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MiRNA-Based Therapies in NHL
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This entry is adapted from the peer-reviewed paper 10.3390/cancers13246324

Non-Hodgkin’s lymphoma (NHL) is a very heterogenous group of lymphoid malignancies originating from different stages of B-cell (~90% of the cases) and T-cell or NK-cell differentiation. Increasing evidence has demonstrated the functional roles of miRNAs and lncRNAs in lymphoma onset and progression, either by acting as tumor-promoting ncRNAs or as tumor suppressors, emphasizing their appeal as lymphoma therapeutics. In fact, their intrinsic ability to modulate multiple dysregulated genes and/or signaling pathways makes them an attractive therapeutic approach for a multifactorial pathology like lymphoma.

lymphoma Non-Hodgkin’s lymphoma miRNAs Therapy

1. miRNA-Based Therapies in NHL

Acting as oncogenic or as tumor suppressors, miRNAs represent a class of master regulators of malignant transformation and progression and, thus, represent powerful candidates as therapeutics (in the role of miRNA mimics) or as therapeutic targets (in the role of antimirs). The first strategy has the rational of targeting tumor-promoting mRNAs via restoring the tumor-suppressive miRNAs in tumor cells by either using synthetic double-stranded miRNA mimics, pre-miR, or plasmid-encoded miRNA genes [1]. On the other hand, the second approach aims to inhibit the levels of oncomiRs, which are frequently overexpressed in cancer, allowing the restoration of the expression of tumor-suppressor targets. Different methodologies of oncomiR inhibition are being developed by using single-stranded antisense, anti-miR oligonucleotides (AMOs), locked nucleic acid (LNA) anti-miRs, antagomiRs, miRNA sponges, and small molecule inhibitors of miRNAs (SMIRs) [1][2][3][4][5][6].
While the theory behind miRNA-based therapy is somehow straightforward, the challenges of this approach reside in its delivery. The presence of multiple ribonucleases and reticuloendothelial system clearance in the blood make miRNAs unstable in the circulation. Moreover, unmodified miRNA antagonists and miRNA mimics are unable to cross the cell membrane or the vascular endothelium due to their negative charges [7]. The efficacy of miRNA delivery depends also on blood perfusion in tumors and cell-specific delivery. Not only the tumor microenvironment, tumor-associated immune cells especially can nonspecifically uptake and capture miRNAs, but also, it is essential to prevent the disruption of the healthy tissue [7][8][9]. Therefore, to overcome these obstacles, numerous miRNA delivery methodologies are being developed, both local and systemic delivery strategies (Table 1).
Despite the difficulty of getting bench-based microRNAs to the bedside, several companies are developing miRNA-based drugs, some of which are already being tested in phase I and phase II clinical trials. In fact, in 2018, the FDA approved the first siRNA drug, Patisiran, to be employed in the treatment of a rare polyneuropathy caused by transthyretin-mediated amyloidosis [10][11][12].
Table 1. Summary of the miRNA mimics or inhibitors tested in vivo.
Table
Chemical Modifications Delivery Systems miRNAs Target Strategy Delivery Route Target Disease Ref.
  Lipid-based miR-34a Restoration Intratumoral
Tail vein		 DLBCL [13]
Lipid-based Subcutaneous MM [14][15]
Viral-based
LNA   miR-155 Inhibition Tail vein Waldenstrom macroglobulinemia [16]
PNA Peptide-based Intravenous B-cell lymphoma [17]
PNA Polymer-based Intravenous
Intratumoral		 [18]
  Viral-based miR-15a/16 Restoration Intravenous
Intraperitoneal		 CLL [19]
  Viral-based miR-144/451 Restoration Subcutaneous B-cell lymphomas [20][21]
  Viral-based miR-181a Restoration Subcutaneous DLBCL [22][23]
  Viral-based miR-27b Restoration Subcutaneous DLBCL [24]
  Lipid-based miR-28 Restoration Intratumoral BLDLBCL [25]
Viral-based Intravenous
  Lipid-based miR-21 Inhibition Subcutaneous MM [26]
  Viral-based miR-17∼92 cluster Inhibition Intratumoral DLBCL [27]
2′ O-methyl-group EV-based miR-125 Inhibition Intraperitoneal AML [28]
Abbreviations: LNA: locked nucleic acid, PNA: peptide nucleic acids, DLBCL: diffuse large B-cell lymphoma, MM: multiple myeloma, CLL: chronic lymphocytic leukemia, BL: Burkitt lymphoma, and AML: acute myeloid leukemia.

2. Local Delivery

Intratumoral injection or local administration of miRNA mimics or inhibitors has shown effective gene silencing and antitumoral effects, with reduced nonspecific uptake by normal healthy tissue and reduced toxicity and immunogenicity compared with systemic delivery. However, the local delivery of miRNAs is limited to localized and readily accessible primary tumors such as melanoma, breast cancer, or cervical cancer. The therapeutic potential of miR-34a replacement therapy was shown in a xenograft model of DLBCL, where the intratumoral administration of synthetic miR-34a mimics resulted in tumor growth inhibition [13]. Trang et al., using an aggressive human non-small cell lung cancer (NSCLC) xenograft model, showed that the intranasal delivery of a lentiviral vector expressing let-7a resulted in an increased expression of let-7 in the lungs and the subsequent growth inhibition of KRAS-dependent lung tumors. Moreover, locally polymer-based delivered let-7b led to a 60–70% reduction of the tumor burden [29]. Sureban et al. developed a nanoparticle-mediated intratumoral delivery of DCAMKL-1-specific siRNA, capable of inducing let-7a and miR-144 expression, which, in turn, repressed proto-oncogene c-Myc and Notch-1 in colorectal cancer xenografts, resulting in tumor growth inhibition [30].
Despite the advantages of the local delivery of miRNAs, this type of approach is primarily limited by the tumors’ location and stage. Therefore, the development of systemic delivery systems is essential to broaden the spectrum to other types of cancers and metastatic cancers. To improve the binding affinity, stability, and target modulation, two converging strategies are applied: chemical modifications of miRNAs and the development of delivery vehicles to encapsulate miRNAs.

3. Systemic Delivery

Advances in the chemical modifications of miRNAs, such as the addition of a 2′-O-methyl group; locked nucleic acid (LNA) oligonucleotides; peptide nucleic acids (PNAs); phosphorothioate-like groups; and cholesterol-, biotin-, and amino-modified oligonucleotides, are being investigated. The addition of a 2′-O-methyl or 2′-O-methoxyethyl group to ribose was shown to enhance the binding affinity and stability of anti-miRNA while efficiently and specifically silence the targeted endogenous miRNAs in numerous tissues, such as the bone marrow [5][31]. LNA-mediated anti-miR-155, targeting the seed region of miR-155, showed a significant inhibition of cell proliferation of low-grade B-cell lymphomas in vitro and decreased the tumor burden in a xenograft mouse model of Waldenstrom macroglobulinemia (WM) [16]. Cheng et al. showed that miR-155 oncomiR, one of the most extensively studied miRNAs for its therapeutic potential, can be silenced by linking PNA anti-miR-155 to a peptide with a low pH-induced transmembrane structure (pHLIP). This conjugation efficiently inhibited the tumor growth and increased mouse survival in a mouse model of lymphoma [17]. LNA anti-mir-122 systemic administration was shown to downregulate, in a dose-dependent manner, liver-specific miR-122, which prevents hepatitis C virus (HCV) replication. The promising results of the LNA anti-mir-122 drug as a preventive therapy for HCV-induced hepatocellular carcinoma (HCC) led to phase II trials for the treatment of HCV infection [32]. Despite the chemical modifications, modified miRNAs have reduced tumor uptake and biodistribution due to rapid renal and hepatic clearances, which results in short half-lives [7]. Therefore, several viral and nonviral vectors are being developed as miRNA delivery systems (Figure 2).
Cancers 13 06324 g002 550
Figure 2. Schematic representation of the commonly used and emerging nanoplatforms for ncRNA delivery. (Abbreviations: PEG: polyethylene glycol and LPS: lipopolysaccharide).

4. Vectors-Based Delivery Systems

4.1. Viral Vectors

Viral vectors, such as lentivirus, adenovirus, and adeno-associated virus (AAV), can carry and deliver miRNA mimics or antagonists to the nuclei of tumor cells. Moreover, the conjugation of targeting moieties to viral capsid proteins by genetic manipulation allows specific delivery into the tumors by enhancing the affinity between viral vectors and cancer-specific receptors [7]. In a study by Kasar et al., the systemic lentiviral delivery of miR-15a/16 restored the expression of these miRNAs in a New Zealand Black (NZB) mouse model of CLL [19]. The viral-mediated delivery of miR-144/451 restored their expression, resulting in the growth inhibition of a B-cell line xenograft in vivo [20][21]. Similarly, the viral-mediated restoration of miR-181a (downregulated in human DLBCL) and miR-27b (downregulated in human DLBCL and splenic marginal zone lymphoma (SMZL)) resulted in the growth inhibition of a human DLBCL-cell line xenograft [22][23][24]. The restoration of miR-28 by both viral vectors or as synthetic, clinically amenable molecules was shown to inhibit tumor growth in human Burkitt (BL) and DLBCL xenografts and in a primary BL murine model after intratumor or systemic administration [25]. Lentivirus-based miR-34a replacement or miR-34a synthetic mimics induced growth inhibition and apoptosis in multiple myeloma (MM) cells in vitro and exerted a powerful antitumor activity in MM xenografts in SCID mice and in a SCID-synth-hu model [15]. Su et al. demonstrated the potential of simultaneous targeting multiple oncomiRs, which are usually upregulated in DLBCL but not in normal cells, as a therapeutic strategy for B-NHL. In this study, they used a synthesized interfering long noncoding RNA (i-lncRNA) that simultaneously inhibited 13 oncomiRs, including five miR-17~92 cluster miRNAs, by competing with the corresponding target mRNAs for binding oncomiRs. Moreover, the treatment approach involving adenovirus-mediated i-lncRNA expression was shown to significantly inhibit human DLBCL xenograft growth [27]. Despite their common use due to their high efficiency, viral-based miRNA delivery systems are still associated with high immunogenicity, toxicity, and size limitations, which impose a serious obstacle to clinical applications. Therefore, nonviral vectors, such as lipid, polymer, inorganic, and extra-cellular vesicle carrier-based approaches, are rising as preferred alternatives for research and clinical studies.

4.2. Nonviral Vectors

Lipid-based nanoparticles are the most frequently used nanodelivery systems because of their easy synthesis, high stability, loading efficiency, low immunogenicity, and versatility of administration routes [33]. To date, there have been several commercially available cationic liposomes that have been routinely used for miRNA delivery, such as Lipofectamine® (Invitrogen, Carlsbad, CA, USA), TransIT® 2020 (Mirus Bio LLC, Madison, WI, USA), SiPORT™ (Invitrogen, Carlsbad, CA, USA), SilentFect™ (Bio-Rad Laboratories, Inc. Hercules, CA, USA), and Oligofectamine™ (Invitrogen, Carlsbad, CA, USA) [34]. The main obstacle that limits the clinical application of cationic lipids is their low delivery efficiency in vivo. To overcome this problem, several new methods for synthesizing lipid nanocomplexes have been developed. For example, the development of neutral liposomes and the conjugation of a polyethylene glycol (PEG) functional group to cationic lipids prevents phagocytosis and prolonged circulation, thus enhancing the overall efficacy [6]. The administration of a lipid-based miR-34a mimic, either intratumorally or systemically (using a neutral lipid emulsion (NLE)), resulted in a 95% and 76% reduction in tumor growth, respectively, in a DLBCL mouse model [13]. MiR-28a-5p, whose expression is frequently reduced in human B-cell neoplasia and associated with the downregulation of downstream BCR-signaling effectors, such as PI3K and AKT, has shown therapeutic potential as a replacement therapy for B-NHL. The administration of synthetic miR-28a-5p mimicked using a liposome delivery approach, impaired proliferation and survival of lymphoma cells, and abrogated tumor growth in MD901 DLBCL and Ramos human BL xenograft mouse models and in a λ-MYC transgenic mouse BL model [25]. Conversely, the lipid-based delivery of miR-21 inhibitors significantly inhibited tumor growth in a human MM xenograft model [26]. More recently, several approaches have emerged to enhance the targeted liposome-based miRNA delivery to specific cells. For example, Di Martino et al. synthesized a stable nucleic acid lipid particle (SNALPS) carrying miR-34a, which showed high-vesicle loading, good transfection efficiency, and stability in the serum. Moreover, SNALPS-mediated miR-34a delivery efficiently inhibited MM cell growth in vitro and in vivo, confirming the high potential of this carrier in miRNA-based therapy [14].
Polymer-based delivery methods primarily use polyethylenimine (PEI), which results from the conjugation of positively charged amine groups with an anionic RNA, preventing RNA degradation and promoting cellular uptake and intracellular release [35]. However, the use of PEIs has been limited in the current clinical research due to their low transfection efficiency and cytotoxicity. The use of other polymers, such as PEG, a nonionic and hydrophilic polymer covalently fused to PEI, can reduce toxicity by improving its biocompatibility. Avci et al. proved that PEG/PEI nanocomplex polymeric vectors improved the stability and transfection efficiency of miR-150 in human leukemia cells [36]. Another approach that has been employed is the FDA-approved biomaterial poly(lactide-co-glycolide) (PLGA), a copolymer of poly lactic acid (PLA) and poly glycolic acid with a well-documented utility for sustained drug release and clinical use. The systemic delivery of PNA anti-miR-155 conjugates encapsulated in PLGA polymer nanoparticles efficiently inhibited miR-155, which, in turn, resulted in reduced tumor growth in vivo, suggesting a therapeutic potential in B-cell tumor models [18].
The advancements in nanotechnology have led to the development of various inorganic compound-based nanoparticles as excellent nanocarriers for miRNA delivery both in vitro and in vivo. Although there is a lack of studies when compared to other types of vectors previously discussed, the majority of studies have focused mainly on gold, Fe3O4-based, and silica-based nanoparticles [37][38][39]. Inorganic compound-based delivery systems have received attention specially due to their high bioactivity, biocompatibility, and chemical stability in vivo [40]. Gold nanoparticles (AuNPs) have shown low cytotoxicity and immunogenicity, and given their physicochemical, optical, and electronic properties, they have been considered as an excellent nonviral miRNA delivery system. A study by Ghosh et al. demonstrated that PEG-conjugated AuNPs are able to successfully deliver miR-1 to cancer cells, showing a high transfection efficiency and low cytotoxicity [41]. Moreover, a multifunctional AuNP was synthesized to simultaneously deliver three anticancer agents—AS1411, doxorubicin, and anti-miR221—to drug-resistant leukemia cells. These nanoparticles were able to induce the miR-221-mediated reduction of cell proliferation and clonogenic potential, induce apoptosis, and sensitize drug-resistant cells, enhancing the chemotherapy efficacy [42].
In recent years, since the discovery of extracellular vesicles (EVs) as natural carriers of biomolecules like miRNAs involved in cell-to-cell communication, the exploitation of EVs for therapeutic applications has been under study. The intrinsic characteristics of EVs, including stability in circulation and biocompatibility, as well as low immunogenicity and toxicity, render them attractive miRNA delivery vehicles. Moreover, the manipulation of their various membrane ligands allows targeted cargo delivery to specific cells and tissues [43]. Usman et al. showed that blood cell-derived EVs carrying anti-miR-125b AMOs efficiently downregulated miR-125 in acute myeloid leukemia (AML) cells in vitro and effectively suppressed leukemia progression in a mouse model [28].
Despite their efficacy and promising potential as a delivery vehicle in conjunction with the targeting ligand on their surfaces, the mass production of EVs and effective packaging methods remain a challenge.

5. Targeting of miRNAs via CRISPR/Cas9

In the past few years, the development of a CRISPR–Cas9 system unveiled a world of new opportunities for the therapeutic targeting of not only coding but also noncoding genes [44]. The CRISPR/Cas9 system has emerged as an excellent option for miRNA therapeutic inhibition. This state-of-the-art genome editing tool permits the inhibition of miRNA expression by targeting their biogenesis sites, resulting in a functional knockout [45]. Specifically, the CRISPR-Cas9- mediated inhibition of miRNA can be achieved by introducing indels (insertions and deletions) in the terminal loop or 5′ region of pre-miRNA, which disrupts Drosha processing [46][47]. Moreover, Chang et al. also reported miRNA knockouts by targeting sequences within/adjacent to Drosha and Dicer processing sites in the secondary stem–loop structures of primary miRNA, which are crucial for processing miRNA biogenesis [48]. In this study, Chang et al. not only demonstrated efficient and specific decreases in mature miRNA levels in vitro with the minimized crossing off-target effects among miRNA members of the same family or those with highly conserved sequences but, also, the in vivo long-term stability of CRISPR/Cas9 miRNA knockdown for up to 30 days [48].
Interestingly, CRISPR/Cas9 technology permits not only the inhibition of a single miRNA but also the simultaneous inhibition of multiple miRNAs. Narayanan et al. performed a CRISPR/Cas9 mutagenesis strategy to abrogate the activity of an entire miRNA family. They screened 45 mutations in 10 miRNA genes both in silico and in vivo and demonstrated that 99% of CRISPR/Cas9 mutations altered the critical sequences within each hairpin primary miRNA structure, blocking the recognition by miRNA biogenesis machinery and thus inhibiting the miRNA family expression in vivo [49].
Despite the recent research regarding the promising utility of CRISPR/Cas gene editing technology as a cancer therapeutic approach, there is still a lack of information when it comes to targeting miRNAs compared to targeting coding genes.

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