CN-121986163-A - Modified UNC13A oligonucleotides

Abstract

Disclosed herein are UNC13A oligonucleotides with one or more spacers or without spacers. In various embodiments, a UNC13A oligonucleotide with a spacer can reduce a mis-spliced UNC13A transcript and increase a full length UNC13A transcript, thereby producing therapeutic efficacy for a neurological disorder such as Amyotrophic Lateral Sclerosis (ALS), frontotemporal dementia (FTD), or Alzheimer's Disease (AD).

Inventors

• S. Hinckley
• D. BROWN
• D. Elbaum
• M. E. Carmelgarn

Assignees

• 奎里斯公司

Dates

Publication Date

20260505

Application Date

20240531

Priority Date

20230602

Claims (20)

1. 1. A modified UNC13A oligonucleotide consisting of 18 oligonucleotide units, said oligonucleotide units comprising at least one spacer.
2. 2. The oligonucleotide of claim 1, wherein the modified UNC13A oligonucleotide comprises a sequence that is at least 85% complementary to an equal length portion of any one of SEQ ID NOs 1-12.
3. 3. The oligonucleotide according to any one of claims 1-2, wherein 16 of said 18 oligonucleotide units are complementary to an equal length portion of any one of SEQ ID NOs 1-12.
4. 4. The oligonucleotide of any one of claims 1-3, wherein the oligonucleotide comprises a segment of up to 7 linked nucleosides.
5. 5. The oligonucleotide of any one of claims 1-4, wherein the oligonucleotide comprises a segment of up to 6, 5, 4, 3, or 2 linked nucleosides.
6. 6. The oligonucleotide of any one of claims 1-5, wherein each segment of the oligonucleotide comprises up to 7 linked nucleosides.
7. 7. The oligonucleotide of any one of claims 4-6, wherein the oligonucleotide comprises a sequence having at least 85% identity to an equal length portion of any one of SEQ ID NOs 13-1283 or 2571-2594.
8. 8. The oligonucleotide of claim 7, wherein the oligonucleotide comprises two spacer regions.
9. 9. The oligonucleotide of claim 8, wherein the oligonucleotide is 100% identical to any one of SEQ ID NOs 2571-2594.
10. 10. The oligonucleotide of any one of claims 1-9, wherein the spacer is a nucleoside substituent group comprising a non-sugar substituent that is not capable of linking to a nucleotide base.
11. 11. The oligonucleotide of claim 10, wherein the spacer is located between position 4 and position 15 of the oligonucleotide.
12. 12. The oligonucleotide of claim 10 or 11, wherein the oligonucleotide further comprises a second spacer, wherein the second spacer is located between position 10 and position 15 of the oligonucleotide.
13. 13. The oligonucleotide of claim 12, wherein the spacer and second spacer are separated in the oligonucleotide by at least 2 nucleobases, at least 3 nucleobases, at least 5 nucleobases, at least 6 nucleobases, or at least 7 nucleobases.
14. 14. The oligonucleotide of any one of claims 11-13, wherein the spacer is located between positions 4 and 9 of the oligonucleotide, and wherein the second spacer is located between positions 10 and 15 of the oligonucleotide.
15. 15. The oligonucleotide of any one of claims 11-14, wherein the spacer is located at position 8 of the oligonucleotide, and wherein the second spacer is located at position 11 of the oligonucleotide.
16. 16. The oligonucleotide of any one of claims 11-14, wherein the spacer is located at position 5 of the oligonucleotide, and wherein the second spacer is located at position 13 of the oligonucleotide.
17. 17. The oligonucleotide of any one of claims 11-14, wherein the spacer is located at position 6 of the oligonucleotide, and wherein the second spacer is located at position 14 of the oligonucleotide.
18. 18. The oligonucleotide of claim 14, wherein at least one of the two spacers is adjacent to a guanine nucleobase.
19. 19. The oligonucleotide of claim 18, wherein each of at least one of the two spacers immediately precedes a guanine nucleobase.
20. 20. The oligonucleotide of any one of claims 10-19, wherein each of the first or second spacer is a nucleoside substituent group comprising a non-sugar substituent, wherein the non-sugar substituent is free of ketone, aldehyde, ketal, hemiketal, acetal, hemiacetal, aminal, or hemiaminal moiety and is incapable of forming a covalent bond with a nucleoside acid base.

Description

Modified UNC13A oligonucleotides Cross Reference to Related Applications The present application claims the benefit and priority of U.S. provisional patent application No. 63/470,722, filed on 2 nd 6 th 2023, the entire contents of which are hereby incorporated by reference in their entirety for all purposes. Technical Field The present application relates generally to methods of treating neurological disorders using UNC13A splice switching antisense oligonucleotides, particularly UNC13A antisense oligonucleotides having one or more spacers targeting UNC13A transcripts. Technical Field Motor neuron disease is a type of neurological disease (neurological disease) that causes motor neurons to degenerate and die, which coordinate spontaneous movement of muscles through the brain. Motor neuron disease may be sporadic or inherited, and may affect upper motor neurons and/or lower motor neurons. Motor neuron diseases include amyotrophic lateral sclerosis, progressive bulbar paralysis, pseudobulbar paralysis, primary lateral sclerosis, progressive muscular atrophy, spinal muscular atrophy, and post-polio syndrome. Amyotrophic Lateral Sclerosis (ALS) is a group of motor neuron diseases affecting about 15,000 individuals in the united states. ALS is characterized by degeneration and death of upper and lower motor neurons, resulting in loss of voluntary muscle control. Motor neuron death is accompanied by muscle fasciculi tremor and atrophy. Early symptoms of ALS include muscle cramps (muscle cramps), muscle spasticity (muscle spasticity), muscle weakness (e.g., affecting the arms, legs, neck, or diaphragm), slurred speech with nasal tones, and difficulty chewing or swallowing. Eventually, the patient loses strength and control over movements, including movements required for speaking, eating, and breathing. Disease progression may be accompanied by weight loss, malnutrition, anxiety, depression, increased risk of pneumonia, muscle cramps, neuropathy, and possibly dementia. Most individuals diagnosed with ALS die from respiratory failure within 5 years of the first appearance of symptoms. Currently, there is no effective treatment for ALS. ALS occurs in individuals of all ages, but most commonly in individuals between 55 and 75 years of age, with a slightly higher incidence in men. ALS may have sporadic or familial characteristics. Sporadic ALS appears to occur randomly, accounting for over 90% of all ALS incidences. Familial ALS accounts for 5-10% of all ALS incidences. FTD refers to a series of progressive neurodegenerative diseases caused by neuronal loss in the frontal and temporal lobes of the brain. FTD is the third most common type of dementia (next to alzheimer's disease and lewy body dementia), and is also the second most common type of dementia in individuals under 65 years of age. FTD is estimated to affect 50,000 to 60,000 individuals in the united states. FTD is characterized by behavioral and personality changes and language dysfunction. Types of FTD include behavioral variant FTD (bvFTD), semantic variant primary progressive aphasia (svPPA), and non-fluent variant primary progressive aphasia (nfvPPA). ALS with FTD is characterized by symptoms associated with FTD, as well as symptoms of ALS such as muscle weakness, atrophy, fascicular tremors, muscle spasticity, speech disorders (dysarthria) and inability to swallow (dysphagia). Individuals typically die from FTD within 5 to 10 years, while ALS with FTD typically causes death within 2 to 3 years of the first occurrence of disease symptoms. As with ALS, there is currently no known treatment for FTD or ALS with FTD, nor is there a known treatment to prevent or delay the progression of both diseases. There is therefore an urgent need to identify compounds and/or compositions capable of preventing, ameliorating and treating neurological diseases such as Amyotrophic Lateral Sclerosis (ALS), frontotemporal dementia (FTD), ALS with FTD, alzheimer's Disease (AD), parkinson's Disease (PD), huntington's disease, progressive Supranuclear Palsy (PSP), brain trauma, spinal cord injury, corticobasal degeneration (CBD), nerve injury (e.g., brachial plexus nerve injury), neuropathy (e.g., chemotherapy-induced neuropathy), TDP43 protein disease (e.g., chronic traumatic brain disease, perry syndrome, dementia with lewy bodies associated with alzheimer's disease, parkinson's disease with or without dementia, and age-related TDP-43 brain disease (LATE) with or without dementia, and age-related TDP-43 brain disease (CARTS) with sclerosis, sensory neuron disease of the face, parkinson dementia complex, multiple system protein disease, CTE and synaptic diseases such as autism. Disclosure of Invention Described herein are oligonucleotides comprising one or more spacer regions and comprising a sequence that is at least 85% complementary to an equal length portion of a UNC13A transcript. In one aspect, provided herein is a modified UNC13A oligonucleotide consisting of 18 oligonuc