LAUSR

The advent of bioinformatics and the invention of DNA sequencing technology have facilitated the development of new drugs based on cell therapy or gene therapy and personalized medicine. For instance, drugs such as Kymriah (tisagenlecleucel), Luxturna (voretigene neparvovec), or Zolgensma (onasemnogene abeparvovec) have made possible treatment of extremely rare diseases that previously could not be cured.1 Recently, the molecular diagnosis of a rare, fatal neurodegenerative condition led to the design, testing, and manufacture of a new customized therapy called Milasen (because it was designed to treat Mila Makovec). Milasen is a splice-modulating antisense oligonucleotide drug tailored and created to treat Batten disease in Mila, a patient with a unique genetic alteration, inherited from her mother, that disrupts a gene called CLN7. This disease led to loss of sight, language, and ability to walk independently. Milasen is a custom piece of genetic code designed to mask the effects of Mila’s mutation, and the cells can produce a normal CLN7 protein. The treatment consists of an initial dose of milasen, which gradually increase every 2 weeks, during the first 5 months. Thereafter, maintenance doses are given every 3 to 4 months and eventually every 2 months. Milasen has produced no adverse side effects to date and has not proved to be a cure for Mila’s disease, but overall, Mila has seen some important improvements since starting treatment.2,3 The antisense oligonucleotide drugs can be customized in a sequence-specific fashion and have a favorable uptake and long half-life in the central nervous system. The relative simplicity of manufacturing oligonucleotide drugs allows for timely small-batch manufacturing.4 The design of milasen was an N-of-1 trial, which pertains to a scheme of prospective (interventional) clinical trials performed on 1 patient, who serves as his/her own control.4 Although the use an N-of-1 trial may benefit a far broader audience by pushing the boundaries of what is possible in personalized medicine, the N-of-1 trial has regulatory limitations, manufacturing capacity issues, and ethical and economical (cost and reimbursement) uncertainties.2,3 The innovation, development, and administration of a drug for a single person, such as milasen, is associated with a high economic cost, given that an investment of time and skill is required to develop the drug. So sustainable funding for such interventions may prove challenging.1,4 Furthermore, there are many clinical uncertainties: What kind of evidence is necessary before exposing a human to a new drug? Which diseases are acceptable? What are the issues regarding safety/ tolerability, dose, and regimen used? and What measures of effectiveness might be used? Therefore, it is necessary to establish the following: types of clinical investigations, and amount and types of safety and effectiveness data to collect, which would allow assessment of the causality, incidence, severity of adverse events, dose-response, and other factors that contribute to understanding the drug safety profile and establish the efficacy for the stated diseases and conditions.4 Similarly, many ethical and societal reservations should be discussed before administration of the treatment. Finally, from a pharmacology perspective, these new developments may generate a novel paradigm. Traditionally, a drug is considered as a chemical substance that interacts with proteins in the body to increase or diminish a physiological function. Once the drug is absorbed into the systemic circulation, it is bound to certain receptor molecules in the cell, generating slight changes in the cell’s function.5 However, the current discovery and development of drugs, for instance, milasen, that act on cells at a genetic level can generate a new concept of drugs; insertion of a short chain of artificially created RNA would correct or regulate the gene expression4 that could be a driver to generate a qualitative change in a physiological function.