Key Information
Rare diseases (RD) affect a small number of people compared to the general population and are mostly genetic in origin. The first clinical signs often appear at birth or in childhood, and patients endure high levels of pain and progressive loss of autonomy frequently associated with short life expectancy. Until recently, the low prevalence of RD and the gatekeeping delay in their diagnosis have long hampered research. The era of nucleic acid (NA)-based therapies has revolutionized the landscape of RD treatment and new hopes arise with the perspectives of disease-modifying drugs development as some NA-based therapies are now entering the clinical stage. Herein, we review NA-based drugs that were approved and are currently under investigation for the treatment of RD. We also discuss the recent structural improvements of NA-based therapeutics and delivery system, which overcome the main limitations in their market expansion and the current approaches that are developed to address the endosomal escape issue. We finally open the discussion on the ethical and societal issues that raise this new technology in terms of regulatory approval and sustainability of production.
Nucleic acids-based drugs aim to fix the genetic problem at its source and emerge as a promising new class of drugs. Recent advances in this field enabled their approval for the treatment of orphan genetic diseases for which no cure was available.
Introduction
Rare diseases (RD), also referred to as orphan diseases, are defined by the European Commission as pathologies that affect less than 5 patients per 10,000 members of the population1external link, opens in a new tab. There are about 7–8000 known and registered RD (5 new RD are described in the medical literature every month) affecting approximately 350 million people worldwide2external link, opens in a new tab,3external link, opens in a new tab. Most patients with RD suffer of serious, chronic, progressive illnesses. Over 75% of RD appear during childhood, such as proximal spinal muscular atrophy, neurofibromatosis, osteogenesis imperfecta, chondrodysplasia or Rett syndrome, and are often associated with lifelong suffering, impaired quality of life and reduced lifespans4external link, opens in a new tab,5external link, opens in a new tab. It is estimated that a third of patients with RD die before their 5th birthday. Even if the potential causes of RD are not fully understood, 80% are genetic in origin6external link, opens in a new tab. Genetic RD are driven by a deficient gene that can be inherited or arise from de novo mutations. Due to the limited patient population, RD are neglected pathologies and effective therapies are still not available for more than 95% of the patients suffering from these conditions7external link, opens in a new tab. The development of new therapeutic tools to treat orphan diseases are often not considered profitable and too expensive, representing a significant unmet medical need for the patients8external link, opens in a new tab.
In 1983, the first attempt to promote orphan drug development was established with the Orphan Drug Act (ODA), which provided financial incentives for the development of new treatments for RD, such as specific financial supports, tax credits, priority review and market9external link, opens in a new tab–11external link, opens in a new tab. The impact of the ODA has been important and hundreds of new orphan drugs were developed. Unfortunately, most of these therapeutic approaches act as symptomatic treatments that delay disease’s progression and/or reduce the disorder’s impact on the patient’s life5external link, opens in a new tab,12external link, opens in a new tab. Existing treatments are mostly based on small molecules and protein-targeting compounds that often display limited efficacy due to low target affinity, inefficient cell penetration and short half-life, leading to drug resistance13external link, opens in a new tab. Nucleic acid (NA)-based drugs may provide better therapeutic options that aim to fix the genetic problem at its source by modifying and repairing the disease-causing gene14external link, opens in a new tab.
Over the past decades, NA drugs including DNA- and RNA-based therapeutics, have been widely exploited to treat a wide range of diseases, especially genetic disorders, and cancers. The first attempt to deliver a gene coding for resistance to neomycin into lymphocytes harvested from cancer patients was published 30 years ago15external link, opens in a new tab. After decades of promises, tempered by great deal of failures, NA-based therapies targeting the gene(s) responsible(s) for various human diseases have now become promising therapeutic tools. Remarkable progresses in NA drugs development were made recently as they are, compared to conventional medicines, relatively rapid to develop more cost-effective, and more specific. They include the development of efficient and safe viral-based gene transfer systems, the discovery of short interfering RNA (siRNA), the development of RNA analogs or major advance regarding the bioavailability of NA‐based drugs by the introduction of chemical modifications that increase nuclease resistance of DNA and RNA oligonucleotides14external link, opens in a new tab.
While no NA-based drugs have been approved so far for the treatment of cancer, 23 of them were approved by the U.S. Food and Drug Administration (FDA) and/or the European Medicines Agency (EMA) and/or the Medicines and Healthcare products Regulatory Agency (MHRA) and/or the Japanese Ministry of Health, Labour and Welfare (MHLW) to treat various rare diseases. This review provides an overview of these approved therapies, first describing the rationale underlying the drug design. Then, we address the issue of the delivery system. Finally, the challenges and opportunities raised by this new class of medication are discussed from multiple perspectives.
Disease-modifying drugs for rare genetic disorders
Rationale underlying nucleic acid-based drugs
Nucleic acid therapeutics open almost infinite possibilities. They can be designed to i) restore the normal biological functions of deficient proteins; ii) halt the production of abnormal deleterious protein while leaving all other proteins unaffected; iii) increase the synthesis of a protein of interest; iv) hide non-sense mutation on the mRNA that prevent the production of a complete protein or correct mutations that affect mRNA splicing. Depending on the chosen objective, several strategies have been developed.
Gene replacement therapies
Gene replacement therapy aims to compensate for abnormal or non‐functional genes by delivering genetic materials into cells, thus introducing a healthy copy of the gene16external link, opens in a new tab. The therapeutic gene expression cassette is delivered with the aid of a vector, most commonly a retrovirus or rarely adenovirus, and is typically composed of a promoter that drives gene transcription, the transgene of interest, and a termination signal to end gene transcription17external link, opens in a new tab. Once being delivered into the host cells, the therapeutic gene is transcribed into mRNA transcripts that are translated into the proteins of interest (Fig. 1external link, opens in a new tab). While this replacement is usually partial, producing a small amount of normal gene product is often sufficient to provide significant health benefits. Although the concept was proposed three decades ago, significant advances were only made over the past decade.