US-20260124321-A1 - COMBINATION THERAPY FOR SPINAL MUSCULAR ATROPHY

US20260124321A1US 20260124321 A1US20260124321 A1US 20260124321A1US-20260124321-A1

Abstract

Aspects of the application relate to compositions and methods for treating spinal muscular atrophy in a subject. In particular, this application provides therapeutic combinations of a recombinant nucleic acid that encodes the survival of motor neuron 1 (SMN1) protein (e.g., in a viral vector), and an antisense oligonucleotide (ASO) that increases full-length survival of motor neuron 2 (SMN2) mRNA (e.g., that is targeted to a nucleic acid molecule encoding the survival of motor neuron 2 (SMN2) and that promotes the inclusion of exon 7 in SMN2 mRNA).

Inventors

Anindya Kumar Sen
Alexander McCampbell

Assignees

BIOGEN MA INC.

Dates

Publication Date: 20260507
Application Date: 20250124

Claims (20)

1 . A method of treating spinal muscular atrophy (SMA) in a subject having SMA, the method comprising administering to the subject: a) an rAAV that comprises a recombinant nucleic acid that encodes the survival of motor neuron 1 (SMN1) protein, and b) nusinersen.
2 . The method of claim 1 , wherein the subject has one or more symptoms of SMA.
3 . The method of claim 2 , wherein the symptoms comprise atrophy of the limb muscles, difficulty or inability walking, or difficulty breathing.
4 . The method of claim 1 , wherein the subject is a human subject selected from the pediatric and adult population.
5 . (canceled)
6 . The method of claim 4 , wherein the subject is younger than 18 years of age.
7 . The method of claim 6 , wherein the subject is around 2 weeks, 1 month, 3 months, 6 months, 1 year, 2 years, 3 years, 4 years, or 5 years of age.
8 - 18 . (canceled)
19 . The method of claim 1 , wherein the rAAV comprises AAV9 capsid proteins.
20 . The method of claim 1 , wherein (i) the rAAV and nusinersen are administered simultaneously; (ii) the rAAV and nusinersen are administered concurrently; or (ii) the rAAV and nusinersen are administered sequentially.
21 - 23 . (canceled)
24 . The method of claim 1 , wherein the rAAV and nusinersen are administered at different frequencies.
25 . The method of claim 20 , wherein the rAAV and nusinersen are administered sequentially.
26 . The method of claim 1 , wherein nusinersen is administered 1-6 times per year.
27 . The method of claim 1 , wherein the rAAV is administered once.
28 . The method of claim 27 , wherein two or more subsequent doses nusinersen alone are administered following an initial administration of the rAAV and nusinersen.
29 . The method of claim 1 , wherein the rAAV is administered at a dose from 2×10 10 to 2×10 14 GC, and nusinersen is administered at a dose from 0.01 to 10 milligrams per kilogram of body weight of the subject.
30 . The method of claim 29 , wherein a total of 5 mg to 20 mg per dose of nusinersen is administered to the subject.
31 . The method of claim 30 , wherein 12 mg per dose of nusinersen is administered to the subject.
32 . The method of claim 1 , wherein the rAAV and/or nusinersen are administered into the intrathecal space of the subject.

Description

RELATED APPLICATIONS This application is a continuation of U.S. application Ser. No. 18/734,379, filed Jun. 5, 2024, which is a continuation of U.S. application Ser. No. 17/268,390, filed Feb. 12, 2021, which is a National Stage entry of PCT Application No. PCT/US19/46720, filed Aug. 15, 2019, which claims the benefit under 35 U.S.C. 119 (e) of the filing date of U.S. Provisional Application Ser. No. 62/764,893, filed Aug. 15, 2018, entitled “COMBINATION THERAPY FOR SPINAL MUSCULAR ATROPHY”, and 62/783,189, filed Dec. 20, 2018, entitled “COMBINATION THERAPY FOR SPINAL MUSCULAR ATROPHY”. The entire contents of each application are incorporated herein by reference. 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 2011256-2501 SL.xml, created on Oct. 17, 2024, which is 44,106 bytes in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety. FIELD The present application relates to methods and compositions for treating spinal muscular atrophy (SMA). BACKGROUND Spinal muscular atrophy (SMA) is a neuromuscular disease caused by mutations in telomeric SMN1, a gene encoding a ubiquitously expressed protein (survival of motor neuron—SMN) involved in spliceosome biogenesis. The SMN gene product is intracellular and SMN deficiency results in selective toxicity to lower motor neurons, resulting in progressive neuron loss and muscle weakness. The severity of the disease is modified by the copy number of a centromeric duplication of the homologous gene (SMN2), which carries a splice site mutation that results in production of only small amounts of the full length SMN transcript. Patients who carry one to two copies of SMN2 present with the severe form of SMA, characterized by onset in the first few months of life and rapid progression to respiratory failure. Patients with three copies of SMN2 generally exhibit an attenuated form of the disease, typically presenting after six months of age. Though many never gain the ability to walk, they rarely progress to respiratory failure, and often live into adulthood. Patients with four SMN2 copies may not present until adulthood with gradual onset of muscle weakness. Although several therapies for SMA have been developed, there remains a need for treatments that increase intracellular SMN activity in motor neurons involved in spinal muscular atrophy for patients having different levels of disease severity. SUMMARY In some aspects, the present application relates to a treatment for spinal muscular atrophy (SMA) that involves a combined administration, to a subject having SMA, of a recombinant nucleic acid encoding Survival motor neuron 1 (SMN1) and an oligomeric compound that increases full-length Survival motor neuron 2 (SMN2) mRNA. In some aspects, a recombinant nucleic acid encoding SMN1 is provided in a viral vector, for example in a recombinant adeno-associated virus (rAAV). In some aspects, an oligomeric compound is an antisense oligonucleotide (ASO) that increases full-length SMN2 mRNA in a subject (e.g., by modulating SMN2 pre-mRNA splicing to increase the inclusion of exon 7 in SMN2 mRNA). In some aspects, the present application relates to a treatment for spinal muscular atrophy (SMA) that involves a combined administration, to a subject having SMA, of a recombinant nucleic acid encoding Survival motor neuron 1 (SMN1) and an oligomeric compound that induces exon-skipping in a nucleic acid encoding Survival motor neuron 2 (SMN2). In some aspects, a recombinant nucleic acid encoding SMN1 is provided in a viral vector, for example in a recombinant adeno-associated virus (rAAV). In some aspects, an oligomeric compound that induces exon-skipping in a nucleic acid encoding SMN2 is an antisense oligonucleotide (ASO) that induces exon-skipping in SMN2 pre-mRNA. In some aspects, the recombinant nucleic acid (e.g., in a viral vector) and the ASO are co-formulated and administered to a subject as a single composition. In some aspects, the recombinant nucleic acid (e.g., in a viral vector) and the ASO are provided as separate compositions, but administered to a subject concurrently (e.g., at the same time or contemporaneously, for example during the same medical visit, for example during the same hour or day). In some aspects, the recombinant nucleic acid (e.g., in a viral vector) and the ASO are provided as separate compositions, and administered to a subject sequentially during separate medical visits (for example, at different times, e.g., on different days) during a course of treatment (e.g., during a treatment regimen over a week, 2-4 weeks, a month, 1-12 months, a year, 2-5 years, or longer). In some aspects, the ASO is administered prior to and/or subsequent to the recombinant nucleic acid. In some aspects, the recombinant nucleic acid (e.g., in a viral vector) and/or ASO are administered at different