According to data from the IQVIA Institute for Human Data Science, global expenditure on orphan drugs exceeded $200 billion in 2020, and it is projected to continue to increase in the coming years. This is partly because of the high cost of individual orphan drugs, which can sometimes reach hundreds of thousands of dollars per patient per year [5].

Hospitals and healthcare systems face considerable burdens with regards to the treatment and management of patients with rare diseases. High costs strain hospital budgets and resources, and patients with rare diseases often require complex and extensive critical care, which can be difficult for hospitals to provide owing to relatively small number of patients and limited specialized expertise. Rare and ultrarare diseases can be challenging to diagnose because of their low incidence and complex symptoms, placing considerable burden on hospital resources. Owing to the small patient population and little financial incentives, the availability of specialized care may be limited. Patients with rare disorders often require care from multiple healthcare providers and specialists such as neonatal intensivists, placing substantial burdens on the hospitals coordinating and managing their care. Rare genetic diseases are becoming increasingly recognized, and their burden on the healthcare system is evident from their high mortality rate, disability, years of life lost, rate of admission or readmission to diverse hospital settings (general pediatric floor, neonatal intensive care unit, pediatric intensive care unit), rate of admission to long-term care and comfort care settings, and cost of illness [1,6,7].

Diagnosing rare genetic disorders remains challenging for patients, doctors, and healthcare systems owing to insufficient characterization of the natural history of several rare diseases. Thus, majority of patients and their parents undergo diagnostic odyssey, which can be a long and exasperating journey for patients and their families seeking an accurate diagnosis. Typically, it can take up to 6 years from symptom onset to a correct diagnosis, during which time patients undergo an average of 14 diagnostic procedures and receive 4.5 diagnoses [8]. Approximately 4,400 genes are currently known to cause 6,300 rare genetic phenotypes (Online Mendelian Inheritance in Man), and recent data suggest that over 9,000 single-gene phenotypes might ultimately be discovered and molecularly defined. Nextgeneration sequencing, including whole-exome and whole-genome sequencing, is an established diagnostic tool used to reveal the genetic background of rare genetic disorders. However, its diagnostic yield is currently less than 50%. Recent advances have made these technologies both affordable and indispensable [9].

An extremely low percentage of rare genetic diseases is currently curable with orphan drugs. Although a few orphan drugs have been developed to treat rare genetic diseases, many remain incurable. According to some estimates, FDA-approved treatments are available for less than 5% of rare genetic disorders, although this number may vary depending on the specific populations and data sources. Additionally, an increasing number of drugs are currently being developed for rare genetic disorders, but hardly a small fraction of the total number of rare genetic disorders has been targeted. Developing orphan drugs can improve a pharmaceutical company’s reputation by demonstrating its willingness to invest in treating rare and often neglected diseases. Several pharmaceutical companies consider the development of orphan drugs a way to diversify their product portfolios and ensure long-term sustainability [10-12]. The development of drugs for rare genetic disorders is a complex and challenging process, and not all companies can do so successfully. Moreover, the prices of orphan drugs are relatively high compared to those of other drugs [13].

Enzyme replacement therapy (ERT) is used to treat lysosomal storage diseases (LSD) caused by lysosomal hydrolase deficiency. ERT involves the introduction of a functional enzyme into the body to compensate for deficient or missing enzymes. ERT was first approved in the 1990s for Gaucher disease, and the first ERT drug replaced placentaderived alglucerase, with imiglycerase in Chinese hamster ovary cells expressing recombinant human-β-glucocerebrosidase. Subsequently, ERT drugs have been developed and approved for more than 10 LSD, including Fabry, Pompe, mucopolysaccharidosis types I,II,IVA, VI, VII, and cholesteryl ester storage diseases (Table 2) [17,18]. In addition, LSD and ERT have recently been used in hypophosphatasia with recombinant human bone-targeted tissue-non-specific alkaline phosphatase [19]. Pegvaliase is an FDA-approved ERT used in adults with phenylketonuria (PKU) and uncontrolled blood phenylalanine concentrations [20]. Coagulation factor replacement therapy is a treatment for hemophilia A and B. Recombinant factors VIII and IX are replaced to compensate for the deficiencies. Novel therapies for hemophilia are currently available, which can be administered via subcutaneous injection, to prolong the drug’s half-life or bypass the inhibitors. Another example is von Willebrand disease, which is caused by deficiency or dysfunction of the von Willebrand factor, a protein involved in blood clotting [21].

Small-molecule therapies have several advantages and disadvantages. Small molecules are typically smaller than biologics and can be easily synthesized in a laboratory. This makes small-molecule therapy less expensive and easier to scale up for commercial use. Small molecules can easily cross cell membranes (such as the blood–brain barrier) and target intracellular proteins and enzymes, making them useful for treating diseases caused by mutations in intracellular signaling pathways. Small molecules can also be administered orally, which is convenient for patients and improves adherence. However, small molecules are often not as specific in their targeting as biologics; moreover, they may have off-target reactions that can cause side effects. Small molecules are metabolized or excreted quickly, limiting their effectiveness and requiring frequent dosing [16].

Biological therapeutic strategies have advantages and disadvantages. Biologics such as monoclonal antibodies feature specific targeting and can bind to specific molecules or receptors on cells, making them useful in treating diseases caused by mutations in cell surface signaling pathways. Biologics have longer half-lives and may require less frequent dosing. Biologics can also target intracellular proteins and enzymes; however, they are typically larger molecules and are more difficult and expensive to produce. It is generally difficult for biologics to penetrate the blood–brain barrier; therefore, disorders involving the central nervous system are not treatable, and biologics are typically administered parenterally, such as intravenously or subcutaneously, which can be inconvenient for patients. Biologics are more likely to induce an immune response, which can limit their effectiveness over time [16,31].

Monoclonal antibodies are laboratory-made proteins that mimic the immune system’s ability to fight off harmful pathogens. These proteins can be used to target specific molecules, such as proteins or receptors, which are involved in disease occurrence. Monoclonal antibody therapy can effectively treat rare genetic disorders by blocking the function of disease-causing proteins or stimulating the immune system to attack the diseased cells. Burosumab is a monoclonal antibody that targets and inhibits fibroblast growth factor 23 (FGF23) activity.Its effectiveness has been proven in X-linked hypophosphatemia, in which FGFR23 is highly elevated, leading to renal phosphate wasting [32]. Eculizumab, a monoclonal antibody against paroxysmal nocturnal hemoglobinuria and atypical hemolytic uremic syndrome, was approved by the FDA in 2007, and its estimated annual cost is $500,000–$700,000 [33]. Familial hypercholesterolemia is a rare genetic disorder caused by mutations in the LDLR, APOB, or PCSK9 genes, all of which are involved in cholesterol metabolism. A rare cause of familial hypercholesterolemia is a gain-of-function mutation of the PCSK9 gene. The FDA has approved 2 PCSK9 inhibitors (alirocumab and evolocumab) to date, both of which reduce low-density lipoprotein (LDL) cholesterol levels by 50%–60% beyond that what is achieved with statin therapy alone in patients with LDL hypercholesterolemia. Over the past few years, the FDA has expanded its approval of PCSK9 inhibitors to include a larger group of people with elevated LDL cholesterol levels who are at high risk of cardiovascular diseases [34,35]. Amyloid transthyretin (ATTR) amyloidosis is a rare, progressive, and fatal disease characterized by accumulation of amyloid fibrils in organs and tissues. Hereditary ATTR (hATTR) is caused by the mutated TTR gene, which encodes for a protein called transthyretin. Monoclonal antibodies can inhibit the formation of amyloid fibrils deposited in various organs of the body. This clinical trial is underway [36].

Antisense oligonucleotide (ASO) therapy treats genetic diseases by modulating the expression of specific genes. An ASO is a short chemically modified strand of nucleic acids that can bind to specific regions of RNA. It can be customized for treating extremely rare genetic disease [37]. ASO or small interfering RNA (siRNA) therapy has been approved for treating several rare genetic diseases, including DMD, spinal muscular atrophy, hATTR, and familial hypercholesterolemia. An ASO is used to skip genetic mutations that cause DMD and allow for the production of a truncated yet functional version of the dystrophin protein. The PTC124 is approved for treating DMD with a specific type of mutation and treats patients by skipping exon 53. Many exon skipping therapies for DMD using oligonucleotides are currently in clinical trials [38].

Spinal muscular atrophy (SMA) is a rare genetic disorder caused by mutations in the SMN1 gene, which encodes a survival motor neuron protein. An ASO is used to increase the expression of SMN2, a functional copy of the SMN1 gene,to compensate for the loss of function caused by SMN1 gene mutations. Nusinersen is an ASO that modulates the splicing of SMN2 premessenger RNA to increase the proportion of full-length transcripts, leading to higher levels of functional SMN proteins. It was approved by the FDA in 2016 and Korea. Its price tag was $750,000 for the first year and $375,000 per year thereafter. Another drug for SMA, risdiplam, is an orally administered and centrally and peripherally distributed small molecule (SMN2 splicing modifier) that modulates SMN2 pre-mRNA splicing to increase SMN protein levels. Risdiplam was first approved for use in the United States in 2020 and then was subsequently approved in the EU [39].

Porphyrias are a family of rare diseases mainly caused by inborn errors in heme biosynthesis. Acute episodes of porphyria are caused by the overproduction of heme precursors (hepatic or erythropoietic). The upregulation of 5-δ-aminolevulinic acid synthase 1 (ALAS1) plays a key role in porphyrias. Givosiran, an ALAS1-directed siRNA that was developed to treat acute hepatic porphyria, was first approved in 2019 by the FDA [40]. Vutrisiran and patisiran have recently received marketing authorization for treating hATTR neuropathy. These agents substantially reduce TTR protein levels by degrading TTR mRNA, particularly degrading mRNA via nuclear RNaseH1 using inotersen or the cytoplasmic RNA by forming a silencing complex with patisiran [41]. Nucleic acid drugs of PCSK9 inhibitors are designed to target PCSK9 mRNA and inhibit intracellular protein translation and PCSK9 protein synthesis by occupying or cutting the targeted mRNAby RNase H1. The current PCSK9 nucleic acid inhibitor, inclisiran, developed by Novartis, was administered via subcutaneous injection [34].

Huntington disease is a rare genetic disorder caused by the expansion of a trinucleotide repeat in the HTT gene, which encodes for the huntingtin protein. An ASO is used to target the mRNA encoding the mutant huntingtin protein and reduce its production, which can slow disease progression. Phase III clinical trials are underway [36].

Gene therapy and genome-editing techniques are promising in treating rare genetic diseases. Gene therapy involves the delivery of functional copies of a missing or defective gene to the cells for correcting the underlying genetic defects. This process, known as gene augmentation, can be achieved using viral vectors, such as adenoviruses or lentiviruses, to deliver therapeutic genes to the appropriate cells. In contrast, gene suppression using siRNA can treat rare diseases caused by the gain of a functional genetic defect [42].

Human gene therapy was first conducted in 1990 in a patient with adenosine deaminase (ADA) deficiency, a rarer and slightly less severe form of severe combined immunodeficiency. However, gene therapy was in the “dark age” owing to the development of adverse events, such as leukemia, or the fatality of vector associated immune reaction. Since the early 21st century, gene therapy has become effective and relatively safe for treating various rare monogenic diseases [40]. Alipogene tiparvovec (Glybera, UniQure, Amsterdam, The Netherlands) is the first gene therapy product approved for lipoprotein lipase deficiency, a rare genetic disorder caused by mutations in the LPL gene. It was approved by the EMA in 2012 but was later withdrawn from the market for commercial reasons. Subsequently, gene therapy products have been increasingly approved for Mendelian disorders by the FDA and the EU. For instance, an autologous CD34+-enriched cell fraction, Strimvelis (GlaxoSmithKline plk, London, UK), which contains CD34+ cells transduced with a retroviral vector that encodes the human ADA cDNA sequence for ADA deficiency (introduced in 2016), and voretigene neparvovec-rzyl (Luxturna, Spark Therapeutics, Philadelphia, USA), for retinal dystrophy caused by mutations in the RPE65 gene, were approved by the FDA in 2017 at a cost of $850,000 per eye [43]. Onasemnogene abeparvovec-xioi (Zolgensma, Novartis, Bazel, Switzerland), another therapeutic for SMA approved by the FDA in 2019, carries a price tag of $2.1 million per treatment [39]. Etranacogene dezaparvovec (Hemgenix, CSL Behring, King of Prussia, PA, USA), an adeno-associated virus vector-based gene therapy for treating adults with hemophilia B (Factor IX deficiency), was approved in 2022, with a price tag of $ 3.5 million, making it among the most expensive drugs worldwide. Betibeglogene autotemcel (Zynteglo, Bluebird Bio, Sommerville, MA, USA) was approved in 2022 to treat β-thalassemia, and hematopoietic stem cells were engineered using a lentivirus to express HBB in patients with certain types of β-thalassemia. Elivaldogene autotemcel (eli-cel; Skysona, Bluebird Bio) was approved in 2022 to slow the progression of neurological dysfunction in boys aged 4–17 years with early active cerebral adrenoleukodystrophy. Skysona (Bluebird Bio)is a single-use treatment that utilizes the patient’s blood stem cells for ex vivo transduction with the lenti-D lentiviral vector to add functional ABCD1 genes to the patient’s hematopoietic stem cells [15].

There are many potentially treatable gene therapies, including lysosomal storage disorders, such as Pompe disease, Gaucher disease, Fabry disease, MPS1, MPS2, and MPS6, although most are currently in phase I/II clinical trial [44]. Genome-editing techniques such as CRISPR-Cas9 and newer-generation genome-editing tools allow for precise and efficient modification of specific regions of the genome [45]. This can be used to correct genetic defects or disrupt the functions of disease-causing genes. Genome-editing can be used to treat a wide range of rare genetic diseases. Examples of diseases potentially treatable with genome-editing technologies include sickle cell anemia, hemophilia, and CF [46]. Currently, there are over 80 phase II and III clinical trials of gene therapy for rare Mendelian disorders [40].

Hematopoietic stem cell transplantation has proven to be effective in many rare genetic disorders. These include Hurler syndrome, Gaucher disease, adrenoleukodystrophy, Canavan disease, severe combined immunodeficiency, Fanconi anemia, and thalassemia. Recently, cell-based gene therapies, such as chimeric antigen receptor T cells, have been engineered to express specific proteins for treating many hematological cancers or lymphomas [15,43]. In addition, liver organ or cell transplantation is promising for treating many inborn errors of metabolism caused by liver-specific enzyme defects such as urea cycle defects and Wilson disease.

Drug repurposing (also known as drug repositioning or drug reprofiling)is the process of redeveloping a compound for use in different diseases and is now becoming an increasingly important therapeutic strategy for rare diseases. It is based on the scientific principle that drugs often interact with multiple targets or pathways and various drugs may act on the same target or pathway. Compounds tend to exhibit off-target effects that trigger undesired or unexpected adverse events; however, these effects may also be advantageous in other indications. An increasing number of repurposing success stories and companies leveraging repurposing strategies has been reported [47]. Finasteride was originally developed to treat benign prostatic hyperplasia but was eventually repurposed for male-pattern baldness. Another example is liraglutide (Saxenda, Novo Nordisk, Hellerup, Denamark), which was originally developed to treat diabetes mellitus and was repurposed to treat obesity. Drug repurposing is considerably faster and less expensive than traditional drug discovery methods. Specifically, the development risk is reduced as repurposed candidates have already been proven as sufficiently safe in preclinical models and at least in early-stage trials in humans; thus, they are less likely to fail from a safety point of view in subsequent efficacy trials. Moreover, phase I clinical trials of the repurposed drugs can be skipped. The required step that remains is to confirm the efficacy in the new indication at preclinical and clinical levels.

The drug repositioning approach canbe a cost-effective and efficient way to develop therapeutic strategies for rare genetic disorders because drug safety and efficacy have already been established, which can accelerate the development process [48]. According to different estimates, the number of repurposed drugs entering the regulatory approval pipeline is increasing, accounting for approximately 20%–30% of all the drugs approved every year. Some examples of drugs under research for rare genetic disorders using the drug repositioning strategy include rapamycin, initially approved as an immunosuppressant and repurposed to treat tuberous sclerosis complex; losartan, initially approved as an antihypertensive and repurposed to treat Marfan syndrome; doxycycline, initially approved as an antibiotic and repurposed to treat osteogenesis imperfecta; and tyrosine kinase inhibitors used for cancer therapy and repurposed to treat rasopathies such as neurofibromatosis type I and Noonan syndrome [49].

The mRNA therapy is a relatively new approach to treating diseases that introduces a synthetic mRNA molecule into the body. Once inside the body, mRNA can be translated by the cells into a functional protein. The success of mRNA therapy in overcoming the coronavirus disease 2019 (COVID-19) pandemic has been unfolded. mRNA therapy is an emerging class of therapies, with multiple mRNA-based cancer immunotherapies and vaccines currently in clinical trials in addition to the COVID-19 vaccine. A promising application of mRNA therapy is to restore or augment proteins following its systemic administration, particularly for inborn errors of metabolism such as methylmalonic acidemia caused by methyl malonyl CoA mutase deficiency and PKU caused by phenylalanine hydroxylase defect [50,51]. The advantage of mRNA therapy over viral gene delivery is that the former bypasses the risk of unintended genomic integration, thereby reducing insertional mutagenesis risks. It produces rapid efficacious responses but requires multiple injections because of transient, half-life-dependent protein expression. It is now feasible to systemically deliver lipid nanoparticles targeting hepatocyte cytoplasm. The use of mRNA chemically modified with uridine derivatives enhances translation and reduces immunogenicity, rendering mRNA therapy more suitable for repeated doses. Overall, mRNA therapy has shown great promise for the treatment of rare diseases by providing a targeted approach for delivering missing or defective proteins. Although this approach remains in its early stages of development, it has the potential to revolutionize the treatment of rare diseases and provide new hope to patients and their families.