Viltolarsen in Japanese Duchenne muscular dystrophy patients: A phase 1/2 study

Komaki, Hirofumi; Takeshima, Yasuhiro; Matsumura, Tsuyoshi; Ozasa, Shiro; Funato, Michinori; Takeshita, Eri; Iwata, Yasuyuki; Yajima, Hiroyuki; Egawa, Yoichi; Toramoto, Takuya; Tajima, Masanori; Takeda, Shin’ichi

doi:10.1002/acn3.51235

Cited by 56 publications

(43 citation statements)

References 27 publications

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“…Clinical trials in different countries provided consistent results. Specifically, DMD patients treated with either high or low doses of Viltolarsen all showed de novo dystrophin expression and exon 53 skipping [ 58 , 59 ]. Disease progression was slowed with higher dose treatments and no serious adverse events were observed [ 58 , 59 ].…”

Section: Aso Mechanisms Of Action and Fda-approved Drugsmentioning

confidence: 99%

The Challenges and Strategies of Antisense Oligonucleotide Drug Delivery

Gagliardi¹,

Ashizawa²

2021

Biomedicines

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Antisense oligonucleotides (ASOs) are used to selectively inhibit the translation of disease-associated genes via Ribonuclease H (RNaseH)-mediated cleavage or steric hindrance. They are being developed as a novel and promising class of drugs targeting a wide range of diseases. Despite the great potential and numerous ASO drugs in preclinical research and clinical trials, there are many limitations to this technology. In this review we will focus on the challenges of ASO delivery and the strategies adopted to improve their stability in the bloodstream, delivery to target sites, and cellular uptake. Focusing on liposomal delivery, we will specifically describe liposome-incorporated growth factor receptor-bound protein-2 (Grb2) antisense oligodeoxynucleotide BP1001. BP1001 is unique because it is uncharged and is essentially non-toxic, as demonstrated in preclinical and clinical studies. Additionally, its enhanced biodistribution makes it an attractive therapeutic modality for hematologic malignancies as well as solid tumors. A detailed understanding of the obstacles that ASOs face prior to reaching their targets and continued advances in methods to overcome them will allow us to harness ASOs’ full potential in precision medicine.

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Section: Aso Mechanisms Of Action and Fda-approved Drugsmentioning

confidence: 99%

The Challenges and Strategies of Antisense Oligonucleotide Drug Delivery

Gagliardi¹,

Ashizawa²

2021

Biomedicines

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“…So far, PMO AONs appear to be well-tolerated and safe in DMD patients following weekly intravenous (IV) administration [ 47 , 48 , 49 ]. However, the neutral charge of PMOs represents a limitation in AON cellular uptake and gives fast clearance in the bloodstream, therefore reducing the therapeutic effect [ 50 ].…”

Section: Rationale For Current Therapeutic Interventions In Dmdmentioning

confidence: 99%

Innovative Therapeutic Approaches for Duchenne Muscular Dystrophy

Fortunato

Rossi

Falzarano

et al. 2021

JCM

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Duchenne muscular dystrophy (DMD) is the most common childhood muscular dystrophy affecting ~1:5000 live male births. Following the identification of pathogenic variations in the dystrophin gene in 1986, the underlining genotype/phenotype correlations emerged and the role of the dystrophin protein was elucidated in skeletal, smooth, and cardiac muscles, as well as in the brain. When the dystrophin protein is absent or quantitatively or qualitatively modified, the muscle cannot sustain the stress of repeated contractions. Dystrophin acts as a bridging and anchoring protein between the sarcomere and the sarcolemma, and its absence or reduction leads to severe muscle damage that eventually cannot be repaired, with its ultimate substitution by connective tissue and fat. The advances of an understanding of the molecular pathways affected in DMD have led to the development of many therapeutic strategies that tackle different aspects of disease etiopathogenesis, which have recently led to the first successful approved orphan drugs for this condition. The therapeutic advances in this field have progressed exponentially, with second-generation drugs now entering in clinical trials as gene therapy, potentially providing a further effective approach to the condition.

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“…Viltolarsen-a PMO originally named NS-065/NCNP-01 [47]-produced dystrophin protein in seven of ten DMD patients with amenable mutations without any severe adverse drug reactions [48]. A phase I/II trial examined viltolarsen's ability to restore dystrophin expression at the doses of 40 mg/kg and 80 mg/kg, respectively, producing 1.21% and 4.81% of normal levels of dystrophin [49]. A 4-week randomized clinical trial followed by a 20-week open-label treatment of patients was also performed.…”

Section: Exon Skipping For Dmdmentioning

confidence: 99%

Restoring Protein Expression in Neuromuscular Conditions: A Review Assessing the Current State of Exon Skipping/Inclusion and Gene Therapies for Duchenne Muscular Dystrophy and Spinal Muscular Atrophy

Sheikh

2021

BioDrugs

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The debilitating neuromuscular disorders Duchenne muscular dystrophy (DMD) and spinal muscular atrophy (SMA), which harm 1 in 5000 newborn males and 1 in 11,000 newborns, respectively, are marked by progressive muscle wasting among other complications. While DMD causes generalized muscle weakness due to the absence of the dystrophin protein, SMA patients generally face motor neuron degeneration because of the lack of the survival motor neuron (SMN) protein. Many of the most promising therapies for both conditions restore the absent proteins dystrophin and SMN. Antisense oligonucleotidemediated exon skipping and inclusion therapies are advancing clinically with the approved DMD therapies casimersen, eteplirsen, golodirsen, and viltolarsen, and the SMA therapy nusinersen. Existing antisense therapies focus on skeletal muscle for DMD and motor neurons for SMA, respectively. Through innovative techniques, such as peptide conjugation and multi-exon skipping, these therapies could be optimized for efficacy and applicability. By contrast, gene replacement therapy is administered only once to patients during treatment. Currently, only onasemnogene abeparvovec for SMA has been approved. Safety shortcomings remain a major challenge for gene therapy. Nevertheless, gene therapy for DMD has strong potential to restore dystrophin expression in patients. In light of promising functional improvements, antisense and gene therapies stand poised to elevate the lives of patients with DMD and SMA.

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Viltolarsen in Japanese Duchenne muscular dystrophy patients: A phase 1/2 study

Cited by 56 publications

References 27 publications

The Challenges and Strategies of Antisense Oligonucleotide Drug Delivery

The Challenges and Strategies of Antisense Oligonucleotide Drug Delivery

Innovative Therapeutic Approaches for Duchenne Muscular Dystrophy

Restoring Protein Expression in Neuromuscular Conditions: A Review Assessing the Current State of Exon Skipping/Inclusion and Gene Therapies for Duchenne Muscular Dystrophy and Spinal Muscular Atrophy

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