Author: Joe Krzeski
Editor: Rachel VanKeulen-Miller
Precision medicine seeks to improve patient outcomes by subclassifying diseases based on their molecular and genetic characteristics with the ultimate goal of developing novel and targeted therapies.1 A notable example of precision medicine is the stratification of breast cancer into distinct subtypes, rather than a singular disease. This shift led to personalized treatment strategies for each subtype and has improved outcomes for breast cancer patients.2 While precision medicine holds great promise across a broad range of conditions, it faces distinct challenges in the area of rare diseases, or disorders affecting fewer than 200,000 individuals in the United States. Though each rare disease is individually uncommon, there are an estimated 7,000 to 10,000 rare diseases that collectively impact approximately 30 million Americans.3 Unfortunately, very few rare diseases have approved disease-modifying treatments from the Food and Drug Administration (FDA) and precision medicine for rare diseases has been hindered, in part, by economic constraints and the biological complexity of each disorder. Despite these challenges, the past decade has seen promising developments—most notably the emergence of antisense oligonucleotides (ASOs), a therapeutic modality that offers new hope for personalized treatments of rare diseases.4,5
Challenges for precision medicine for rare diseases
Like many areas of therapeutic development, precision medicine for rare diseases is often constrained by economic challenges. On average, bringing a new therapy to patients takes 20 years and demands around $700 million in investment.6 Moreover, there is inherent risk in this process as only about 10% of therapies successfully progress from Phase I clinical trials to FDA approval.7 Therapeutic developers are frequently incentivized to target conditions with larger patient populations to ensure a viable return on investment. As a result, precision medicine for rare diseases often lacks sufficient investment. Nevertheless, a number of industry, academic, and nonprofit organizations remain committed to advancing treatments for rare diseases.8,9 These organizations are partly driven by incentives from the Orphan Drug Act, which provides tax credits and market exclusivity to companies with potential treatments for rare diseases.10
In addition to economic factors, the biological complexity of rare diseases hinders precision medicine. Many rare diseases stem from genetic mutations, often involving mutations within a single gene.11 However, even within single-gene disorders, the types of mutations can vary widely. An example of this is Angelman syndrome (AS), a rare neurodevelopmental disorder characterized by intellectual disability, epilepsy, and motor problems.12 AS is caused by deletions or mutations in a particular gene called UBE3A, which generates a protein necessary for the removal of other proteins. Full deletions of the UBE3A gene, which result in the complete absence of UBE3A protein, are generally linked to more severe symptoms compared to missense mutations that alter a single amino acid, which result in a non-functional UBE3A protein. Still, there are other types of mutations that contribute to AS pathology.13 The diversity of these UBE3A mutations subclassifies a rare disease into even rarer subtypes (Figure 1). While treatment strategies can be developed to overcome this challenge, each subtype may require unique and targeted treatments.
Antisense oligonucleotides (ASOs) pave the way
Regulators, industry partners, academics, and interest groups have leveraged ASOs to overcome the challenges facing therapeutic development for rare diseases. ASOs are small, synthetic strands of nucleotides that can be engineered to bind specific regions of RNA (ribonucleic acid).14,15 The safety and efficacy profile of this therapeutic class is underscored by FDA-approval of thirteen ASOs since 1998, including ones developed for rare diseases. A major advantage of ASOs is that they are highly customizable and can be designed to treat a variety of genetic predispositions.5
These factors culminated in the development of the first ASO designed to treat a single patient—a young girl diagnosed with neuronal ceroid lipofuscinosis 7 (CLN7 disease).16 CLN7 disease is a rare genetic disorder that affects ~1:100,000 individuals and is caused by mutations in the MFSD8 gene that result in severe neurodegeneration, seizures, and early-life mortality.17 This particular patient had a unique mutation in the MFSD8 gene that was amenable to ASO treatment. In 2017, under the leadership of Dr. Timothy Wu at Boston Children’s Hospital, a dedicated team of scientists and clinicians developed an ASO called milasen in just ten months as a treatment. Milasen was administered through an expanded access Investigational New Drug (IND) application, which permits the use of non-FDA-approved therapeutics for life-threatening conditions with no other treatment options. While the patient unfortunately passed away due to the natural progression of CLN7 disease, milasen reduced both the frequency and duration of the patient’s seizures.16 Milasen represents a pioneering effort in personalized medicine—ushering in new possibilities for treating rare genetic diseases.
Since the development of milasen, additional ASOs have been created to treat rare diseases, particularly in single patients. In 2019, an ASO called jacifusen was used to treat a rare and aggressive form of amyotrophic lateral sclerosis (ALS). Although the patient ultimately passed away due to the natural course of the disease, jacifusen showed potential in slowing the progression of symptoms.18 This encouraging result has spurred a clinical trial to evaluate the safety and efficacy of jacifusen in a broader ALS patient population.19 This case highlights how insights from individualized treatments can inform and scale therapeutic approaches for larger groups. Overall, ASOs are advancing personalized medicine for rare diseases by driving innovation and expanding treatment options.
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