Oligonucleotides as Therapeutic Agents

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1		Annalisa Masi	--	3150	2023-12-29 10:38:14	\|
2	format	Jason Zhu	-18 word(s)	3132	2024-01-02 04:33:26	\|

This entry is adapted from the peer-reviewed paper 10.3390/ijms25010146

Nucleic acids have emerged as powerful biomaterials, revolutionizing the field of biomedicine. Nucleic acids, including deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), possess unique properties such as molecular recognition ability, programmability, and ease of synthesis, making them versatile tools in biosensing and for gene regulation, drug delivery, and targeted therapy.

nucleic acid DNA microRNA (miRNA) small interfering RNA (siRNA)

1. Therapeutic Applications of Antisense Oligonucleotides

ASOs are synthetic ODNs, usually 8–30 nucleotides long, that are specifically designed to bind to premessenger RNA (pre-mRNA) and/or mRNA by Watson–Crick base pairing, resulting in a high specificity to the target. They represent potential therapeutic agents for various human diseases. ASOs, unlike traditional drugs, interact with pre-mRNA and/or mRNA and modulate protein expression, offering the potential to halt protein malfunction and eliminate the source of disease. In the last decades, considerable efforts have been made to find new ASOs with a maximum therapeutic profile to treat rare and genetic disorders, cancer, viral infections, and neurodegenerative disorders (Figure 1) ^[1]^[2]^[3].

Figure 1. Indicative areas of application of antisense drugs. This figure was created by using Bio-render (www.biorender.com, accessed on 1 November 2023).

Although the design and preparation of ASOs involve several steps, they can be synthesized quite quickly, generally using solid-phase methods. First, the specific mRNA target or gene sequence to be modulated for therapeutic purposes must be identified, then the oligonucleotide sequence (DNA or RNA) complementary to the target mRNA must be designed and synthesized. To improve ASO stability, binding affinity, and resistance to degradation by nucleases, chemical modifications can be introduced. Common modifications include phosphorothioate backbone linkages and nucleotide modifications such as LNA, PNA, and PMO ^[4]^[5]^[6]. Comprehensive studies revealed that ASOs can exert their effects through two distinct mechanisms: RNA cleavage and RNA blockage.

In the RNA cleavage mechanism, ASOs are specifically designed, targeting an RNA molecule through complementary base pairing. Once bound, ASOs recruit cellular enzymes called ribonucleases, which cleave or cut the RNA molecule at the ASO’s binding site. This cleavage leads to the degradation of the RNA, preventing its translation into protein. This mechanism is particularly effective for targeting disease-causing RNA molecules, such as those associated with genetic disorders or viral infections.

ASOs can also work by blocking the normal function of RNA molecules without causing their cleavage (RNA blockage mechanism). In this mechanism, ASOs bind to the target RNA molecule, typically at specific regions such as the untranslated regions (UTRs) or regulatory sequences. By occupying these binding sites, ASOs interfere with the normal interactions between the RNA and cellular factors, such as ribosomes or other proteins, which are essential for their proper function. This disruption can prevent the RNA from being translated into protein or alter its processing, stability, or localization. RNA blockage is often employed to modulate gene expression, regulate protein production, or correct aberrant splicing events. The choice of mechanism depends on the specific therapeutic goals and the characteristics of the target RNA molecule ^[2]^[7].

Research is ongoing to explore the selective action of ASOs, which results in fewer side effects and less toxicity than traditional drugs ^[1]. ASOs encounter significant challenges during application due to their limited ability to permeate the plasma membrane. To be effective, they must possess some fundamental characteristics, including resistance to degradation, avoidance of renal clearance, escape from protein sequestration, ability to cross the capillary endothelium and the intracellular plasma membrane, resistance to degradation in the lysosome, and the capability to cross the blood–brain barrier (BBB) for central nervous system (CNS) treatments ^[8]. Until now, numerous ASO-based therapies have focused on localized delivery, for example, targeting the eye or spinal cord, where it is easier to reach the target. The eye, considered an immune-privileged organ, has been extensively studied for ASO therapies (e.g., pegaptanib and fomivirsen). In contrast, for central nervous system applications, the effectiveness of direct injections of ASOs into the cerebrospinal fluid via lumbar puncture (e.g., nusinersen) has been shown ^[9]. Furthermore, the liver, with its robust perfusion and presence of receptors that facilitate absorption, serves as a prevalent release site for ASOs. As described above, developing safe and selective methods to cross the BBB represents a significant challenge. Moreover, it is necessary to ensure that ASOs specifically target RNA sequences associated with neurodegenerative diseases to avoid off-target effects that might lead to undesirable outcomes. Additionally, the development of effective delivery systems capable of targeting specific brain regions and delivering ASOs in therapeutically relevant quantities represents an additional challenge. Minimizing the immune responses triggered by ASOs is also crucial to preventing adverse reactions in patients ^[10]. To overcome these challenges, new studies are exploring a range of methods. Advances in sequencing technologies and computational biology enable more precise target identification and design. Using nanoparticles, viral vectors, or exosomes as delivery vehicles can enhance the targeted delivery of ASOs to specific brain regions, improving cellular uptake and reducing degradation ^[11]^[12]. Chemical modifications can also reduce immunogenicity, while rigorous testing and modifications are essential to create ASOs with minimal immune response ^[13]^[14]. Several ASOs have been introduced targeting neurodegenerative and neuromuscular disorders, although the development of ASOs for the latter diseases is a complex and ongoing process, involving interdisciplinary collaboration, extensive testing, and regulatory oversight ^[15]^[16].

In the context of Huntington’s disease (HD), antisense therapies aim to lower the expression of the Huntingtin protein. The innovative approach involves single-stranded ASOs utilizing the RNase H1 mechanism ^[17]^[18]. Currently, three drugs are undergoing clinical trials: NCT02519036, NCT03225846, and NCT03225833 ^[16]^[19]. Regarding Alzheimer’s disease, therapies aimed at disaggregating and eliminating β-amyloid have been a focal point of pharmaceutical investigation over the last two decades, albeit with restricted success ^[20]. The strategy of ASOs is to decrease the intracellular load of tau, thereby decreasing the creation and dissemination of intracellular neurofibrillary tangles ^[21]. Comparable to observations made with huntingtin-targeted ASOs, a 2′-MOE-modified gapmer ASO against tau RNA demonstrated a dose-dependent decrease in tau expression, with enduring effects for more than four months. PS19 transgenic mice carrying the human P301S mutation were found to have tau aggregates prevented and reversed after administration of tau-targeted RNase H ASO. Following toxicological studies, a phase 1 clinical trial was initiated for a microtubule-associated protein tau-targeted ASO in patients with mild Alzheimer’s disease (NCT03186989) ^[16].

Over the past twenty years, the progress in the development of therapies for amyotrophic lateral sclerosis (ALS) has been rapid. Hereditary types of ALS represent an interesting prospect for antisense therapies, as targeting the mutant protein or RNA is a clear objective with minimized risk.

Currently, clinical trials are underway for ASOs targeting SOD1, C9orf72, FUS, and ATXN2, which are associated with familial or sporadic forms of ALS. ASOs using RNase H-dependent cleavage mechanisms are predominantly employed in preclinical testing and clinical trials for ALS ^[14]^[16]. Another important application field in which ASOs have been studied is the potential treatment of cancer. Their main mechanism of action is based on binding to specific genes that are overexpressed or mutated in cancer cells, leading to tumor growth suppression and cell death. An example of this is the use of ASOs to target the oncogene B-cell lymphoma 2 (Bcl2), which has been observed to stimulate apoptosis in cancer cells and inhibit tumor formation.

ASOs have also been used to target miRNAs that control gene expression and are linked to cancer. A preliminary investigation successfully suppressed mouse lung cancers by delivering tumor suppressor miRNA mimics using ASOs incorporated in a neutral lipid emulsion ^[22]. ASOs have been widely employed in nonsmall cell lung cancer (NSCLC) therapy to target key gene regulators involved in the malignant phenotype. Some of the targeted genes include Bcl2, protein kinase B, Kirsten rat sarcoma virus (KRAS), vascular endothelial growth factor, signal transducer and activator of transcription 3, clusterin, and protein kinase C alpha (PKC alpha) ^[23]. Currently, aprinocarsen (NCT00017407, NCT0034268) and custirsen (NCT01630733, NCT00138658) are under clinical trials targeting PKC alpha and clusterin, respectively, which are associated with NSCLC.

Inflammatory diseases encompass a broad range of conditions characterized by chronic inflammation and immune dysregulation. ASOs have emerged as a promising therapeutic strategy for addressing these conditions. Rheumatoid arthritis, inflammatory bowel disease (including Crohn’s disease and ulcerative colitis), and psoriasis are examples of inflammatory diseases where ASOs have demonstrated potential benefits. They can be designed to target specific genes or gene products involved in the inflammatory response, thereby modulating the immune system and reducing inflammation. ASOs targeting specific cytokines, such as tumor necrosis factor-alpha, interleukins (ILs), and interferons, have been investigated for conditions like rheumatoid arthritis, Crohn’s disease, and psoriasis. By blocking the production of these cytokines or their receptors, ASOs can dampen the pro-inflammatory signaling cascades that drive disease progression ^[24]. In particular, Karras et al. investigated the anti-inflammatory effect of an inhaled IL-4 receptor-α antisense oligonucleotide (IL-4Rα) in mouse models. By reducing IL-4Rα protein expression in various lung cells, including eosinophils, dendritic cells, macrophages, and airway epithelium, the modified IL-4Rα showed promise in mitigating allergic lung inflammation and airway hyperreactivity associated with asthma/allergy ^[25]. The investigation of SMAD family member 7 (Smad7) ASOs as a potential treatment for inflammatory bowel disease by inhibition of transforming growth factor-β1, which plays a role in mucosal inflammation in the gut, Smad7 ASOs were found safe and tolerable by patients with Crohn’s disease ^[26].

Additionally, ASOs can be used to modulate the activity of chemokines, which are involved in the activation and recruitment of immune cells during inflammation. A particular type of ASO called 2′-deoxy-2′-fluoro-D-arabinonucleic acid ASO was studied in a mouse model of spinal cord injury (SCI) to inhibit a specific chemokine called CCL3. This was shown to reduce inflammation at the site of injury, paving the way for possible therapies to treat SCI and other central nervous system disorders. Additional investigations are required to comprehensively assess the therapeutic potential and safety of this approach in the clinical setting ^[27].

2. Therapeutic Applications of RNA Interference (RNAi)

RNAi is a process, which uses double-stranded RNA in a sequence-specific way, that implies the mRNA degradation and the suppression of target gene expression. RNAi can be achieved by either siRNA or miRNA.

The miRNA and siRNA are small molecules of RNA, with the former ranging in length from 19 to 23 nucleotides and the latter from 20 to 25 nucleotides, that are implicated in RNA interference and work through similar mechanisms: they are processed by Dicer inside the cell and are incorporated into the complex RNA-induced silencing complex (RISC) ^[28]^[29]. siRNAs, called short interfering RNA, are a class of double-stranded noncoding RNA molecules, and they have primary roles in biology ^[30]; miRNAs are single-stranded, noncoding molecules from endogenous noncoding RNA, meaning that they are synthesized inside the cell. Some differences between these two molecules can be spotted: siRNAs block the expression of one specific target mRNA, whereas miRNAs regulate the post-transcriptional expression of multiple mRNAs depending on their mechanism of imperfect complementarity, except the seed region (which is located at 5′ miRNA), which must be perfectly complementary. Another important region of miRNA is called 3′ supplementary, which encompasses nucleotides from 12 to 16; this region is important for target recognition ^[31].

siRNA therapeutics are based on the introduction of synthetic double-stranded RNA, which cause the inhibition of a specific gene mRNA to generate gene silencing. The design of siRNA is quite difficult; the gene silencing caused by siRNA depends on the region of mRNA that is complementary. Understanding the relationship between siRNA and mRNA binding can facilitate the design of siRNA with optimal efficiency. Many siRNA design algorithms have been developed to predict the efficacy ^[32]^[33]. However, the efficacy must be validated by experimental methods. One of the major drawbacks of using siRNA can be the off-target effects due to downregulation of unintended, unpredicted targets. To make siRNA therapeutics feasible, numerous efforts have been made to reduce their off-target effects, which limit their therapeutic effect ^[34].

Many interesting previously published reports focus on the design of siRNA and miRNA for therapeutic applications ^[28]^[35]. One of the most recently approved drugs based on siRNA, inclisiran (LEQVIO; Novartis), is a conjugate of N-acetylgalactosamine (GalNac)-modified siRNA, which is shown to decrease cholesterol levels in plasma. It works via an RNAi mechanism of action and could ameliorate outcomes for patients with atherosclerotic cardiovascular disease. There are four other drugs currently in the clinical phase 3: (1) vutrisiran (NCT04153149), for the treatment of transthyretin-mediated amyloidosis, including both hereditary and wild-type amyloidosis ^[36]; (2) tivanisiran (NCT04819269), a topically designed siRNA for the treatment of dry eye disease; (3) teprasiran (NCT03510897), a siRNA used for the temporary inhibition of p53-mediated cell death for the treatment of acute kidney injury; and (4) fitusiran (NCT03417102), a siRNA therapeutic targeting the antithrombin to rebalance hemostasis in people with hemophilia A or B. There are two main therapeutic strategies based on miRNAs: miRNA inhibition therapy and miRNA replacement therapy. Inhibition therapy is similar to the antisense approach, which involves the singles-stranded RNAs that behave as miRNA antagonists for the inhibition of endogenous miRNA. Replacement therapy involves synthetic miRNAs (called mimics) that replace miRNA’s expressions that are normally repressed ^[37].

miRNAs modulate both physiological and pathological processes, playing a crucial role in regulating cell functions such as proliferation, differentiation, and apoptosis. Overexpression or underexpression of miRNAs are associated with many diseases, including cancer. The deregulation of miRNAs could contribute to tumor onset, development, invasion, and metastasis, which are known to be the hallmarks of cancer.

miRNAs that are overexpressed in cancer are called oncomiR and are the targets of inhibition therapy, whereas miRNAs that are downregulated and that act as tumor suppressors are targets of so-called replacement therapy ^[38].

In miRNA replacement therapy, the tumor suppressor miRNAs are replaced by synthetic miRNAs to restore lost function resulting from the downregulation of key miRNAs, for example, let-7 and miRNA-34a to achieve the same biological function as endogenous miRNAs.

The double-stranded mimic is made of a guide strand (the one actively recognizing the target) that has a similar sequence in its nucleotides, and a passenger strand, which is complementary to the guide, that is discharged during the process. The double structure can facilitate the loading of RNA molecules into the RISC, thereby promoting gene silencing. In vivo, miRNA therapeutics could activate the innate immune system through Toll-like receptors ^[39] and could generate off-target effects leading to significant undesirable effects. Chemical modification of natural oligonucleotides is the major approach to ameliorate stability and cellular uptake. The appropriate dose of miRNA therapeutics is crucial for boosting their efficiency and potency in cell/tissue and preventing the immunogenic response ^[40]. The first synthetic potential miRNA to enter clinical trials was MRX34 (NCT01829971) for cancer treatment ^[41]. For primary liver cancer or liver metastasis from other solid tumors, MRX34 was formulated to deliver a mimic of miRNA-34 using liposomes ^[42].

TargomiRs (NCT02369198) consist of a miRNA-16 mimic, an uptake system based on nonliving bacterial minicell nanoparticles, and an antiepidermal growth factor receptor antibody as the targeting moiety. Introducing synthetic exogenous miRNA-16, another tumor suppressor, mimics promoted the inhibition of tumor-promoting gene transcription and therefore tumor growth ^[43]. Many tumor suppressor miRNAs, such as miRNA-7, miRNA-126, miRNA-143/145, miRNA-200, miRNA-355, and the members of the let-7 families ^[44]^[45], have been identified as downregulating oncogenes. The use of double-stranded miRNA mimics has some drawbacks for drug development, for example, the synthesis of the passenger strand doubles the time and cost requirements for its production, and the passenger could cause off-target effects ^[46]. The use of single-stranded, chemically modified miRNA mimics such as miR-34a, miR-124, miR-122, and miR-216b was also investigated and showed promising effects ^[47]. A single-stranded miR-126b mimic, with modified UNA, was conjugated with two palmityl chains on the surface of 1-palmitoyl-2-oleoyl-sn-glycero-3-phosphocholine liposomes and was functionalized with the TAT cell-penetrating peptide. The sequence was tested to inhibit KRAS in two pancreatic ductal adenocarcinoma cell lines, showing that the NP functionalized with TAT-Pal and 126b-Pal, respectively, induced an ~70% decrease in protein KRAS and ~40% inhibition of colony formation ^[48]. In their study, Piacenti and colleagues ^[49] developed a series of single-stranded PNA analogues of miRNA-34a with different lengths to target 3′ UTR mRNA of MYCN. miRNa-34a acted as a tumor suppressor in many tumors including neuroblastoma. miRNA-34a is a direct regulator of the MYCN oncogene, whose overexpression is a prominent biomarker for neuroblastoma phenotype ^[50].

The PNA/RNA duplexes held very promising features of affinity and stability and in terms of cellular uptake despite the presence of multiple mismatches. Furthermore, an 8-mer PNA sequence, conjugated with a peptide carrier, was found to show moderate internalization in NB Kelly cells without any transfection agents ^[51].

In another study, Dhuri et al. proposed a tail camp γPNA (tcγPNA-155) to target the oncomiR-155 by base-pairing W-C and Hoogstein to create a stable clamp and inhibit their activity. The sequence γPNA-155 was delivered into tumors and inhibited the growth of the tumor in lymphoma (DLBCL) ^[52]. Instead of targeting the full length oncomiR, short-cationic PNAs targeting the seed region were proposed as a next-generation antimiR agent. The cation seed-based PNA oligomers were synthesized with three lysine or arginine units, and they were encapsulated in poly(lactic-co-glycolic acid) PLGA NPs to enhance the delivery. Arginine containing antiseed PNA-155 was reported to cause superior inhibition of the target, and systemic delivery of PNA-155 loaded PLGA NPs prevented the growth of tumors (DLBCL xenografts) ^[53]. The same authors also developed positively charged PLGA/poly-L-histidine–based nanoparticles to encapsulate the full-length PNA-155 targeting the miR-155 and showed a sixfold reduction in the growth of DLBCL xenografts ^[54].

Additionally, a sequence γPNA (8 mer) targeting the miR-155 seed region was conjugated at the N-terminus with lauric acid (C12) and conferred an amphiphilic shape resulting in self-assembly. The sequence γPNA-155-LA was formulated in vesicles (∼100 nm) with ethanol and demonstrated cellular uptake and the inhibition in vitro of miRNA-155 ^[55]. Another approach is to target simultaneously multiple oncomiRs to enhance their anticancer activity.

The PNA sequence, formulated with PLGA NPs and designed to be complementary to oncomiRs-155 and -21, demonstrated an approximately 80% reduction in the viability of lymphoma cells. This exceeded the efficacy of individual treatments, which achieved around a 50% reduction ^[56].

Both PS and PNA ASOs, when delivered via PLGA NPs, exhibited similar inhibition of miR-155 (~90%) and miR-21 (~50%) in lymphoma cells. Many oncomiRs, including miR-21, miR-10b, and miR 221, were assessed towards blocking the progression of glioblastoma multiforme (GBM), an aggressive tumor. Various synthetic oncomiRs, including miR-10b, miR-21, miR-221, and miR-93, were tested to evaluate their therapeutic activity in GBM. Concomitant use of oncomiRs-155 and oncomiRs-221 integrated with temozolomide was demonstrated to induce apoptosis in the T98G glioma cell line ^[57].

Targeting specific oncomiRs-10b or -21 has demonstrated anticancer efficacy in vivo models of GBM. The concurrent inhibition of both oncomiRs-10b and -21 in GBM has been evaluated by few studies, though. Wang et al. synthesized two tiny (8-mer) cationic γ-modified PNAs to target the seed region, respectively, of oncomiRs-10b and -21. The oligomers based on modified γPNAs were entrapped in NPs formed by PLA/HPG-CHO and were tested in a mouse model of GBM ^[58].

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Subjects: Biochemistry & Molecular Biology

Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :

Maria Moccia

Barbara Pascucci

Michele Saviano

Maria Teresa Cerasa

Michael A. Terzidis

Chryssostomos Chatgilialoglu

Annalisa Masi

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Update Date: 02 Jan 2024

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1. Therapeutic Applications of Antisense Oligonucleotides

2. Therapeutic Applications of RNA Interference (RNAi)

References