siRNA-based Therapeutics for Orphan/Rare Diseases

Over the last decades, clinical gene therapy faced a hundred obstacles and a large number of failures. However, it now has achieved huge progress in modern medicine and is finding a path into the clinical trials and the medical market. Small interfering RNAs (siRNAs) are considered as the most promising class of RNA-based therapeutic drugs, because their mechanism of action is catalytic and all siRNA molecules can inactivate targeted RNA oligonucleotide in a sequence-specific manner. Since the discovery of RNA interference (RNAi) and the development of the first oligomeric RNAs that initiate RNAi in mammalian, significant advances have been made in the exploitation of therapeutic siRNAs, particularly in many human diseases. Several drugs have been approved by the Food and Drug Administration (FDA) for the treatment of orphan/rare diseases, and numerous excellent genes and cell-based gene therapies for this illness are in the evaluation stage before their translation into the clinic in the immediate future.

siRNA-based Therapeutics

Figure 1. RNA interference (RNAi) pathway. (Bobbin, 2016)

RNAi is a naturally occurred process that can protect the organism from exogenous infection. It knocks down the expression of target genes in a specific sequence recognition mode. After the RNAi mechanism being shown in 1998, RNAi modalities, such as siRNAs and microRNAs (miRNAs), have become a powerful experimental approach in basic research. After chemically synthesized siRNA was manifested to enable efficient gene silencing, it has been widely accepted that siRNA is a valuable and promising therapeutic platform. Consequently, a siRNA therapeutic (bevasiranib) has already been developed and entered a Phase I clinical assessment in 2004. Then, more than 30 siRNA-based therapeutics have been designed, synthesized, and investigated in clinical trials, to cure diseases, including but not limited to transthyretin-mediated amyloidosis (a rare disease), hypercholesterolemia, diabetic macular edema, delayed graft function, non-arteritic anterior ischemic optic neuropathy, Ebola virus infection, hepatitis B virus (HBV) infection, hepatitis C virus (HCV) infection, and cancers, amongst others.

siRNA-based Therapeutics for Orphan Diseases

Figure 2. The therapeutic mechanism of patisiran (ONPATTRO). (Setten, 2019)

An orphan (rare) disease is defined as a disorder that frequently affects less than 200,000 individuals (approximately 0.07% of the American population). Later, the definition is expanded to disorders that influence plenty of individuals for which drug development is impossible, because of the expectation of such a drug wouldn't be enough to cover development costs. There're ~6,000 orphan diseases that have been identified and maintained as a list by the Office of Rare Diseases (ORD) at the National Institutes of Health (NIH). Most rare diseases are found to have patient populations of fewer than 100.

Several of the orphan diseases in the summary are well-known, for example, sickle cell anemia, cystic fibrosis, Huntington disease, Lou Gehrig disease, and Tourette syndrome, while many aren't familiar by people such as pachyonychia congenita (PC). The majority of orphan diseases show a genetic origin component that demonstrates little or no treatment options and aren't studied rigorously. The rising number of successful clinical trials has driven the development of gene therapy methods to comprise more widespread applicability, for instance, in rare diseases, cancers, chronic or progressive diseases, or in metabolic disorders.

Today, siRNA technology enables accurate and efficient target gene silencing processes by using RNAi mechanisms, which could compromise gene expression and regulate gene activity via cleaving mRNA or inhibiting its translation. Gene therapy originally concentrated on orphan diseases with detrimental monogenetic defects, such as primary immunodeficiencies (PID), for which this treatment was thought of the last, if not the only therapeutic choice. In 2018, FDA approved the first-ever siRNA product, patisiran (trade name: Onpattro), marking a remarkable milestone in the history of RNAi technology and clearing the way for a novel class of therapeutic. It is a therapy for the rare hereditary disease transthyretin-mediated (hATTR) amyloidosis in adult patients. In the Phase III clinical trial, patisiran improved many clinical manifestations of this disease and proved safe administration of a siRNA product.

Potential Drugs for Orphan Diseases

Gene therapy has gradually applied for the treatment, cure, or prevention of various human disorders. In terms of the type of disease, this technique can be achieved either by transporting a functional, therapeutic gene for the defective or missing endogenous counterpart or by reducing the expression levels of a harmful and defective gene product, using multiple sophisticated tools including siRNA and other oligonucleotides, viral and non-viral vehicles. Here, the review outlines existing drugs in the different stages of clinical trials for rare diseases and continually focuses on some of the problems and strategies associated with developing therapies for small patient populations.

The ability to collect sufficient money and resources to effectively develop siRNA-based therapeutics for orphan diseases remains an arduous task. As a reliable expert and partner in the gene therapy industry, Creative Biolabs is committed to the design and development of RNAi drugs for orphan diseases and pays attention to the state of the current clinical pipeline and prospects for more unique siRNA products. If you want to know more about gene therapy or related RNAi custom services, please directly contact us or send an e-mail with your specific request.

References

1. Bobbin, M.L.; et al. (2016). RNA interference (RNAi)-based therapeutics: delivering on the promise? Annu Rev Pharmacol Toxicol. 56: 103-122.
2. Setten, R.L.; et al. (2019). The current state and future directions of RNAi-based therapeutics. Nat Rev Drug Discov. 2019, 18(6): 421-446.