US-12624356-B2 - Compounds and methods for modulating PLP1

Abstract

Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of PLP1 RNA in a cell or subject, and in certain instances reducing the amount of proteolipid protein 1 in a cell or subject. Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom or hallmark of a leukodystrophy. Such symptoms and hallmarks include hypotonia, nystagmus, optic atrophy, respiratory distress, motor delays, cognitive dysfunction, speech dysfunction, spasticity, ataxia, seizures, choreiform movements, and death. Such leukodystrophies include Pelizaeus-Merzbacher disease.

Inventors

• Susan M. Freier

Assignees

• IONIS PHARMACEUTICALS, INC.

Dates

Publication Date

20260512

Application Date

20230626

Claims (20)

1. 1 . A modified oligonucleotide according to the following chemical structure: or a salt thereof.
2. 2 . The modified oligonucleotide of claim 1 , which is the sodium salt or the potassium salt.
3. 3 . A population of modified oligonucleotides of claim 1 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom.
4. 4 . A population of modified oligonucleotides of claim 2 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom.
5. 5 . A pharmaceutical composition comprising the modified oligonucleotide of claim 1 , and a pharmaceutically acceptable diluent.
6. 6 . A pharmaceutical composition comprising the population of modified oligonucleotides of claim 3 , and a pharmaceutically acceptable diluent.
7. 7 . A pharmaceutical composition comprising the population of modified oligonucleotides of claim 4 , and a pharmaceutically acceptable diluent.
8. 8 . A pharmaceutical composition comprising the modified oligonucleotide of claim 2 , and a pharmaceutically acceptable diluent.
9. 9 . The pharmaceutical composition of claim 5 , wherein the pharmaceutically acceptable diluent is artificial cerebrospinal fluid or phosphate-buffered saline (PBS).
10. 10 . The pharmaceutical composition of claim 6 , wherein the pharmaceutically acceptable diluent is artificial cerebrospinal fluid or phosphate-buffered saline (PBS).
11. 11 . The pharmaceutical composition of claim 7 , wherein the pharmaceutically acceptable diluent is artificial cerebrospinal fluid or phosphate-buffered saline (PBS).
12. 12 . The pharmaceutical composition of claim 8 , wherein the pharmaceutically acceptable diluent is artificial cerebrospinal fluid or phosphate-buffered saline (PBS).
13. 13 . The pharmaceutical composition of claim 9 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and artificial cerebrospinal fluid.
14. 14 . The pharmaceutical composition of claim 12 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and artificial cerebrospinal fluid.
15. 15 . The pharmaceutical composition of claim 9 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and PBS.
16. 16 . The pharmaceutical composition of claim 12 , wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and PBS.
17. 17 . A modified oligonucleotide according to the following chemical structure:
18. 18 . A population of modified oligonucleotides of claim 17 , wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotide are stereorandom.
19. 19 . A pharmaceutical composition comprising the modified oligonucleotide of claim 17 , and a pharmaceutically acceptable diluent.
20. 20 . A pharmaceutical composition comprising the population of modified oligonucleotides of claim 18 , and a pharmaceutically acceptable diluent.

Description

SEQUENCE LISTING The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled BIOL0382SEQ.xml, created on May 23, 2023, which is 2,012 Kb in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety. FIELD Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of proteolipid protein 1 (PLP1) RNA in a cell or subject, and in certain instances reducing the amount of proteolipid protein 1 in a cell or subject. Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom or hallmark of a leukodystrophy. Such symptoms and hallmarks include hypotonia, nystagmus, optic atrophy, respiratory distress, motor delays, cognitive dysfunction, speech dysfunction, spasticity, ataxia, seizures, choreiform movements, and death. Such leukodystrophies include Pelizaeus-Merzbacher disease. BACKGROUND Pelizaeus-Merzbacher disease (PMD) is a severe and fatal childhood X-linked leukodystrophy, associated with an extensive loss or lack of myelination of the central nervous system, and is caused by duplications or sequence variations in the gene encoding proteolipid protein 1 (PLP1). Hundreds of mutations in PLP1 have been identified, and lead to a toxic gain-of-function due to PLP1 misfolding and dysmyelination (Hobson, G., 2012, Semin. Neurol. 32, 62-67; Nevin, Z. S., 2017, American J. Hum. Genetics 100, 617-634; Sima, A. A. F., et al., 2009, Acta Neuropathologica 118, 431-439). The majority of PMD cases are due to overexpression of otherwise normal PLP1 protein, as a result of duplications or triplications of PLP1 (Inoue, K., 2005, Neurogenetics 6, 1-16; Karim, S. A., 2010, Glia 58, 1727-1738). PLP1 is expressed in myelinating oligodendrocytes and oligodendrocyte progenitor cells (OPCs) in the central nervous system (CNS), where it is responsible for about 50% of the total protein content of myelin and in Schwann cells in the peripheral nervous system (PNS) (Klugman, W., et al., 1997, Neuron 18, 59-70; Harlow, D. E., et al., 2014, J. Neurosci. 34, 1333-1343; Baumann, N., et al., 2001, Physiol. Rev. 81, 871-927). Because of the genetic heterogeneity associated with PMD, symptoms and hallmarks vary and have been grouped into two main categories: connatal and classic. The connatal form (severe/early onset) of PMD is caused by mutations in PLP1, leading to dysmyelination. This most severe form of PMD leads to mortality in early childhood, typically within the first few years of life, and presents symptoms such as nystagmus and respiratory distress, extrapyramidal signs, laryngeal stridor, feeding difficulties, optic atrophy, seizures, and extreme neonatal hypotonia. The classic form, associated with PLP1 overexpression due to PLP1 duplication or triplication, presents before the first year of age with a constellation of motor delays, hypotonia, nystagmus, and/or motor delay in early childhood, with the development of progressive spasticity, ataxia, and/or choreiform movements through adolescence and early adulthood. Other PMD phenotypes include the transitional form of PMD, associated with PLP1 overexpression or with PLP1 mutations, which combines clinical features of both the classic and connatal forms. A less severe phenotype, Spastic paraplegia type 2 (SPG2), has a later onset than classic PMD, and is associated with a mild, late-onset spasticity in the legs or assorted mild peripheral neuropathies with minimal CNS deficits. Patients with PLP1 deletions (“null” patients) have significantly milder symptoms than patients with PLP1 mutations or duplications, and can live until 40-60 years old. There are no approved therapies for PMD, with current therapy mainly being limited to palliative symptom management (Nevin, 2017; Inoue, 2005; Madry, J., et al., 2010, Neurol. Neurochir. Pol. 44, 511-515; Osorio, M. J., et al., 2017, Stem Cells 35, 311-315; Wang, P-J, et al., 2001, J. Clin. Neurophys. 18, 25-32). Currently there is a lack of acceptable options for treating leukodystrophies such as PMD. It is therefore an object herein to provide compounds, methods, and pharmaceutical compositions for the treatment of such diseases. SUMMARY OF THE INVENTION Provided herein are compounds, methods and pharmaceutical compositions for reducing the amount or activity of PLP1 RNA, and in certain embodiments reducing the expression of proteolipid protein 1 in a cell or animal. In certain embodiments, the subject has a disease or disorder associated with overexpression of PLP1 or a mutation in PLP1. In certain embodiments, the subject has a leukodystrophy. In certain embodiments, the subject has Pelizaeus-Merzbacher disease. In certain embodiments, compounds useful for reducing the amount or activity of PLP1 RNA are oligomeric compounds. In certain embodiments, compounds useful for reducing the amount or activity of PLP1 R