Abstract
After decades of research and development, the number of approved oligonucleotide therapeutics is growing exponentially, with 10 in the past decade (2010–2020). It is a very exciting time to be a part of the field.
Many of the recent approvals are for rare genetic diseases, with rare defined as affecting <200,000 patients in the United States. These diseases affect all age groups and are devastating to patients and their families. Although progress is being made, there are thousands of rare conditions to be addressed, 95% of which remain without treatment [1,2]. This is especially true of ultrarare disease or “N = 1” diseases, where there may be only a handful of affected patients (or even single families or single individuals). The N = 1 term also applies to situations where there are multiple mutations that can result in a disease, but the patient or family has a specific individual mutation that is eligible to mutation-specific treatment.
This was the case in the development of “Milasen,” the world's first personalized oligonucleotide medicine. The drug was developed for Mila, a child who had CLN7 Batten disease, and whose MFSD8 gene had a unique mutation not discovered with others with her condition. Her mutation was located deep in intron 6 and caused aberrant splicing of the MFSD8 transcript, thus abolishing protein production. Milasen was the antisense oligonucleotide designed to bind to the splicing acceptor region in intron 6 and inhibits aberrant splicing, rescuing correct splicing events and protein production.
The development of Milasen was spearheaded by Tim Yu, MD, PhD, at Boston Children's Hospital and was a huge endeavor. Owing to the severe and rapidly progressive nature of Mila's disease, a short development timeline was required to have any chance of helping. Dr. Yu and his team managed to gain FDA approval to treat Mila in <1 year, laying the foundation for many other personalized medicines in the future.
Crucial to creating this opportunity was the role of the family, particularly Mila's mother, who persisted in trying to establish a complete diagnosis, leading to the connection to Boston's Children Hospital. In many cases, it is too common for patients with rare diseases to go years without a diagnosis, and these delays can result in ineffectual treatments that are disheartening for all involved. Mila's Miracle Foundation, originally founded to raise money to develop a cure for CLN7 Batten disease, now aims to help other children in Mila's situation. Their story is a testament to the power of patients and patient advocates can have in the development of a therapeutic.
One of the reviews in this issue by O'Reilly et al. details the invaluable role patients play in this process, highlighting key features of the interactions between all stakeholders (academic, industry, and patients). These include setting realistic medical expectations about the chances of success, as well as other critical ways that researchers and patients can educate one another: about science, and risks, and about the symptoms and clinical outcomes that are most meaningful as diseases progress.
Since this historic moment, many other researchers have been inspired by Mila's story and are working on the development of personalized medicines for other diseases. There are now several academic centers around the world developing these types of medicines, including the RNA Therapeutics Institute (UMass Med Center, US), the Dutch center for RNA Therapeutics (Netherlands), and the 1 Mutation 1 Medicine (1M1M) consortium (Europe), the nonprofit organization N-Lorem (US), and the N = 1 Collaborative (N1C, global).
In this issue, N-Lorem founder Dr. Stan Crooke describes the mission of his initiative, dedicated to the development of these medicines for free. A European perspective, from a regulatory and ethical perspective, on these N = 1 therapeutics is provided by Dr. Matthis Synofzik, using antisense oligonucleotide development for rare neurological diseases as a case study.
Although exciting, there are several ethical questions raised from the development of these personalized medicines, including who should develop these types of therapeutic antisense oligonucleotides? Which patients' diseases can be treated through this approach? And how do we maximize patient access to treatments? An article by Dr. Lisa Kearns et al. discusses the ethical considerations as well as the policies that are needed to be in place to develop these therapeutics responsibly.
Recognizing both the promise and the challenges to the development of personalized oligonucleotides, the Oligonucleotide Therapeutics Society established an N = 1 taskforce to publish guidance on this topic. The briefing document (https://www.oligotherapeutics.org/rare-disease-task-force/rare-disease-briefing-document/) provides information on a range of key parts of the drug development process for oligonucleotide therapeutics. A key section of the briefing document is the requirement for high standards with manufacturing of these oligonucleotides.
A review in this issue by Dr. Marc Lemaitre provides on the requirements for manufacturing and Chemistry Manufacturing and Controls of these therapeutics that will be approved by the FDA. The FDA has also published its guidance on these personalized oligonucleotides (https://www.fda.gov/regulatory-information/search-fda-guidance-documents/ind-submissions-individualized-antisense-oligonucleotide-drug-products-administrative-and-procedural).
Given my own experience, with my mum having Huntington's disease, it is inspiring to see the power of patients (and advocates) in the development of therapeutics for N = 1 diseases, where there is a small patient population. It is also impressive to see that these diseases have become the focus for many stakeholders with pathways forward for disease development. Both Tim and I are honored and extremely grateful to be asked to be guest editors on this special issue.