, wherein the antisense compound comprises the nucleic acid sequence of SEQ ID NO:

1.

37. The method of any one of claims 32-36, wherein the nucleic acid sequence of the antisense compound comprises a modified nucleic acid sequence of AL*GL*AL*a*t*g*g*c*a*c*a*t*c*t*5mCL*TL*TL*GL(SEQ ID NO: 2), wherein:lower case letters denote DNA nucleosides;IPTS / 128916176.1 945mC denotes a 5-methylcytosine nucleoside; superscript L denotes a locked nucleic acid (LNA) nucleoside; and asterisks denote phosphorothioate internucleoside linkages.

38. The method of any one of claims 32-37, wherein the first loading dose comprises from about 6 mg to about 9 mg, about 7 mg to about 8.5 mg, or about 8 mg of the antisense compound.

39. The method of any one of claims 32-38, further comprising administering a second loading dose.

40. The method of claim 39, wherein the second loading dose comprises from about 5 mg to about 10 mg, about 6 mg to about 9 mg, about 7 mg to about 8.5 mg, or about 8 mg of the antisense compound.

41. The method of claim 39, wherein the second loading dose is administered between about 21 days to about 35 days, about 22 days to about 34 days, about 23 days to about 33 days, about 24 days to about 32 days, about 25 days to about 31 days, about 26 days to about 30 days, about 27 days to about 29 days, or about 28 days after the first loading dose.

42. The method of any one of claims 32-41, further comprising administering a third loading dose.

43. The method of claim 42, wherein the third loading dose comprises from about 5 mg to about 10 mg, about 6 mg to about 9 mg, about 7 mg to about 8.5 mg, or about 8 mg of the antisense compound.

44. The method of claim 42, wherein the third loading dose is administered between about 21 days to about 35 days, about 22 days to about 34 days, about 23 days to about 33 days, about 24 days to about 32 days, about 25 days to about 31 days, about 26 days to about 30 days, about 27 days to about 29 days, or about 28 days after the second loading dose.

45. The method of any one of claims 32-44, wherein the method does not include administering a fourth loading dose.IPTS / 128916176.1 9546. The method of any one of claims 32-45, wherein the first maintenance dose comprises from about 7 mg to about 13 mg, about 6 mg to about 12 mg, about 8 mg to about 11 mg, about 9 mg to about 10.5 mg, or about 10 mg of the antisense compound.

47. The method of claim 46, wherein the first maintenance dose is administered between about 50 days to about 70 days, about 51 days to about 67 days, about 52 days to about 64 days, about 53 days to about 61 days, about 54 days to about 58 days, about 55 days to about 57 days, or about 56 days after a final loading dose.

48. The method of claim 47, wherein the method comprises a lapse period between a final loading dose and the first maintenance dose, wherein the lapse period is between about 28 days to about 56 days, between about 35 days to about 49 days, about 28 days, or about 56 days.

49. The method of any one of claims 32-47, further comprising administering a second maintenance dose comprising from about 9 mg to about 15 mg, about 10 mg to about 14 mg, about 11 mg to about 13 mg, or about 12 mg of the antisense compound.

50. The method of claim 49, wherein the second maintenance dose comprises from about 9 mg to about 15 mg, about 11 mg to about 14 mg, about 12 mg to about 14.5 mg, or about 14 mg of the antisense compound.

51. The method of claim 49 or 50, wherein the second maintenance dose is administered between about 50 days to about 90 days, about 51 days to about 80 days, about 52 days to about 70 days, about 53 days to about 60 days, about 54 days to about 57 days, or about 56 days after administration of the first maintenance dose.

52. The method of any one of claims 49-51, wherein the second maintenance dose is administered between about 50 days to about 90 days, about 60 days to about 89 days, about 70 days to about 88 days, about 80 days to about 87 days, about 82 days to about 88 days, or about 84 days after administration of the first maintenance dose.

53. The method of any one of claims 32-52, further comprising administering one or more additional maintenance doses comprising from about 10 mg to about 16 mg of the antisense compound, wherein each of the one or more additional maintenance doses is equal to or higher than the first maintenance dose.IPTS / 128916176.1 9654. The method of claim 53, wherein each of the one or more additional maintenance doses comprises from about 11 mg to about 16 mg, from about 12 mg to about 15 mg, from about 13 mg to about 14.5 mg, or about 14 mg of the antisense compound.

55. The method of claim 53 or 54, wherein one of the one or more additional maintenance doses is administered between about 50 days to about 90 days, about 51 days to about 80 days, about 52 days to about 70 days, about 53 days to about 60 days, about 54 days to about 57 days, or about 56 days after administration of the second maintenance dose.

56. The method of claim 53 or 54, wherein one of the one or more additional maintenance doses is administered between about 50 days to about 90 days, about 60 days to about 89 days, about 70 days to about 88 days, about 80 days to about 87 days, about 82 days to about 88 days, or about 84 days after administration of the second maintenance dose.

57. The method of claim 53 or 54, wherein the one or more additional maintenance doses are administered Q2M.

58. The method of claim 53 or 54, wherein the one or more additional maintenance doses are administered Q3M.

59. The method of any one of claims 32-58, wherein the second maintenance dose is higher than the first maintenance dose.

60. The method of claim 32, further comprising: administering a second loading dose of about 8 mg of the antisense compound about 28 days after administration of the first loading dose; administering a third loading dose of about 8 mg of the antisense compound about 56 days after administration of the first loading dose; and administering a second maintenance dose comprising a dose of about 12 mg of the antisense compound about 56 days after administration of the first maintenance dose;IPTS / 128916176.1 97administering a third maintenance dose comprising a dose of about 14 mg of the antisense compound about 56 days after administration of the second maintenance dose, wherein the first loading dose comprises a dose of about 8 mg of the antisense compound and the first maintenance dose comprises a dose of about 10 mg of the antisense compound and is administered about 56 days after administration of the third loading dose.

61. The method of claim 32, further comprising: administering a second loading dose of about 8 mg of the antisense compound about 28 days after administration of the first loading dose; administering a third loading dose of about 8 mg of the antisense compound about 56 days after administration of the first loading dose; administering a fourth loading dose of about 8 mg of the antisense compound about 84 days after administration of the first loading dose; and administering a second maintenance dose comprising a dose of about 14 mg of the antisense compound about 84 days after administration of the first maintenance dose; administering a third maintenance dose comprising a dose of about 14 mg of the antisense compound about 84 days after administration of the second maintenance dose, wherein the first loading dose comprises a dose of about 8 mg of the antisense compound, and the first maintenance dose comprises a dose of about 10 mg of the antisense compound and is administered about 56 days after administration of the fourth loading dose.

62. A method of treating Angelman syndrome (AS) in a human subject in need thereof, the method comprising: (a) administering a first loading dose of about 5 mg to about 10 mg of an antisense compound comprising a nucleic acid sequence complementary to a UBE3A-AS transcript; (b) positioning the human subject into an inverted position after administration of the first loading dose;IPTS / 128916176.1 98(c) administering a first maintenance dose of about 6 mg to about 14 mg of the antisense compound; and (d) administering a second maintenance dose of about 8 mg to about 16 mg of the antisense compound.

63. A method of treating Angelman syndrome (AS) in a plurality of human subjects in need thereof from a patient population, the method comprising: (a) administering a first loading dose of about 5 mg to about 10 mg of an antisense compound comprising a nucleic acid sequence complementary to a UBE3A-AS transcript; (b) positioning the human subject into an inverted position after administration of the first loading dose; (c) administering a first maintenance dose of about 6 mg to about 14 mg of the antisense compound; and (d) administering a second maintenance dose of about 8 mg to about 16 mg of the antisense compound.

64. The method of claim 62 or 63, wherein positioning the human subject into the inverted position comprises positioning the human subject into the Trendelenburg position.

65. The method of any one of claims 62-64, wherein the human subject is positioned in the inverted position for about 30 minutes to about 60 minutes, about 40 minutes to about 50 minutes, or about 45 minutes.

66. The method of any one of claims 62-65, wherein the antisense compound comprises the nucleic acid sequence of SEQ ID NO:

1.

67. The method of any one of claims 62-66, wherein the nucleic acid sequence of the antisense compound comprises a modified nucleic acid sequence of AL*GL*AL*a*t*g*g*c*a*c*a*t*c*t*5mCL*TL*TL*GL(SEQ ID NO: 2), wherein: capital letters denote RNA nucleosides; lower case letters denote DNA nucleosides; 5mC denotes a 5-methylcytosine nucleoside;IPTS / 128916176.1 99superscript L denotes a locked nucleic acid (LNA) nucleoside; and asterisks denote phosphorothioate internucleoside linkages.

68. The method of any one of claims 62-67, wherein the first loading dose comprises from about 6 mg to about 9 mg, about 7 mg to about 8.5 mg, or about 8 mg of the antisense compound.

69. The method of any one of claims 62-68, further comprising administering a second loading dose.

70. The method of claim 69, wherein the second loading dose comprises from about 5 mg to about 10 mg, about 6 mg to about 9 mg, about 7 mg to about 8.5 mg, or about 8 mg of the antisense compound.

71. The method of claim 69, wherein the second loading dose is administered between about 21 days to about 35 days, about 22 days to about 34 days, about 23 days to about 33 days, about 24 days to about 32 days, about 25 days to about 31 days, about 26 days to about 30 days, about 27 days to about 29 days, or about 28 days after the first loading dose.

72. The method of any one of claims 62-71, further comprising administering a third loading dose.

73. The method of claim 72, wherein the third loading dose comprises from about 5 mg to about 10 mg, about 6 mg to about 9 mg, about 7 mg to about 8.5 mg, or about 8 mg of the antisense compound.

74. The method of claim 72 or 73, wherein the third loading dose is administered between about 21 days to about 35 days, about 22 days to about 34 days, about 23 days to about 33 days, about 24 days to about 32 days, about 25 days to about 31 days, about 26 days to about 30 days, about 27 days to about 29 days, or about 28 days after the second loading dose.

75. The method of any one of claims 62-74, wherein the method does not include administering a fourth loading dose.IPTS / 128916176.1 10076. The method of any one of claims 62-75, wherein the first maintenance dose comprises from about 7 mg to about 13 mg, about 6 mg to about 12 mg, about 8 mg to about 11 mg, about 9 mg to about 10.5 mg, or about 10 mg of the antisense compound.

77. The method of claim 76, wherein the first maintenance dose is administered between about 50 days to about 70 days, about 51 days to about 67 days, about 52 days to about 64 days, about 53 days to about 61 days, about 54 days to about 58 days, about 55 days to about 57 days, or about 56 days after a final loading dose.

78. The method of claim 76 or 77, wherein the method comprises a lapse period between the a final loading dose and the first maintenance dose, wherein the lapse period is between about 28 days to about 56 days, between about 35 days to about 49 days, about 28 days, or about 56 days.

79. The method of any one of claims 62-77, wherein the second maintenance dose comprises from about 9 mg to about 15 mg, about 10 mg to about 14 mg, about 11 mg to about 13 mg, or about 12 mg of the antisense compound.

80. The method of any one of claims 62-77, wherein the second maintenance dose comprises from about 9 mg to about 15 mg, about 11 mg to about 14 mg, about 12 mg to about 14.5 mg, or about 14 mg of the antisense compound.

81. The method of any one of claims 62-80, wherein the second maintenance dose is administered between about 50 days to about 90 days, about 51 days to about 80 days, about 52 days to about 70 days, about 53 days to about 60 days, about 54 days to about 57 days, or about 56 days after administration of the first maintenance dose.

82. The method of any one of claims 62-80, wherein the second maintenance dose is administered between about 50 days to about 90 days, about 60 days to about 89 days, about 70 days to about 88 days, about 80 days to about 87 days, about 82 days to about 88 days, or about 84 days after administration of the first maintenance dose.

83. The method of any one of claims 62-82, further comprising administering one or more additional maintenance doses comprising from about 10 mg to about 16 mg of the antisense compound, wherein each of the one or more additional maintenance doses is equal to or higher than the first maintenance dose.IPTS / 128916176.1 10184. The method of claim 83, wherein each of the one or more additional maintenance doses comprises from about 11 mg to about 16 mg, from about 12 mg to about 15 mg, from about 13 mg to about 14.5 mg, or about 14 mg of the antisense compound.

85. The method of claim 83 or 84, wherein one of the one or more additional maintenance doses is administered between about 50 days to about 90 days, about 51 days to about 80 days, about 52 days to about 70 days, about 53 days to about 60 days, about 54 days to about 57 days, or about 56 days after administration of the second maintenance dose.

86. The method of claim 83 or 84, wherein one of the one or more additional maintenance doses is administered between about 50 days to about 90 days, about 60 days to about 89 days, about 70 days to about 88 days, about 80 days to about 87 days, about 82 days to about 88 days, or about 84 days after administration of the second maintenance dose.

87. The method of claim 83 or 84, wherein the one or more additional maintenance doses are administered Q2M.

88. The method of claim 83 or 84, wherein the one or more additional maintenance doses are administered Q3M.

89. The method of any one of claims 62-88, wherein the second maintenance dose is higher than the first maintenance dose.

90. The method of claim 62, further comprising: administering a second loading dose of about 8 mg of the antisense compound about 28 days after administration of the first loading dose; administering a third loading dose of about 8 mg of the antisense compound about 56 days after administration of the first loading dose; and administering a third maintenance dose comprising a dose of about 14 mg of the antisense compound about 56 days after administration of the second maintenance dose, wherein the first loading dose comprises a dose of about 8 mg of the antisense compound, the first maintenance dose comprises a dose of about 10 mg of theIPTS / 128916176.1 102antisense compound and is administered about 56 days after administration of the third loading dose, and the second maintenance dose comprises a dose of about 12 mg of the antisense compound and is administered about 56 days after administration of the first maintenance dose.

91. The method of claim 62, further comprising: administering a second loading dose of about 8 mg of the antisense compound about 28 days after administration of the first loading dose; administering a third loading dose of about 8 mg of the antisense compound about 56 days after administration of the first loading dose; and administering a fourth loading dose of about 8 mg of the antisense compound about 84 days after administration of the first loading dose; and administering a third maintenance dose comprising a dose of about 14 mg of the antisense compound about 84 days after administration of the second maintenance dose, wherein the first loading dose comprises a dose of about 8 mg of the antisense compound, the first maintenance dose comprises a dose of about 10 mg of the antisense compound and is administered about 56 days after administration of the fourth loading dose, the second maintenance dose comprises a dose of about 14 mg of the antisense compound and is administered about 84 days after administration of the first maintenance dose.

92. In a method of treating Angelman syndrome (AS) in a human subject in need thereof, the method comprising: administering a first loading dose of an antisense compound comprising a nucleic acid sequence complementary to a UBE3A-AS transcript; and administering a first maintenance dose of the antisense compound, wherein the improvement comprises: administering a second maintenance dose of about 8 mg to about 16 mg of the antisense compound, wherein the first loading dose of the antisense compound is about 5 mg to about 10 mg,IPTS / 128916176.1 103wherein the first maintenance dose of the antisense compound is about 6 mg to about 14 mg.

93. In a method of treating Angelman syndrome (AS) in a plurality of human subjects of a patient population, the method comprising: administering a first loading dose of an antisense compound comprising a nucleic acid sequence complementary to a UBE3A-AS transcript; and administering a first maintenance dose of the antisense compound, wherein the improvement comprises: administering a second maintenance dose of about 8 mg to about 16 mg of the antisense compound, wherein the first loading dose of the antisense compound is about 5 mg to about 10 mg, wherein the first maintenance dose of the antisense compound is about 6 mg to about 14 mg.

94. The method of claim 92 or 93, wherein the antisense compound comprises the nucleic acid sequence of SEQ ID NO:

1.

95. The method of any one of claims 92-94, wherein the nucleic acid sequence of the antisense compound comprises a modified nucleic acid sequence of AL*GL*AL*a*t*g*g*c*a*c*a*t*c*t*5mCL*TL*TL*GL(SEQ ID NO: 2), wherein:lower case letters denote DNA nucleosides; 5mC denotes a 5-methylcytosine nucleoside; superscript L denotes a locked nucleic acid (LNA) nucleoside; and asterisks denote phosphorothioate internucleoside linkages.

96. The method of any one of claims 92-95, wherein the first loading dose comprises from about 6 mg to about 9 mg, about 7 mg to about 8.5 mg, or about 8 mg of the antisense compound.

97. The method of any one of claims 92-96, wherein the method further comprises administering a second loading dose.IPTS / 128916176.1 10498. The method of claim 97, wherein the second loading dose comprises from about 5 mg to about 10 mg, about 6 mg to about 9 mg, about 7 mg to about 8.5 mg, or about 8 mg of the antisense compound.

99. The method of claim 97, wherein the second loading dose is administered between about 21 days to about 35 days, about 22 days to about 34 days, about 23 days to about 33 days, about 24 days to about 32 days, about 25 days to about 31 days, about 26 days to about 30 days, about 27 days to about 29 days, or about 28 days after the first loading dose.

100. The method of any one of claims 92-99, wherein the method further comprises administering a third loading dose.

101. The method of claim 100, wherein the third loading dose comprises from about 5 mg to about 10 mg, about 6 mg to about 9 mg, about 7 mg to about 8.5 mg, or about 8 mg of the antisense compound.

102. The method of claim 100, wherein the third loading dose is administered between about 21 days to about 35 days, about 22 days to about 34 days, about 23 days to about 33 days, about 24 days to about 32 days, about 25 days to about 31 days, about 26 days to about 30 days, about 27 days to about 29 days, or about 28 days after the second loading dose.

103. The method of any one of claims 92-102, wherein the method does not include administering a fourth loading dose.

104. The method of any one of claims 92-103, wherein the improvement further comprises: positioning the human subject into an inverted position after administration of the first, second, and / or third loading dose.

105. The method of claim 104, wherein positioning the human subject into the inverted position comprises positioning the human subject into the Trendelenburg position.IPTS / 128916176.1 105106. The method of any one of claims 104 or 105, wherein the human subject is positioned in the inverted position for about 30 minutes to about 60 minutes, about 40 minutes to about 50 minutes, or about 45 minutes.

107. The method of any one of claims 92-106, wherein the first maintenance dose comprises from about 7 mg to about 13 mg, about 6 mg to about 12 mg, about 8 mg to about 11 mg, about 9 mg to about 10.5 mg, or about 10 mg of the antisense compound.

108. The method of claim 107, wherein the first maintenance dose is administered between about 50 to about 70 days, about 51 to about 67 days, about 52 to about 64 days, about 53 to about 61 days, about 54 to about 58 days, about 55 to about 57 days, or about 56 days after a final loading dose.

109. The method of any one of claims 92-108, wherein the second maintenance dose comprises from about 9 mg to about 15 mg, about 10 mg to about 14 mg, about 11 mg to about 13 mg, or about 12 mg of the antisense compound.

110. The method of any one of claims 92-109, wherein the second maintenance dose comprises from about 9 mg to about 15 mg, about 11 mg to about 14 mg, about 12 mg to about 14.5 mg, or about 14 mg of the antisense compound.

111. The method of any one of claims 92-110, wherein the second maintenance dose is administered between about 50 days to about 90 days, about 51 days to about 80 days, about 52 days to about 70 days, about 53 days to about 60 days, about 54 days to about 57 days, or about 56 days after administration of the first maintenance dose.

112. The method of any one of claims 92-111, wherein the second maintenance dose is administered between about 50 days to about 90 days, about 60 days to about 89 days, about 70 days to about 88 days, about 80 days to about 87 days, about 82 days to about 88 days, or about 84 days after administration of the first maintenance dose.

113. The method of any one of claims 92-112, wherein the improvement further comprises administering one or more additional maintenance doses comprising fromIPTS / 128916176.1 106about 10 mg to about 16 mg of the antisense compound, wherein each of the one or more additional maintenance doses is equal to or higher than the second maintenance dose.

114. The method of claim 113, wherein each of the one or more additional maintenance doses comprises from about 11 mg to about 16 mg, from about 12 mg to about 15 mg, from about 13 mg to about 14.5 mg, or about 14 mg of the antisense compound.

115. The method of claim 113 or 114, wherein one of the one or more additional maintenance doses is administered between about 50 to about 90 days, about 51 to about 80 days, about 52 to about 70 days, about 53 to about 60 days, about 54 to about 57 days, or about 56 days after administration of the second maintenance dose.

116. The method of claim 113 or 114, wherein one of the one or more additional maintenance doses is administered between about 50 to about 90 days, about 60 to about 89 days, about 70 to about 88 days, about 80 to about 87 days, about 82 to about 88 days, or about 84 days after administration of the second maintenance dose.

117. The method of claim 113 or 114, wherein the one or more additional maintenance doses are administered Q2M.

118. The method of claim 113 or 114, wherein the one or more additional maintenance doses are administered Q3M.

119. The method of any one of claims 92-118, wherein the second maintenance dose is higher than the first maintenance dose.

120. The method of claim 92, wherein the improvement further comprises: administering a third maintenance dose comprising a dose of about 14 mg of the antisense compound about 56 days after administration of the second maintenance dose, wherein the first maintenance dose comprises a dose of about 10 mg of the antisense compound and the second maintenance dose comprises a dose of about 12 mg of the antisense compound and is administered about 56 days after administration of the first maintenance dose.IPTS / 128916176.1 107121. The method of claim 92, wherein the improvement further comprises: administering a third maintenance dose comprising a dose of about 14 mg of the antisense compound about 84 days after administration of the second maintenance dose, wherein the first maintenance dose comprises a dose of about 10 mg of the antisense compound and the second maintenance dose comprises a dose of about 14 mg of the antisense compound and is administered about 84 days after administration of the first maintenance dose.

122. In a method of treating Angelman syndrome (AS) in a human subject in need thereof, the method comprising: administering a first loading dose of an antisense compound comprising a nucleic acid sequence complementary to a UBE3A-AS transcript; and administering a first maintenance dose of the antisense compound, wherein the improvement comprises: positioning the human subject into an inverted position after administration of the first loading dose; wherein the first loading dose of the antisense compound is about 5 mg to about 10 mg, wherein the first maintenance dose of the antisense compound is about 6 mg to about 14 mg.

123. In a method of treating Angelman syndrome (AS) in a plurality of human subjects of a patient population, the method comprising: administering a first loading dose of an antisense compound comprising a nucleic acid sequence complementary to a UBE3A-AS transcript; and administering a first maintenance dose of the antisense compound, wherein the improvement comprises: positioning the human subject into an inverted position after administration of the first loading dose; wherein the first loading dose of the antisense compound is about 5 mg to about 10 mg,IPTS / 128916176.1 108wherein the first maintenance dose of the antisense compound is about 6 mg to about 14 mg.

124. The method of claim 122 or 123, wherein positioning the human subject into the inverted position comprises positioning the human subject into the Trendelenburg position.

125. The method of any one of claims 122-124, wherein the human subject is positioned in the inverted position for about 30 minutes to about 60 minutes, about 40 minutes to about 50 minutes, or about 45 minutes.

126. The method of any one of claims 122-125, wherein the antisense compound comprises the nucleic acid sequence of SEQ ID NO:

1.

127. The method of any one of claims 122-126, wherein the nucleic acid sequence of the antisense compound comprises a modified nucleic acid sequence of AL*GL*AL*a*t*g*g*c*a*c*a*t*c*t*5mCL*TL*TL*GL(SEQ ID NO: 2), wherein: capital letters denote RNA nucleosides; lower case letters denote DNA nucleosides; 5mC denotes a 5-methylcytosine nucleoside; superscript L denotes a locked nucleic acid (LNA) nucleoside; and asterisks denote phosphorothioate internucleoside linkages.

128. The method of any one of claims 122-127, wherein the first loading dose comprises from about 6 mg to about 9 mg, about 7 mg to about 8.5 mg, or about 8 mg of the antisense compound.

129. The method of any one of claims 122-128, wherein the method further comprises administering a second loading dose.

130. The method of claim 129, wherein the second loading dose comprises from about 5 mg to about 10 mg, about 6 mg to about 9 mg, about 7 mg to about 8.5 mg, or about 8 mg of the antisense compound.

131. The method of claim 129, wherein the second loading dose is administered between about 21 days to about 35 days, about 22 to about 34 days, about 23 days toIPTS / 128916176.1 109about 33 days, about 24 to about 32 days, about 25 to about 31 days, about 26 to about 30 days, about 27 to about 29 days, or about 28 days after the first loading dose.

132. The method of any one of claims 122-131, further comprising administering a third loading dose.

133. The method of claim 132, wherein the third loading dose comprises from about 5 mg to about 10 mg, about 6 mg to about 9 mg, about 7 mg to about 8.5 mg, or about 8 mg of the antisense compound.

134. The method of claim 132, wherein the third loading dose is administered between about 21 days to about 35 days, about 22 to about 34 days, about 23 days to about 33 days, about 24 to about 32 days, about 25 to about 31 days, about 26 to about 30 days, about 27 to about 29 days, or about 28 days after the second loading dose.

135. The method of any one of claims 122-134, wherein the method does not include administering a fourth loading dose.

136. The method of any one of claims 122-135, wherein the first maintenance dose comprises from about 7 mg to about 13 mg, about 6 mg to about 12 mg, about 8 mg to about 11 mg, about 9 mg to about 10.5 mg, or about 10 mg of the antisense compound.

137. The method of claim 136, wherein the first maintenance dose is administered between about 50 days to about 70 days, about 51 days to about 67 days, about 52 days to about 64 days, about 53 days to about 61 days, about 54 days to about 58 days, about 55 days to about 57 days, or about 56 days after a final loading dose.

138. The method of claim 136 or 137, wherein the method comprises a lapse period between the a final loading dose and the first maintenance dose, wherein the lapse period is between about 28 days to about 56 days, between about 35 days to about 49 days, about 28 days, or about 56 days.

139. The method of any one of claims 122-137, wherein the method further comprises administering a second maintenance dose comprising from about 9 mg toIPTS / 128916176.1 110about 15 mg, about 10 mg to about 14 mg, about 11 mg to about 13 mg, or about 12 mg of the antisense compound.

140. The method of claim 139, wherein the second maintenance dose comprises from about 9 mg to about 15 mg, about 11 mg to about 14 mg, about 12 mg to about 14.5 mg, or about 14 mg of the antisense compound.

141. The method of claim 139 or 140, wherein the second maintenance dose is administered between about 50 days to about 90 days, about 51 days to about 80 days, about 52 days to about 70 days, about 53 days to about 60 days, about 54 days to about 57 days, or about 56 days after administration of the first maintenance dose.

142. The method of any one of claims 139-141, wherein the second maintenance dose is administered between about 50 days to about 90 days, about 60 days to about 89 days, about 70 days to about 88 days, about 80 days to about 87 days, about 82 days to about 88 days, or about 84 days after administration of the first maintenance dose.

143. The method of any one of claims 122-142, wherein the improvement further comprises administering one or more additional maintenance doses comprising from about 10 mg to about 16 mg of the antisense compound, wherein each of the one or more additional maintenance doses is equal to or higher than the first maintenance dose.

144. The method of claim 143, wherein each of the one or more additional maintenance doses comprises from about 11 mg to about 16 mg, from about 12 mg to about 15 mg, from about 13 mg to about 14.5 mg, or about 14 mg of the antisense compound.

145. The method of claim 143 or 144, wherein one of the one or more additional maintenance doses is administered between about 50 days to about 90 days, about 51 days to about 80 days, about 52 days to about 70 days, about 53 days to about 60 days, about 54 days to about 57 days, or about 56 days after administration of the second maintenance dose.IPTS / 128916176.1 111146. The method of claim 143 or 144, wherein one of the one or more additional maintenance doses are administered between about 50 days to about 90 days, about 60 days to about 89 days, about 70 days to about 88 days, about 80 days to about 87 days, about 82 days to about 88 days, or about 84 days after administration of the second maintenance dose.

147. The method of claim 143 or 144, wherein the one or more additional maintenance doses are administered Q2M.

148. The method of claim 143 or 144, wherein the one or more additional maintenance doses are administered Q3M.

149. The method of any one of claims 122-148, wherein the second maintenance dose is higher than the first maintenance dose.

150. The method of claim 122, further comprising: administering a second maintenance dose comprises a dose of about 12 mg of the antisense compound and is administered about 56 days after administration of the first maintenance dose; and administering a third maintenance dose comprising a dose of about 14 mg of the antisense compound about 56 days after administration of the second maintenance dose, wherein the first maintenance dose comprises a dose of about 10 mg of the antisense compound.

151. The method of claim 122, further comprising: administering a second maintenance dose comprising a dose of about 14 mg of the antisense compound and is administered about 84 days after administration of the first maintenance dose; and administering a third maintenance dose comprising a dose of about 14 mg of the antisense compound about 84 days after administration of the second maintenance dose, wherein the first maintenance dose comprises a dose of about 10 mg of the antisense compound.IPTS / 128916176.1 112152. In a method of treating Angelman syndrome (AS) in a human subject in need thereof, the method comprising: administering a first loading dose of an antisense compound comprising a nucleic acid sequence complementary to a UBE3A-AS transcript; and administering a first maintenance dose of the antisense compound, wherein the improvement comprises: positioning the human subject into an inverted position after administration of the first loading dose; administering a second maintenance dose of about 8 mg to about 16 mg of the antisense compound, wherein the first loading dose of the antisense compound is about 5 mg to about 10 mg, the first maintenance dose of the antisense compound is about 6 mg to about 14 mg.

153. In a method of treating Angelman syndrome (AS) in a plurality of human subjects of a patient population, the method comprising: administering a first loading dose of an antisense compound comprising a nucleic acid sequence complementary to a UBE3A-AS transcript; and administering a first maintenance dose of the antisense compound, wherein the improvement comprises: positioning the human subject into an inverted position after administration of the first loading dose; administering a second maintenance dose of about 8 mg to about 16 mg of the antisense compound, wherein the first loading dose of the antisense compound is about 5 mg to about 10 mg, the first maintenance dose of the antisense compound is about 6 mg to about 14 mg.

154. The method of claim 152 or 153, wherein positioning the human subject into the inverted position comprises positioning the human subject into the Trendelenburg position.IPTS / 128916176.1 113155. The method of any one of claims 152-154, wherein the human subject is positioned in the inverted position for about 30 minutes to about 60 minutes, about 40 minutes to about 50 minutes, or about 45 minutes.

156. The method of any one of claims 152-155, wherein the antisense compound comprises the nucleic acid sequence of SEQ ID NO:

1.

157. The method of any one of claims 152-156, wherein the nucleic acid sequence of the antisense compound comprises a modified nucleic acid sequence of AL*GL*AL*a*t*g*g*c*a*c*a*t*c*t*5mCL*TL*TL*GL(SEQ ID NO: 2), wherein: capital letters denote RNA nucleosides; lower case letters denote DNA nucleosides; 5mC denotes a 5-methylcytosine nucleoside; superscript L denotes a locked nucleic acid (LNA) nucleoside; and asterisks denote phosphorothioate internucleoside linkages.

158. The method of any one of claims 152-157, wherein the first loading dose comprises from about 6 mg to about 9 mg, about 7 mg to about 8.5 mg, or about 8 mg of the antisense compound.

159. The method of any one of claims 152-158, wherein the method further comprises administering a second loading dose.

160. The method of claim 159, wherein the second loading dose comprises from about 5 mg to about 10 mg, about 6 mg to about 9 mg, about 7 mg to about 8.5 mg, or about 8 mg of the antisense compound.

161. The method of claim 159, wherein the second loading dose is administered between about 21 days to about 35 days, about 22 days to about 34 days, about 23 days to about 33 days, about 24 days to about 32 days, about 25 days to about 31 days, about 26 days to about 30 days, about 27 days to about 29 days, or about 28 days after the first loading dose.

162. The method of any one of claims 152-161, wherein the method further comprises administering a third loading dose.IPTS / 128916176.1 114163. The method of claim 162, wherein the third loading dose comprises from about 5 mg to about 10 mg, about 6 mg to about 9 mg, about 7 mg to about 8.5 mg, or about 8 mg of the antisense compound.

164. The method of claim 162 or 163, wherein the third loading dose is administered between about 21 days to about 35 days, about 22 days to about 34 days, about 23 days to about 33 days, about 24 days to about 32 days, about 25 days to about 31 days, about 26 days to about 30 days, about 27 days to about 29 days, or about 28 days after the second loading dose.

165. The method of any one of claims 152-164, wherein the first maintenance dose comprises from about 7 mg to about 13 mg, about 6 mg to about 12 mg, about 8 mg to about 11 mg, about 9 mg to about 10.5 mg, or about 10 mg of the antisense compound.

166. The method of claim 165, wherein the first maintenance dose is administered between about 50 days to about 70 days, about 51 days to about 67 days, about 52 days to about 64 days, about 53 days to about 61 days, about 54 days to about 58 days, about 55 days to about 57 days, or about 56 days after a final loading dose.

167. The method of claim 165 or 166, wherein the method comprises a lapse period between the a final loading dose and the first maintenance dose, wherein the lapse period is between about 28 days to about 56 days, between about 35 days to about 49 days, about 28 days, or about 56 days.

168. The method of any one of claims 152-166, wherein the second maintenance dose comprises from about 9 mg to about 15 mg, about 10 mg to about 14 mg, about 11 mg to about 13 mg, or about 12 mg of the antisense compound.

169. The method of any one of claims 152-168, wherein the second maintenance dose comprises from about 9 mg to about 15 mg, about 11 mg to about 14 mg, about 12 mg to about 14.5 mg, or about 14 mg of the antisense compound.

170. The method of any one of claims 152-169, wherein the second maintenance dose is administered between about 50 days to about 90 days, about 51 days to about 80 days, about 52 days to about 70 days, about 53 days to about 60 days, about 54IPTS / 128916176.1 115days to about 57 days, or about 56 days after administration of the first maintenance dose.

171. The method of any one of claims 152-170, wherein the second maintenance dose is administered between about 50 days to about 90 days, about 60 days to about 89 days, about 70 days to about 88 days, about 80 days to about 87 days, about 82 days to about 88 days, or about 84 days after administration of the first maintenance dose.

172. The method of any one of claims 152-171, wherein the improvement further comprises administering one or more additional maintenance doses comprising from about 10 mg to about 16 mg of the antisense compound, wherein each of the one or more additional maintenance doses is equal to or higher than the first maintenance dose.

173. The method of claim 172, wherein each of the one or more additional maintenance doses comprises from about 11 mg to about 16 mg, from about 12 mg to about 15 mg, from about 13 mg to about 14.5 mg, or about 14 mg of the antisense compound.

174. The method of claim 172 or 173, wherein one of the one or more additional maintenance doses is administered between about 50 days to about 90 days, about 51 days to about 80 days, about 52 days to about 70 days, about 53 days to about 60 days, about 54 days to about 57 days, or about 56 days after administration of the second maintenance dose.

175. The method of claim 172 or 173, wherein one of the one or more additional maintenance doses is administered between about 50 days to about 90 days, about 60 days to about 89 days, about 70 days to about 88 days, about 80 days to about 87 days, about 82 days to about 88 days, or about 84 days after administration of the second maintenance dose.

176. The method of claim 172 or 173, wherein the one or more additional maintenance doses are administered Q2M.IPTS / 128916176.1 116177. The method of claim 172 or 173, wherein the one or more additional maintenance doses are administered Q3M.

178. The method of any one of claims 152-177, wherein the second maintenance dose is higher than the first maintenance dose.

179. The method of claim 152, further comprising administering a second loading dose and administering a third loading dose without further administering a fourth loading dose.

180. The method of claim 152, further comprising: administering a third maintenance dose comprising a dose of about 14 mg of the antisense compound about 56 days after administration of the second maintenance dose, wherein the first maintenance dose comprises a dose of about 10 mg of the antisense compound and the second maintenance dose comprises a dose of about 12 mg of the antisense compound and is administered about 56 days after administration of the first maintenance dose.

181. The method of claim 152, further comprising: administering a third maintenance dose comprising a dose of about 14 mg of the antisense compound about 84 days after administration of the second maintenance dose, wherein the first maintenance dose comprises a dose of about 10 mg of the antisense compound and the second maintenance dose comprises a dose of about 14 mg of the antisense compound and is administered about 84 days after administration of the first maintenance dose.

182. The method of any one of claims 1-181, wherein each loading dose and maintenance dose is administered to the human subject via intrathecal (IT) lumbar puncture (LP).

183. The method of any one of claims 1-182, wherein the method achieves a concentration of the antisense oligonucleotide in the brain of the subject that isIPTS / 128916176.1 117maintained between about 500 ng / g and about 8000 ng / g between the first loading dose and at least the first maintenance dose.

184. The method of any one of claims 1-182, wherein the method achieves a concentration of the antisense oligonucleotide in the brain of the subject that is maintained between about 1000 ng / g and about 7000 ng / g between the first loading dose and at least the first maintenance dose.

185. The method of any one of claims 1-182, wherein the method achieves a concentration of the antisense oligonucleotide in the brain of the subject that is maintained between about 2000 ng / g and about 4000 ng / g between the first loading dose and at least the first maintenance dose.

186. The method of any one of claims 1-182, wherein the method achieves a concentration of the antisense oligonucleotide in the brain of the subject that is maintained below about 6500 ng / g between the first loading dose and at least the first maintenance dose.

187. The method of any one of claims 1-186, wherein the method avoids causing radiculopathy in the human subject.

188. The method of any one of claims 1-187, wherein the method avoids causing elevated cerebrospinal fluid (CSF) protein levels in the human subject.

189. The method of any one of claims 1-188, wherein the volume of each loading dose and / or maintenance dose is between 1 mL and 10 mL.

190. The method of any one of claims 1-189, wherein the human subject is between about 4 years of age and about 18 years of age or 4 years of age to less than 18 years of age.

191. The method of any one of claims 1-190, further comprising administering a steroid premedication.

192. The method of claim 191, comprising administering the steroid prior to intrathecal (IT) lumbar puncture (LP) administration of the first loading dose.

193. The method of claim 191 or 192, wherein the steroid is a corticosteroid.IPTS / 128916176.1 118194. The method of claim 193, wherein the corticosteroid is dexamethasone.

195. The method of any one of claims 191-194, wherein administering the steroid comprises intravenous administration or oral administration of the steroid.

196. The method of claim 195, wherein intravenous administration of the steroid comprises intravenous administration at 0.3 mg / kg of dexamethasone or dose- equivalent of an alternative corticosteroid.

197. The method of claim 195, wherein administering the steroid comprises orally administering the steroid at 0.3 mg / kg of dexamethasone or dose-equivalent of an alternative corticosteroid one day before the first loading dose.

198. The method of any one of claims 191-194, wherein the steroid premedication is administered within about 0.5 hours to about 5 hours, within about 1 hour to about 4 hours, within about 1.5 hours to about 3 hours, or within about 2 hours prior to administration of any or each loading dose.

199. The method of any one of claims 1-198, further comprising administering a flush of artificial cerebrospinal fluid (aCSF) after administration of any or each loading dose.

200. The method of claim 199, further comprising administering a flush of aCSF after administration of any or each maintenance dose.

201. The method of claim 199 or 200, wherein the flush of aCSF comprises a volume of 1 mL to 10 mL.

202. The method of any one of claims 199-201, wherein the flush of aCSF is administered as a bolus injection over one to two minutes.

203. The method of any one of claims 199-202, wherein the flush of aCSF is administered prior to positioning the human subject in an inverted position.

204. A method of treating Angelman syndrome (AS) in a human subject in need thereof, the method comprising:IPTS / 128916176.1 119(a) administering a first loading dose of about 2 mg to about 6 mg of an antisense compound comprising a nucleic acid sequence complementary to a UBE3A-AS transcript; (b) administering a first maintenance dose of about 4 mg to about 8 mg of the antisense compound; and (c) administering a second maintenance dose of about 6 mg to about 10 mg of the antisense compound.

205. The method of claim 204, wherein the antisense compound comprises the nucleic acid sequence of SEQ ID NO:

1.

206. The method of any one of claims 204-205, wherein the nucleic acid sequence of the antisense compound comprises a modified nucleic acid sequence of AL*GL*AL*a*t*g*g*c*a*c*a*t*c*t*5mCL*TL*TL*GL(SEQ ID NO: 2), wherein:lower case letters denote DNA nucleosides; 5mC denotes a 5-methylcytosine nucleoside; superscript L denotes a locked nucleic acid (LNA) nucleoside; and asterisks denote phosphorothioate internucleoside linkages.

207. The method of any one of claims 204-206, wherein the first loading dose comprises from about 3 mg to about 5 mg, or about 4 mg of the antisense compound.

208. The method of any one of claims 204-207, further comprising administering a second loading dose.

209. The method of claim 208, wherein the second loading dose comprises from about 2 mg to about 6 mg, about 3 mg to about 5 mg, or about 4 mg of the antisense compound.

210. The method of claim 208, wherein the second loading dose is administered between about 21 days to about 35 days, about 22 days to about 34 days, about 23 days to about 33 days, about 24 days to about 32 days, about 25 days to about 31 days, about 26 days to about 30 days, about 27 days to about 29 days, or about 28 days after the first loading dose.IPTS / 128916176.1 120211. The method of any one of claims 210, further comprising administering a third loading dose.

212. The method of claim 211, wherein the third loading dose comprises from about 2 mg to about 6 mg, about 3 mg to about 5 mg, or about 4 mg of the antisense compound.

213. The method of claim 211, wherein the third loading dose is administered between about 21 days to about 35 days, about 22 days to about 34 days, about 23 days to about 33 days, about 24 days to about 32 days, about 25 days to about 31 days, about 26 days to about 30 days, about 27 days to about 29 days, or about 28 days after the second loading dose.

214. The method of any one of claims 204-213, wherein the method does not include administering a fourth loading dose.

215. The method of any one of claims 204-214, further comprising: positioning the human subject into an inverted position after administration of the first, second, and / or third loading dose.

216. The method of claim 215, wherein positioning the human subject into the inverted position comprises positioning the human subject into the Trendelenburg position.

217. The method of any one of claims 215 or 216, wherein the human subject is positioned in the inverted position for about 30 minutes to about 60 minutes, about 40 minutes to about 50 minutes, or about 45 minutes.

218. The method of any one of claims 204-217, wherein the first maintenance dose comprises from about 5 mg to about 7 mg, or about 6 mg of the antisense compound.

219. The method of claim 218, wherein the first maintenance dose is administered between about 50 days to about 70 days, about 51 days to about 67 days, about 52 days to about 64 days, about 53 days to about 61 days, about 54 days to about 58 days, about 55 days to about 57 days, or about 56 days after a final loading dose.IPTS / 128916176.1 121220. The method of claim 218 or 219, wherein the method comprises a lapse period between a final loading dose and the first maintenance dose, wherein the lapse period is between about 28 days to about 56 days, between about 35 days to about 49 days, about 28 days, or about 56 days.

221. The method of any one of claims 1-220, wherein the second maintenance dose comprises from about 7 mg to about 9 mg, or about 8 mg of the antisense compound.

222. The method of any one of claims 1-221, wherein the second maintenance dose is administered between about 50 days to about 90 days, about 51 days to about 80 days, about 52 days to about 70 days, about 53 days to about 60 days, about 54 days to about 57 days, or about 56 days after administration of the first maintenance dose.

223. The method of any one of claims 1-221, wherein the second maintenance dose is administered between about 50 days to about 90 days, about 60 days to about 89 days, about 70 days to about 88 days, about 80 days to about 87 days, about 82 days to about 88 days, or about 84 days after administration of the first maintenance dose.

224. The method of any one of claims 1-223, further comprising administering one or more additional maintenance doses comprising from about 6 mg to about 12 mg of the antisense compound, wherein each of the one or more additional maintenance doses is equal to or higher than the second maintenance dose.

225. The method of claim 224, wherein each of the one or more additional maintenance doses comprises from about 7 mg to about 11 mg, about 8 to about 10 mg, or about 10 mg of the antisense compound.

226. The method of claim 224 or 225, wherein one of the one or more additional maintenance doses is administered between about 50 days to about 90 days, about 51 days to about 80 days, about 52 days to about 70 days, about 53 days to about 60 days, about 54 days to about 57 days, or about 56 days after administration of the second maintenance dose.

227. The method of claim 224 or 225, wherein one of the one or more additional maintenance doses is administered between about 50 days to about 90 days, about 60 days to about 89 days, about 70 days to about 88 days, about 80 days to about 87IPTS / 128916176.1 122days, about 82 days to about 88 days, or about 84 days after administration of the second maintenance dose.

228. The method of claim 224 or 225, wherein the one or more additional maintenance doses are administered Q2M.

229. The method of claim 224 or 225, wherein the one or more additional maintenance doses are administered Q3M.

230. The method of any one of claims 204-229, wherein the second maintenance dose is higher than the first maintenance dose.

231. The method of claim 204, further comprising: administering a second loading dose of about 4 mg of the antisense compound about 28 days after administration of the first loading dose; administering a third loading dose of about 4 mg of the antisense compound about 56 days after administration of the first loading dose; and administering a third maintenance dose comprising a dose of about 10 mg of the antisense compound about 56 days after administration of the second maintenance dose, wherein the first loading dose comprises a dose of about 4 mg of the antisense compound, the first maintenance dose comprises a dose of about 6 mg of the antisense compound and is administered about 56 days after administration of the third loading dose, and the second maintenance dose comprises a dose of about 8 mg of the antisense compound and is administered about 56 days after administration of the first maintenance dose.

232. The method of claim 204, further comprising: administering a second loading dose of about 4 mg of the antisense compound about 28 days after administration of the first loading dose; administering a third loading dose of about 4 mg of the antisense compound about 56 days after administration of the first loading dose; and administering a fourth loading dose of about 4 mg of the antisense compound about 84 days after administration of the first loading dose; andIPTS / 128916176.1 123administering a third maintenance dose comprising a dose of about 10 mg of the antisense compound about 84 days after administration of the second maintenance dose, wherein the first loading dose comprises a dose of about 4 mg of the antisense compound, the first maintenance dose comprises a dose of about 6 mg of the antisense compound and is administered about 56 days after administration of the fourth loading dose, the second maintenance dose comprises a dose of about 8 mg of the antisense compound and is administered about 84 days after administration of the first maintenance dose.

233. The method of any one of claims 204-232, wherein the human subject is less than 4 years of age.

234. The method of any one of claims 204-233, wherein the human subject is greater than 12 months of age and less than 4 years of age.

235. The method of any one of claims 204-234, wherein the human subject is greater than 12 months of age and less than 4 years of age at the time of administering the first loading dose.

236. The method of any one of claims 204-235, wherein the method comprises administering the second loading dose or a dose subsequent to the second loading dose after the human subject achieves the age of 4 years.

237. The method of claim 236, comprising increasing the amount of the antisense compound administered to the human subject having achieved the age of 4 years by about 2 mg per dose of the antisense compound up to a maximum of about 12 mg to about 16 mg of the antisense compound.

238. The method of claim 237, comprising increasing the amount of the antisense compound administered to the human subject having achieved the age of 4 years by about 2 mg per dose of the antisense compound up to a maximum of about 14 mg of the antisense compound.IPTS / 128916176.1 124

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