Indication |
mRNA Target |
Mechanism |
Research |
Lead selection & Optimization |
IND Enabling |
Clinical |
Worldwide Rights |
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Neuromuscular |
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DUCHENNE MUSCULAR DYSTROPHY
Duchenne muscular dystrophy (DMD) is an X-linked, progressive muscle wasting disease caused by mutations in the DMD gene that result in either truncated non-functional dystrophin protein, or little to no protein. Our approach leverages exon skipping to restore the reading-frame of the RNA to produce a near-full length copy of the dystrophin protein.
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Dystrophin Exon 51 |
Exon Skipping |
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DUCHENNE MUSCULAR DYSTROPHY
Duchenne muscular dystrophy (DMD) is an X-linked, progressive muscle wasting disease caused by mutations in the DMD gene that result in either truncated non-functional dystrophin protein, or little to no protein. Our approach leverages exon skipping to restore the reading-frame of the RNA to produce a near-full length copy of the dystrophin protein.
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Dystrophin Exon 44, 45, 53 |
Exon Skipping |
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Myotonic Dystrophy type 1
Myotonic Dystrophy type 1 is a genetic
neuromuscular disorder caused by a mutation in the DMPK gene, resulting
in a trinucleotide (CUG) repeat expansion in the expressed RNA. Our DM1
program targets and destroys the toxic CUG repeats.
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Mutant DMPK |
Destruction or blocking |
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NeuroDegeneration |
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Amyotrophic Lateral Sclerosis (C9orf72)
C9orf72-related Amyotrophic Lateral Sclerosis
(ALS) is a genetic motor neuron disorder caused by a mutation in the
C9orf72 gene, resulting in hexanucleotide (G4C2 and C4G2) repeat
expansions. Our C9orf72-ALS program targets and destroys the
hexanucleotide repeats.
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Mutant C9orf72 |
Destruction |
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Frontotemporal
Dementia (C9ORF72) Here will be some content …
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Mutant C9orf72 |
Destruction |
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DMD is a rare, fatal X-linked recessive degenerative neuromuscular disorder caused by mutations in the dystrophin gene. The disease affects approximately 1 in every 3500–5000 males born worldwide. Patients experience progressive muscle wasting, difficulty controlling movement, respiratory failure and heart failure leading to full-time wheelchair use starting as early as 12 years old, and a significant reduction in life expectancy.
The dystrophin gene is the largest human gene. Mutations causing DMD can occur at various places in the gene and most result in large exon deletions or duplications, and production of no or dysfunctional dystrophin protein. Dystrophin plays a key structural role in muscle.
An estimated 80% of all DMD patients have mutations in the dystrophin gene that are amenable to exon skipping. Our initial target populations include more than 40% of exon-skipping amenable patients. AAV gene therapy delivers the highest level of muscle targeting compared to other targeting approaches, enabling a durable response with a single administration.
We are advancing multiple programs for DMD. Our lead DMD development candidate targets exon 51.
Leveraging the Bespoke strategy described below, we plan to rapidly advance additional DMD development candidates to address additional mutations, starting with exons 53, 45 and 44. Under the guidelines set out by the Bespoke Gene Therapy Consortium, we plan to leverage a consistent vector backbone design across all of our DMD development candidates, while switching out only the targeting sequence(s) for the exon in question.
DM1 is a genetic neuromuscular disorder caused by a mutation in the DMPK gene and is the most common muscular dystrophy in adults, affecting about 40,000–100,000 patients in the U.S. DM1 results in weakness of the skeletal muscles and myotonia, which is the inability to relax muscles at will. DM1 also affects the heart leading to cardiac arrythmias and skeletal and smooth muscle weakness that results in difficulty breathing, difficulty swallowing etc. These, and other characteristics of the disease, lead to a reduced life expectancy.
The mutation is a repeat expansion of a CTG sequence in the non-coding 3’ untranslated region (UTR) of the DMPK gene. At the RNA level, the expanded CUG RNA repeats form RNA foci and sequester muscleblind-like (MBNL) proteins, that have key functions in the transition of fetal-to-mature alternative splicing switch. In DM1, MBNL is sequestered and not available to perform its normal alternative splicing regulatory functions, leading to signature DM1-associated splicing dysfunction and persistence of a fetal alternative splicing signature in DM1 patients.
The C9orf72 gene mutation is a repeated expansion of hexanucleotide sequences (G4C2 and C4G2) in the non-coding portion of the gene. Both the sense and antisense strands can be translated as dipeptides that are toxic to cells. In addition, the transcribed RNA forms secondary structures that may sequester regulatory RNA binding proteins (RBPs) and activate double-stranded RNA related stress response pathways. The C9orf72 mutation can lead to both amyotrophic lateral sclerosis, or ALS, and frontotemporal dementia, or FTD.
C9orf72-related ALS is a genetic degenerative motor neuron disorder which accounts for approximately 40% of familial ALS and 10% of sporadic ALS. The estimated incidence of the disease in the U.S. is 1.5–2.2 cases per 100,000 people. ALS is caused by the degeneration of motor neurons that lead to progressive muscle wasting, weakness and muscle atrophy and eventual death from respiratory failure 2–5 years after diagnosis.
C9orf72-related FTD is a rare genetic neurodegenerative disease resulting from the degeneration of the frontal and temporal cortical lobes, resulting in cognitive and language impairment. Symptoms often involve personality or mood changes, compulsive or repetitive behaviors and lack of emotion, inhibition or social tact. An estimated 250,000 people in the U.S have FTD and approximately 25.9% of the cases arise as a result of the C9orf72 gene mutation.
Our C9orf72-related ALS/FTD program targets and destroys both the sense and antisense transcripts to reduce the levels of toxic dipeptides and RNA mediated toxicity.
We leverage our Cas13d payload with two guide RNA sequences, which we have shown can successfully target and destroy both the sense and antisense transcripts in patient cells and animal models.
Importantly, this approach is allele selective and maintains normal levels of wild-type C9orf72 as measured by mRNA.