Compositions and methods of treating amyotrophic lateral sclerosis (ALS)
Inventors
Sah, Dinah Wen-Yee • Hou, Jinzhao • Nonnenmacher, Mathieu E. • Zhou, Pengcheng • Hossbach, Markus • Deckert, Jochen
Assignees
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Publication Number
US-12123002-B2
Publication Date
2024-10-22
Expiration Date
Abstract
The present invention relates to small interfering RNA (siRNA) molecules against the SOD1 gene, adeno-associated viral (AAV) vectors encoding siRNA molecules and methods for treating amyotrophic lateral sclerosis (ALS) using the siRNA molecules and AAV vectors.
Core Innovation
The invention relates to treatment of amyotrophic lateral sclerosis (ALS) using siRNA-encoding viral vectors, including adeno-associated virus (AAV) vectors. The vectors are configured to silence SOD1, including mutant SOD1, wild-type SOD1, or both, by an AAV vector genome in which a nucleic acid sequence positioned between two inverted terminal repeats (ITRs) encodes a sense strand sequence and an antisense strand sequence of a siRNA duplex. The sense strand sequence comprises SEQ ID NO: 381, and the antisense strand sequence comprises SEQ ID NO: 363.
The approach includes modulatory polynucleotide placement and AAV-miRNA expression vector construction using inverted terminal repeats (ITRs), with optional structural components such as flanking regions and/or loop regions relative to the sense and antisense sequences. The description emphasizes delivery approaches intended to bypass and/or penetrate the blood-brain barrier (BBB) and the blood spinal cord barrier for CNS targeting.
The invention is directed to treating and/or ameliorating amyotrophic lateral sclerosis (ALS) in a subject in need of treatment by administering an AAV-based pharmaceutical composition comprising an AAV particle with a capsid protein and the AAV vector genome encoding the SOD1-inhibiting siRNA duplex. The stated scope includes ALS treatment contexts such as familial ALS, sporadic ALS, and ALS stages, including early, middle, and late disease stages.
Claims Coverage
The partial claim set includes three independent claims that jointly cover a specific AAV vector genome encoding a defined SOD1-targeting siRNA duplex, the defined SOD1-inhibiting siRNA duplex itself, and an ALS treatment method using an AAV pharmaceutical composition carrying that duplex.
AAV vector genome encoding defined SOD1 siRNA duplex between ITRs
An adeno-associated viral (AAV) vector genome comprising a nucleic acid sequence positioned between two inverted terminal repeats (ITRs), wherein the nucleic acid sequence encodes a sense strand sequence and an antisense strand sequence of a siRNA duplex, wherein the sense strand sequence comprises SEQ ID NO: 381, and the antisense strand sequence comprises SEQ ID NO: 363.
Defined SOD1 siRNA duplex with specified sense and antisense sequences
A siRNA duplex for inhibiting expression of SOD1 comprising a sense strand sequence and an antisense strand sequence, wherein the sense strand sequence comprises the nucleotide sequence of SEQ ID NO: 381, and the antisense strand sequence comprises the nucleotide sequence of SEQ ID NO: 363.
Method for treating ALS with AAV particle delivering the defined SOD1 siRNA duplex
A method for treating and/or ameliorating amyotrophic lateral sclerosis (ALS) in a subject in need of treatment, comprising administering a therapeutically effective amount of a pharmaceutical composition comprising an adeno-associated viral (AAV) particle with an AAV capsid protein and an AAV vector genome positioned between two inverted terminal repeats (ITRs), wherein the nucleic acid sequence encodes a sense strand sequence and an antisense strand sequence of a siRNA duplex with the sense strand sequence of SEQ ID NO: 381 and the antisense strand sequence of SEQ ID NO: 363.
Overall, the claims coverage centers on an AAV vector genome and a corresponding SOD1-targeting siRNA duplex defined by the specific sense and antisense sequences (SEQ ID NO: 381 and SEQ ID NO: 363), and a method of treating and/or ameliorating ALS by administering an AAV-based pharmaceutical composition carrying that duplex.
Stated Advantages
Inhibits or suppresses SOD1 expression, including reduction of SOD1 mRNA and/or SOD1 protein.
Treats and/or ameliorates amyotrophic lateral sclerosis (ALS).
Reduces CNS SOD1 expression.
Improves ALS symptoms including motor neuron degeneration, muscle weakness, muscle atrophy, breathing difficulty, dysarthria, fasciculations, and frontotemporal dementia (FTD).
Extends survival / prolongs premature death.
Enables CNS targeting by bypassing and/or penetrating the blood-brain barrier (BBB) and the blood spinal cord barrier using intravenous and direct intrathecal/intraventricular administration.
Documented Applications
Treating and/or ameliorating amyotrophic lateral sclerosis (ALS) in a subject in need of treatment using an AAV pharmaceutical composition carrying an siRNA duplex that inhibits expression of SOD1.
Inhibiting expression of SOD1 in CNS cells and/or CNS regions, including motor neurons and other CNS cells such as astrocytes.
Treatment of amyotrophic lateral sclerosis (ALS) by delivering siRNA-encoding viral vectors to the CNS to silence SOD1 (mutant, wild-type, or both).
Application across ALS disease stages including early, middle, and late disease stages, with outcomes described as symptom improvement and survival extension.
Use of AAV vectors for systemic and CNS-directed administration routes (intravenous and direct intrathecal/intraventricular) to achieve CNS-directed SOD1 suppression.
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