Milasen: The Emerging Era of Patient-Customized N-of-1 Antisense Oligonucleotides as Therapeutic Agents for Genetic Diseases.

Antisense oligonucleotide (AON) therapy has shown great promise in recent years for the treatment of numerous diseases, primarily in the neuromuscular field. While most often discussed in the context of diseases where AONs are already approved for use, AON therapy also serves as an ideal therapeutic modality for ultrarare N-of-1 genetic diseases given its sequence-specific nature and high degree of customization to an individual mutation. Batten disease is a debilitating and fatal neurodegenerative disease affecting children, characterized by impaired lysosomal storage and progressive neurodegeneration. No cure exists for this disease, and there remains an unmet medical need for effective therapeutics for Batten disease. In this chapter, we outline the landmark N-of-1 development of milasen, an antisense oligonucleotide therapy for a single patient with Batten disease. We highlight the development of milasen, as well as the suitability and limitations of antisense oligonucleotides for N-of-1 therapies and other personalized medicines. We also discuss the current state of N-of-1 therapy development, and how the history of milasen has contributed to the ongoing development of other N-of-1 therapies including atipeksen.