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June 26, 2019

Severe Lipodystrophy Following Prolonged Subcutaneous Administration of Antisense Oligonucleotides

Author Affiliations
  • 1Department of Dermatology, Leiden University Medical Center, Leiden, the Netherlands
  • 2Department of Pediatrics and Dermatology, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland
JAMA Dermatol. Published online June 26, 2019. doi:10.1001/jamadermatol.2019.1404

Antisense oligonucleotides (AONs) are short, synthetic nucleic acids that hybridize with specific complementary RNA sequences to modulate protein expression. The AON-based therapies hold great promise for various genetic, neoplastic, and inflammatory diseases.1 This new class of drugs can be administered subcutaneously, intramuscularly, and intravenously. Mild injection site reactions (ISRs) have been reported after subcutaneous administration of AONs.2 However, little is known about long-term adverse events. Duchenne muscular dystrophy (DMD) is 1 of the first diseases where experimental treatment with AONs was investigated.1,3 Being the most common form of muscular dystrophy, DMD is caused by mutation of the DMD gene that leads to the formation of a truncated nonfunctional dystrophin protein. The severity of DMD can be temporarily alleviated through exon skipping of DMD transcripts, leading to the formation of a shortened, but partially functional, dystrophin protein. The experimental drug drisapersen (Kyndrisa, Biomarin) is a sterile, clear solution containing 200 mg/mL of 2′-O-methyl-phosphorothioate AONs, 20 nucleotides in length, with the sequence 5′-UCAAGGAAGAUGGCAUUUCU-3′, designed to induce skipping of exon 51 of DMD transcripts.4 Here, we report the development of severe lipodystrophy in patients with DMD following prolonged subcutaneous administration of AONs.

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