exo-siRNA and shRNA-mediated gene silencing approaches for MJD/SCA3.
Abstract
Machado-Joseph disease (MJD), also named spinocerebellar ataxia type 3 (SCA3), is a dominantly inherited neurodegenerative disease caused by abnormal CAG expansions in MJD1 gene, which translate to an overexpanded tract of glutamines in the ataxin-3 (ATXN3) protein. Since the identification of the causative gene, a huge effort was made toward the development of animal models for MJD/SCA3, to increase the understanding of the molecular mechanisms underpinning disease pathogenesis, and to develop therapeutic strategies for the disease. Nevertheless, until now there are no therapies available capable of stopping or delaying the disease progression, which culminates with the death of the patients. Therefore, there is an urgent unmet need for therapeutic solutions, for which gene therapy stands out. The RNA interference (RNAi) mechanism discovery allowed the identification of small RNA molecules with the ability to regulate gene expression. For gene therapy, RNAi provided a way to silence mutant genes, which are particularly useful in dominantly inherited diseases. In the last years, several studies have focused on using RNAi molecules to target mutant ATXN3. The results showed that this could be an efficient and safe strategy for modifying MJD/SCA3 progression. Now, an additional effort must be done to translate these results into clinical trials.
Keywords
- Machado-Joseph disease/spinocerebellar ataxia type 3
- ataxin-3
- RNA interference technology
- (non-) allele-specific gene silencing
- exogenous small interfering RNAs
- short hairpin RNAs
- artificial microRNAs
- microRNA mimics
1. Introduction
1.1 Machado-Joseph disease
Machado-Joseph disease (MJD), also named spinocerebellar ataxia type 3 (SCA3), is an inherited and rare neurodegenerative disease, usually with adult-onset, and is considered the most common autosomal dominant ataxia worldwide. It is part of the group of polyglutamine (polyQ) disorders. The group currently includes nine disorders — Huntington’s disease (HD), dentatorubral pallidoluysian atrophy (DRPLA), spinal and bulbar muscular atrophy (SBMA), and six different spinocerebellar ataxias (SCA1/2/3/6/7/17). These disorders are caused by abnormal expansions of the CAG trinucleotide in the coding region of the causative genes, which are translated into abnormally long polyQ tracts in the respective proteins [1, 2, 3, 4]. MJD/SCA3 was initially described in Portuguese descendants in the United States. Among SCAs, its relative frequency is higher in countries such as Brazil [5], Portugal [6, 7], China [8], Germany [9], and Japan [10, 11]. In the Azores islands, the disease has the highest prevalence registered worldwide (1:140 on the small island of Flores) [12].
The main clinical manifestation of MJD/SCA3 is progressive cerebellar ataxia – motor incoordination that can affect balance, gait, and speech [13]. Other symptoms of the disease include a pyramidal syndrome with brisk deep tendon reflexes and spasticity; peripheral neuropathy with amyotrophy; oculomotor abnormalities with nystagmus, eyelid retraction and progressive external ophthalmoplegia; facial and lingual fasciculation; and extrapyramidal signs like dystonia and rigidity [14, 15, 16, 17, 18]. The neurodegenerative process in MJD/SCA3 affects multiple neuronal systems, particularly cerebellum, brainstem, basal ganglia, spinal cord, and some cranial nerves [19, 20].
MJD/SCA3 is caused by the abnormal expansion of the CAG trinucleotide in the coding region of the
There is no cure for MJD/SCA3. However, several therapeutic strategies (Figure 1) have been developed to counteract the disease pathogenesis at different stages, namely RNA interference (RNAi)-based approaches. Considering the pathological features, the strategies involve targeting (i) mutant mRNA, (ii) mutant protein aggregation, (iii) toxic proteolytic cleavage of mutant protein, (iv) protein clearance pathways (autophagy and ubiquitin-proteasome system), (v) posttranslational modifications, (vi) transcriptional dysregulation, (vii) mitochondrial dysfunction, (viii) calcium homeostasis, and (ix) neuroprotective pathways. In quite general terms, the RNAi technology constitutes a powerful tool that allows targeting the mutant ATXN3 mRNA, thereby controlling the mutant ATXN3 protein expression [34].
1.2 RNA interference mechanism
All scientific discoveries have precedents, and the RNAi mechanism was no exception. In the late 1980s and early 1990s, plant biologists, trying to genetically increase the purple pigmentation of petunias’ flowers, were surprised when they noticed, not as expected, that introducing multiple extra copies of a gene that codes for “purple flowers,” via
Since then, the discovery of the RNAi mechanism, numerous studies have furthered our understanding of the RNAi mechanism, and how RNAi could be an extremely useful experimental tool for learning what genes do and for the development of potential therapeutic strategies.
1.2.1 Endogenous RNA interference mechanism
The endogenous RNAi mechanism is an evolutionarily conserved process used by cells to regulate gene expression. In general terms, the naturally occurring key molecules of the endogenous RNAi mechanism are categorized into three classes: microRNAs (miRNAs), endogenous small interfering RNAs (endo-siRNAs), and PIWI-interacting RNAs (piRNAs). The most extensively studied class is the class of the miRNAs. All those regulatory RNAs are small noncoding RNAs that have a particular homology for specific genes, and a wide variety of expression patterns, especially in a time and a cell or tissue-dependent manner [40, 41, 42].
The endogenous RNAi mechanism (Figure 2) has been deeply implicated in several aspects of animal and plant development and their regular physiological functioning, namely cell differentiation, cell proliferation, and cell death. It has been involved in the pathophysiological processes of numerous diseases, as well. Additionally, the endogenous RNAi mechanism also provides antiviral “molecular defense” response and restricts “genomic parasites,” such as transposable elements. It is known that RNAi can effectively protect hosts against viruses, by intercepting and inhibiting viral transcripts through miRNAs. RNAi can also protect cells against transposable elements, both by degrading the transcripts of transposable elements and by preventing the expression of transposable elements through heterochromatin formation [43, 44, 45, 46].
In animals, the miRNA pathway, the most notorious pathway, can be divided into multiple steps. Initially, in the nucleus, the miRNA genes are transcribed into long primary transcripts, the primary miRNAs (pri-miRNAs), that have a stem-loop structure flanked by single-stranded regions corresponding to the 5′ end (with 7-methylguanosine) and 3′ end (with the poly-A tail). The transcription is generally processed by RNA polymerase II [47, 48]. Then, the pri-miRNAs are cleaved at the opposite extremity of the loop by Drosha, a ribonuclease type III (RNase III), generating miRNA precursors, the precursor miRNAs (pre-miRNAs), which maintain the stem-loop structure but with a 2-nucleotide 3′ overhang. During the process, Drosha forms an enzymatic complex with another protein, the dsRNA-binding protein DiGeorge syndrome critical region gene 8 (DGCR8), that stabilizes the pri-miRNAs. The complex mentioned above is known as a microprocessor [49, 50, 51, 52]. Additional proteins, such as the enhancer of the rudimentary homolog (ERH), can also interact with the microprocessor, modulating its catalytic activity [53].
Still in the nucleus, the pre-miRNAs associate with the dsRNA-binding protein exportin-5 that transfers them to the cytoplasm, in the presence of the Ras-related nuclear- GTP-binding protein (Ran-GTP) [54, 55]. After the hydrolysis of GTP, the pre-miRNAs are released and intercepted by a cluster of proteins containing the RNase III Dicer and the dsRNA-binding proteins HIV-1 transactivating response (TAR)- RNA-binding protein (TRBP) and protein kinase R (PKR) activator (PACT). Dicer recognizes the 2-nucleotide 3′ overhang of the pre-miRNAs (through its Piwi-Argonaut-Zwille (PAZ) domain, an RNA-binding domain) and cleaves the loop extremity. That originates miRNAs duplexes of approximately 21–23 nucleotides in length (on each strand) harboring 2-nucleotide 3′ overhangs at both extremities. The proteins TRBP and PACT stabilize the pre-miRNAs during the process [56, 57, 58, 59].
After the previous processing step catalyzed by Dicer, the cluster of proteins containing Dicer, TRBP, and PACT provides a structural landing platform for the recruitment of another protein, argonaute (habitually argonaute-2), which associates with the miRNA duplexes, recognizing the 2-nucleotide 3′ overhangs (like Dicer, argonaute has a PAZ domain). Altogether, the proteins above are the major members of the RNA-induced silencing complex (RISC), which mediates later the messenger RNA (mRNA) silencing. The RISC becomes active when only one of the strands of the miRNA duplexes (guide strand, antisense strand, mature miRNA, or simply miRNA or miR) remains associated with argonaute. The other strand (the passenger strand, the sense strand) is removed and rapidly degraded [60, 61, 62]. If the nucleotide-pairing between the two strands of the miRNA duplexes is imperfect, it seems to be argonaute itself, through its endonucleolytic strand-dissociating activity, which dissociates the guide strand and the passenger strand (the most likely pathway since the miRNA duplexes frequently have mismatches). If the nucleotide-pairing is perfect or near-perfect, it is suggested that RNA helicases, through their strand-unwinding activity, separate the two strands [63, 64, 65]. Experimental evidence suggests that miRNA duplexes dissociation starts at the extremity with the lowest thermodynamic stability. The strand that has its 5′ end at this extremity is the one that preferentially remains associated with argonaute, and acts later as a guide strand in the mRNA silencing [66].
The final step of the miRNA pathway occurs when the miRNAs bound to argonaute selectively recognize and bind to the target mRNAs, and then the miRNAs-mRNAs macrostructures are degraded. The specificity of the mRNA recognition derives primarily from the high-level complementarity of the nucleotide sequence comprising the nucleotides 2–8 of the 5′ end of the miRNAs, known as seed region, with the 3′ untranslated region (UTR) of the mRNAs (in general, but the miRNAs can also target coding regions). Moreover, some experimental data revealed an additional nucleotide sequence in the miRNAs, termed supplementary region, comprising at least the 13–16 nucleotides, that seems to be equally important in the specificity of the mRNA recognition, given the high-level complementarity with the 3′ UTR of the mRNAs, as well. The importance increases when the complementarity of the seed region is suboptimal. As a rule, except for the localized nucleotide sequences mentioned above, the complementarity of the remaining nucleotides of the miRNAs with the 3’ UTR of the mRNAs is partial, and the occurrence of mismatches and bulges is common and naturally tolerated [67, 68, 69, 70]. After the miRNAs selectively recognize and bind to the target mRNAs, the miRNAs-mRNAs macrostructures, along with argonaute, are transported to cytoplasmic compartments called processing bodies (P-bodies) that promote its degradation. In this way, the miRNAs lead to the silencing of the target mRNAs, inhibiting the translation (or, in fact, leading to the silencing of the corresponding genes) [71, 72].
Considering the endo-siRNA pathway, in animals, there are several dsRNAs sources, which constitute endo-siRNAs precursors and ultimately originate endo-siRNAs. These sources include i) pairs of transposable element transcripts, which are formed by two transcripts from a single transposable element bi-directionally transcribed [73, 74]; ii) pairs of cis-natural antisense transcripts (cis-NATs), which are formed by two overlapping transcripts from the same genomic locus) [75]; iii) pairs of trans-NATs (also known as gene-pseudogene pairs), which are formed by two overlapping transcripts from distinct genomic loci, usually a gene mRNA and a pseudogene transcript [76]; and iv) hairpin RNA transcripts with stem-loop structure, which result from the transcription of long inverted repeats [77]. The endo-siRNAs precursors are long dsRNAs and, once in the cytoplasm, they are processed by Dicer into smaller endo-siRNAs duplexes of around 20–23 nucleotides in length (on each strand). After the RISC assembly and the subsequent strand selection, the endo-siRNAs bound to argonaute selectively recognize and bind to the target RNAs, such as transposon transcripts or endogenous mRNAs. Then, the endo-siRNAs-RNAs macrostructures are directly cleaved by argonaute in the RISC. This differs from the miRNA pathway due to the high-level complementarity of the entire nucleotide sequence of the endo-siRNAs with the target RNAs [78, 79, 80, 81].
The piRNA pathway was originally described in the
During posttranscriptional gene silencing, additional antisense piRNAs are generated through an amplification mechanism termed the ping-pong cycle. In the cytoplasm, aubergine, through its normal slicer activity, naturally generate transposon transcript fragments that are used in the ping-pong cycle as sense piRNAs intermediates. Following a maturation process, which includes trimming to the appropriate length, the sense piRNAs intermediates originate mature sense piRNAs. Then, the sense piRNAs are loaded into the PIWI protein argonaute-3 (Mili in mice and Hili in humans) that subsequently cleaves the piRNA precursors, producing more antisense piRNAs with sequences identical, or near-identical to the original triggers. The ping-pong cycle continues with the aubergine loading once again [82, 83, 90, 91, 92].
1.2.2 RNA interference mechanism mediated by artificial RNA effector molecules
The endogenous RNAi mechanism can be artificially triggered to induce specific gene silencing by different RNA effector molecules: exogenous (exo)-siRNAs, short hairpin RNAs (shRNAs), artificial miRNAs, and miRNA mimics [93]. The exo-siRNAs are usually double-stranded molecules of around 21–23 nucleotides in length, chemically synthesized, and their guide strand has full complementarity with the target mRNAs. The delivery occurs using non-expression-based systems, including nanoparticles, such as lipid-based nanoparticles or polymer-derived nanoparticles. The exo-siRNAs are designed to mimic miRNA duplexes and enter the endogenous RNAi mechanism upon being loaded into the RISC in the cytoplasm. Following the strand selection, the passenger strand is degraded, whereas the guide strand bound to argonaute associates with specific complementary mRNAs, targeting them for direct cleavage by argonaute [94, 95]. The exo-siRNAs can be incorporated into stem-loop structures and originate shRNAs, when integrated into an artificial stem-loop, mimicking pre-miRNAs, or artificial miRNAs, when integrated into a backbone that derives from a natural pri-miRNA backbone, mimicking a pri-miRNA. Like exo-siRNAs, the guide strand of shRNAs and artificial miRNAs typically has full complementarity with the target mRNAs. Both molecules are delivered by expression-based systems, such as plasmids or viral vectors. Following viral-mediated transduction and subsequent transcription within the nucleus, the shRNAs are translocated to the cytoplasm by exportin-5. Then occurs Dicer processing and incorporation into the RISC. The next steps are like those of exo-siRNAs. In turn, the artificial miRNA genesis is most upstream and requires an additional step — Drosha processing within the nucleus [96, 97]. The miRNA mimics are synthetic double-stranded molecules comprising a guide strand that is designed to recognize and bind to a target mRNA with partial complementarity, as a mature miRNA. In fact, the guide strand typically corresponds to a naturally occurring mature miRNA, for a proper miRNA replacement and a natural mode of action silencing target mRNAs. The miRNAs mimics can be directly delivered by non-expression-based vectors or delivered by expression-based vectors. Depending on the delivery method, the miRNA mimics enter the endogenous RNAi mechanism as mentioned for the previous effector molecules [98, 99].
A possible categorization of the delivery systems is to divide them into expression-based vectors and non-expression-based vectors. The expression-based vectors are considered much more efficient, especially the viral vectors, by allowing the effector molecules to permanently silence a target gene upon one single administration. In contrast, the non-expression-based vectors are generally safer and easier to produce. Their transient nature allows an interruption of the administration [100].
Although RNAi technology has a widely recognized potential as a therapeutic strategy, its efficiency has been questioned due to unintended effects that culminate in cell dysfunction or even animal death [101]. The cytotoxic effects include i) the saturation of the endogenous RNAi processing machinery, which derives from the overexpression of the effector molecules [101, 102]; ii) the induction of the immune response, due to the activation of cellular sensors that typically recognize foreign RNA and DNA, which then leads to the production of proinflammatory cytokines and interferons [103, 104]; and iii) potential off-target effects, which in general derive from unintended interactions between the guide strand of the effector molecules and other transcripts containing complementary sequences [105, 106].
2. Therapeutic strategies for Machado-Joseph disease based on RNA interference
MJD/SCA3 is caused by a specific genetic mutation — a CAG repeat expansion — in the coding region of the
Considering all this, several therapeutic strategies for MJD/SCA3 based on RNAi have been conceived, involving gene silencing mediated by exo-siRNAs and shRNAs (Table 1) and gene silencing mediated by artificial miRNAs and miRNA mimics (Table 2).
Effector molecule | Allele specificity | Expression system | Delivery system | Reference |
---|---|---|---|---|
shRNA | Non-allele-specific | HEK 293T1 cell model and lentiviral mouse model | Transfection and lentivirus-mediated transduction | [112] |
exo-siRNA targeting CAG repeat expansion | Non-allele-specific | Patient-derived fibroblasts | Transfection | [113] |
exo-siRNAs and shRNAs targeting G/C SNP | Allele-specific | COS-72 cell model | Transfection and adenovirus-mediated transduction | [114] |
exo-siRNA targeting G/C SNP | Allele-specific | HEK 293T cell model | Transfection | [115] |
shRNA targeting G/C SNP | Allele-specific | HEK 293T cell model, lentiviral rat and mouse models, and transgenic mouse model | Transfection and lentivirus-mediated transduction | [116, 117, 118] |
exo-siRNA targeting G/C SNP | Allele-specific | Neuro2a cell model, lentiviral and transgenic mouse models | SNALP-mediated transfection | [119] |
exo-siRNAs targeting CAG repeat expansion | Allele-specific | Patient-derived fibroblasts | Transfection | [120] |
shRNA targeting CAG repeat expansion | Allele-specific | Patient-derived fibroblasts | Lentivirus-mediated transduction | [121] |
ss-exo-siRNAs targeting CAG repeat expansion | Allele-specific | Patient-derived fibroblasts | Transfection | [122] |
Effector molecule | Allele specificity | Expression system | Delivery system | Reference |
---|---|---|---|---|
Artificial miRNA targeting 3′ UTR of ATXN3 | Non-allele-specific | Transgenic mouse model | AAV-mediated transduction | [123, 124] |
Artificial miRNAs targeting exons within ATXN3 | Non-allele-specific | Heterozygous knock-in mouse model | AAV-mediated transduction | [125] |
miR-25 mimic | (Naturally) non-specific | HEK 293T1 cell model | Transfection | [126] |
mir-9, mir-181a and mir-494 mimics | (Naturally) non-specific | HEK 293T cell model and lentiviral mouse model | Transfection and lentivirus-mediated transduction | [127] |
2.1 Exogenous small interfering RNA and short hairpin RNA-mediated gene silencing
The gene silencing mediated by exo-siRNAs and shRNAs, applied to MJD/SCA3, can be divided into two distinct categories: (i) non-allele-specific gene silencing and (ii) allele-specific gene silencing. The non-allele-specific silencing constitutes the most straightforward methodology, and unselectively silences both wild-type and mutant genes. On the other hand, allele-specific silencing is a more accurate methodology that allows the selective silencing of the mutant gene. The allele distinction is particularly important when the wild-type protein is essential for cellular function. To accomplish the allele distinction, differences between both transcripts of the genes, such as single-nucleotide polymorphisms (SNPs) and the CAG repeat itself, are used to design the effector molecules [128, 129].
2.1.1 Non-allele-specific gene silencing
In a non-allele-specific gene silencing approach on MJD/SCA3, following
In another study, an exo-siRNA targeting the CAG repeat expansion and delivered by a liposome-based vector strongly reduced both mutant ATXN3 and wild-type ATXN3 protein levels, in MJD/SCA3 patient-derived fibroblasts. Furthermore, similar results were obtained for huntingtin, in a HD context, with the same exo-siRNA. It shows that a gene silencing approach targeting the CAG repeat expansion can be beneficial for different polyQ diseases [113].
Mouse and
2.1.2 Allele-specific gene silencing
Extensive efforts on MJD/SCA3 have been made toward allele-specific silencing of the mutant ATXN3. Several allele-specific approaches have been focused on a SNP (
Later it was demonstrated in rodent models of MJD/SCA3 that it is possible to selectively and efficiently silence the mutant ATXN3
In a less invasive approach, following the validation of its efficacy in neuronal cells, an exo-siRNA, encapsulated in SNALPs, targeting the
Differently, and in a
An alternative approach reported a potent and allele-selective inhibition of the mutant ATXN3 expression using chemically modified single-stranded exo-siRNAs (ss-exo-siRNAs) targeting the CAG repeat expansion, in MJD/SCA3 patient-derived fibroblasts. It was also observed that the ss-exo-siRNAs, which were delivered by a liposome-based vector, bind to argonaute (argonaute-2) and promote its recruitment to the ATXN3 mRNA, validating the involvement of the RNAi pathway in the gene silencing mediated by ss-exo-siRNAs. Besides the RNAi mechanism, a non-RNAi-related process was found to affect the gene expression after the addition of the ss-exo-siRNAs, the alternative splicing, which is a typical mode of action of the antisense oligonucleotides (ASOs). Altogether, this approach shows that chemically modified ss-exo-siRNAs have properties of conventional exo-siRNAs and ASOs. Like exo-siRNAs, the ss-exo-siRNAs can operate through the RNAi pathway, and like ASOs, the ss-exo-siRNAs are single-stranded, simplifying their synthesis and chemical modification, and can trigger the alternative splicing [122].
2.2 Artificial microRNA and microRNA mimic-mediated gene silencing
As previously mentioned, an artificial miRNA consists of an exo-siRNA and a scaffold based on a natural pri-miRNA [97]. Considering that, similarly to exo-siRNAs, the gene silencing mediated by artificial miRNAs can be divided into non-allele-specific or allele-specific gene silencing. In a non-allele-specific approach, an artificial miRNA targeting the 3′ UTR of ATXN3 mRNA and delivered by adeno-associated virus (AAVs) was able to decrease efficiently the human mutant ATXN3 expression in the cerebellum of a transgenic mouse model of MJD/SCA3 [123, 124]. It was also observed less neuronal nuclear accumulation of the mutant ATXN3. In addition, the silencing of the mutant ATXN3 resulted in a partial normalization of the endogenous miRNA steady-state levels in mice. Although the mouse wild-type ATXN3 expression has not been affected
Some miRNA screening studies on MJD/SCA3 have shown that the expression of several miRNAs is dysregulated and closely associated with the neuropathology in SCA3/MJD [137, 138]. Since the miRNA mimics are generated to behave as endogenous miRNAs, and its guide strand is designed to correspond to a naturally occurring mature miRNA, the miRNA mimics are particularly useful to restore the function of a miRNA downregulated in a disease condition [98, 99]. That was accomplished on MJD/SCA3 using miR-25, which was found to be significantly downregulated in the serum of patients. Following transfection, the upregulation of miR-25 strongly reduced both the mutant ATXN3 and wild-type ATXN3 levels, by interacting with the 3′ UTR of the mRNA, in human cell cultures. miR-25 also decreased protein aggregation, suppressed early apoptosis, and increased cell viability [126]. A different study identified three miRNAs — mir-9, mir-181a, and mir-494 — whose expression is downregulated in human MJD/SCA3 iPSC-derived neurons and other MJD/SCA3 cellular and animal models. All of them interact with the 3′ UTR of the mRNA and are highly expressed in the brain. The reestablishment of the three miRNAs, encoded by plasmids or lentivirus, led to an efficient reduction of human mutant ATXN3 levels in human cell cultures and a lentiviral mouse model, and a decrease of the protein aggregation and neuronal dysfunction in the lentiviral mouse model. The upregulation of mir-9 and mir-181a also affected the mouse wild-type ATXN3 levels
Another interesting but different study, based on a miRNA overexpression but not using miRNA mimics, performing an enhancer-promoter (EP) screen for modifiers through overexpression, showed that the miRNA bantam is a potent modulator in the neuropathology of MJD/SCA3 in a
3. Conclusions
An enormous effort was made by researchers to develop several gene silencing strategies based on RNAi molecules for MJD/SCA3. The results obtained decisively point to a huge therapeutic potential of these molecules. Overall, most of the studies showed both using allele or non-allele-specific strategies that various pathological features are mitigated, including in rodent models. Additionally, in several of these studies, the safety profile of the RNAi molecules was also assessed, corroborating their safety and increasing their therapeutic value. Nevertheless, an additional effort must be made to translate these preclinical results to human clinics, starting with their testing in clinical trials (searching on clinicalstrials.gov, there are no RNAi-based clinical trials yet). The approval in Europe and the US of an RNAi-based gene therapy for hereditary amyloid transthyretin (hATTR) amyloidosis, ONPATTRO® (patisiran), opens the way for these therapies and provides new hope for the RNAi-based gene therapies for MJD/SCA3 and other polyglutamine diseases.
Acknowledgments
We want to thank the projects and institutions funding Clévio Nóbrega laboratory, including the Portuguese Science and Technology Foundation (FCT) project (ALG-01-0145-FEDER-29480), “SeGrPolyQ” with CRESC ALGARVE 2020 cofunding, the French Muscular Dystrophy Association (AFM-Téléthon), ATAXIA UK, and the CureCSB project. JMC is supported by a Ph.D. fellowship from FCT (SFRH/BD/148760/2019).
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