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Effect of anti-miR21 on top of pre-emptive ACEi therapy in Alport mice of 129/SvJ genetic background (see schematic illustration of animal study design). (a) Lifespan of Alport mice displayed as a Kaplan-Meier-survival curve (n= 8) and (b) as a box plot (n= 8). (c) Proteinuria (n = 3) and (d) blood urea nitrogen (BUN) in different stages of progressive renal disease (anti-miR-21 n = Effect of anti-miR21 on top of pre-emptive ACEi therapy in Alport mice of 129/SvJ genetic background (see schematic illustration of animal study design). (a) Lifespan of Alport mice displayed as a Kaplan-Meier-survival curve (n= 8) and (b) as a box plot (n= 8). (c) Proteinuria (n = 3) and (d) blood urea nitrogen (BUN) in different stages of progressive renal disease (anti-miR-21 n = 2; all other groups n = 3; data displayed as mean ± SEM). The excretion of albumin and high molecular weight proteins represents the glomerular damage due to the GBM-defect in Alport syndrome. BUN correlates inversely to renal function and was close to normal values in ACEi and ACEi + anti-miR-21-treated Alport mice. * p < 0.05.
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Col4a3−/− Alport mice serve as an animal model for renal fibrosis. MicroRNA-21 (miR-21) expression has been shown to be increased in the kidneys of Alport syndrome patients. Here, we investigated the nephroprotective effects of Lademirsen anti-miR-21 therapy. We used a fast-progressing Col4a3−/− mouse model with a 129/SvJ background and an intermed...
Citations
... RNA therapeutics are helpful in genetic and acquired CKD cases, the therapies targeting them include the use of siRNAs for modulating the RNA interface pathway. This pathway although is in effect in normal physiology and functioning of cells, the exogenous siRNA can target and degrade specific mRNA, thereby regulating the activity of genes by suppressing their expression resulting in post-translational gene silencing [51]. This newer molecular therapy demands the need of a delivery vehicle to transport and prevent the breakdown of oligonucleotides in the bloodstream, however, challenges towards the size and charge of the RNA therapeutics limit its use [117]. ...
... This newer molecular therapy demands the need of a delivery vehicle to transport and prevent the breakdown of oligonucleotides in the bloodstream, however, challenges towards the size and charge of the RNA therapeutics limit its use [117]. Similar to siRNA, miRNA-21 has been identified for use in Alport syndrome, with results of sub-cutaneous injection of anti-miRNA-21 Phase 2 trial results anticipated in later 2023 to be promising [51,118]. Chronic renal diseases resulting from frequent bouts of glomerulonephritis have been observed to benefit from frequent administration of siRNA. ...
Metabolic syndrome (MetS) is a prevalent and intricate health condition affecting a significant global population, character
ized by a cluster of metabolic and hormonal disorders disrupting lipid and glucose metabolism pathways. Clinical manifesta
tions encompass obesity, dyslipidemia, insulin resistance, and hypertension, contributing to heightened risks of diabetes and
cardiovascular diseases. Existing medications often fall short in addressing the syndrome’s multifaceted nature, leading to
suboptimal treatment outcomes and potential long-term health risks. This scenario underscores the pressing need for inno
vative therapeutic approaches in MetS management. RNA-based treatments, employing small interfering RNAs (siRNAs),
microRNAs (miRNAs), and antisense oligonucleotides (ASOs), emerge as promising strategies to target underlying biological
... It is predicted that lademirsen can increase the effectiveness of current anti-fibrotic therapy agents, especially in renal fibrosis and other fibrotic conditions. 81,88 Downregulation of inflammamiR miR-29 was reported in several organs and tissue fibrosis. 89,90 To restore decreased miR-29 expression and to rescue the fibrosis phenotype, mimic miR-29 (remlarsen/MRG-201) was produced by miRagen Therapeutics, Inc. ...
microRNAs (miRNAs) are small non‐protein‐coding RNAs which are essential regulators of host genome expression at the post‐transcriptional level. There is evidence of dysregulated miRNA expression patterns in a wide variety of diseases, such as autoimmune and inflammatory conditions. These miRNAs have been termed “inflammamiRs.” When working with miRNAs, the method followed, the approach to treat or diagnosis, and the selected biological material are very crucial. Demonstration of the role of miRNAs in particular disease phenotypes facilitates their evaluation as potential and effective therapeutic tools. A growing number of reports suggest the significant utility of miRNAs and other small RNA drugs in clinical medicine. Most miRNAs seem promising therapeutic options, but some features associated with miRNA therapy like off‐target effect, effective dosage, or differential delivery methods, mainly caused by the short target's sequence, make miRNA therapies challenging. In this review, we aim to discuss some of the inflammamiRs in diseases associated with inflammatory pathways and the challenge of identifying the most potent therapeutic candidates and provide a perspective on achieving safe and targeted delivery of miRNA therapeutics. We also discuss the status of inflammamiRs in clinical trials.
... In this context, variations in the expression profile of miRNAs (e.g., miR-7b-3p, miR-22-3p, miR-127-3p, miR-181a-5p, miR-214-5p, and miR-223-3p) and lncRNAs (lnc-EVI5L-1, lnc-FAM72B-4, lnc-KIN-1, lnc-MB-6, lnc-SERPINI1-2, and lnc-TIGD1L2-3) have been found to be associated with kidney stones [154][155][156]. Moreover, some miRNAs and lncRNAs that have been reported to have prospective therapeutic relevance in kidney stone disease include miR-34a, miR-30c-5p, miR-204, LINC00339, and LINC01197 [157][158][159][160][161]. Similarly, recent outcomes support that anti-miR-21 can be applied to the treatment of Alport syndrome, a genetic disorder that impacts the glomerular basement membrane and leads to progressive kidney damage [162], while Lorenzen et al. [163] documented that the expression levels of miR-24 and miR-126 are altered in individuals with Escherichia coli O104:H4-induced hemolytic uremic syndrome and could be used as biomarkers. Even so, there are still several kidney diseases in which the regulatory functions of miRNAs and lncRNAs remain to be explored in depth, such as medullary sponge kidney, nephronophthisis, cystinosis, Dent's disease, fibrillary glomerulonephritis, among others. ...
MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are two crucial classes of transcripts that belong to the major group of non-coding RNAs (ncRNAs). These RNA molecules have significant influence over diverse molecular processes due to their crucial role as regulators of gene expression. However, the dysregulated expression of these ncRNAs constitutes a fundamental factor in the etiology and progression of a wide variety of multifaceted human diseases, including kidney diseases. In this context, over the past years, compelling evidence has shown that miRNAs and lncRNAs could be prospective targets for the development of next-generation drugs against kidney diseases as they participate in a number of disease-associated processes, such as podocyte and nephron death, renal fibrosis, inflammation, transition from acute kidney injury to chronic kidney disease, renal vascular changes, sepsis, pyroptosis, and apoptosis. Hence, in this current review, we critically analyze the recent findings concerning the therapeutic inferences of miRNAs and lncRNAs in the pathophysiological context of kidney diseases. Additionally, with the aim of driving advances in the formulation of ncRNA-based drugs tailored for the management of kidney diseases, we discuss some of the key challenges and future prospects that should be addressed in forthcoming investigations.
... On mice with Duchenne muscular dystrophy showed that Ang (1-7) downregulated miR-21 expression accompanied by a decrease of TGF-β/Smad expression, ECM deposition in the kidney so that these effects reversed by MasR deficient or MasR antagonist (A-779) treatment (68). Combination therapy of ACEi Ramipril with anti-miR-21 Lademirsen (ACEi + anti-miR-21) compared to treatment of ACEi alone in the Alport Syndrome (AS) mice attenuated tubulo-interstitial fibrosis by decreasing the TGF-β expression and ECM protein production and deposition [90]. In the rat mesangial cells (MCs) and tubular epithelial cells (TECs) treated with Ang II, overexpression of Smad7 lead to up-regulation of miR-29b and down-regulation of miR-21 followed by inhibition of TGF-β signaling and ECM expression [91]. ...
Kidney fibrosis is one of the complications of chronic kidney disease (CKD (and contributes to end-stage renal disease which requires dialysis and kidney transplantation. Several signaling pathways such as renin–angiotensin system (RAS), microRNAs (miRNAs) and transforming growth factor-β1 (TGF-β1)/Smad have a prominent role in pathophysiology and progression of renal fibrosis. Activation of classical RAS, the elevation of angiotensin II (Ang II) production and overexpression of AT1R, develop renal fibrosis via TGF-β/Smad pathway. While the non-classical RAS arm, Ang 1–7/AT2R, MasR reveals an anti-fibrotic effect via antagonizing Ang II. This review focused on studies illustrating the interaction of RAS with sexual female hormone estradiol and miRNAs in the progression of renal fibrosis with more emphasis on the TGF-β signaling pathway. MiRNAs, especially miRNA-21 and miRNA-29 showed regulatory effects in renal fibrosis. Also, 17β-estradiol (E2) is a renoprotective hormone that improved renal fibrosis. Beneficial effects of ACE inhibitors and ARBs are reported in the prevention of renal fibrosis in patients. Future studies are also merited to delineate the new therapy strategies such as miRNAs targeting, combination therapy of E2 or HRT, ACEis, and ARBs with miRNAs mimics and antagomirs in CKD to provide a new therapeutic approach for kidney patients.
... Currently, anti-miR21 therapy in combination with ramipril is in clinical trials. In mice, this combination therapy produced a 20% increase in lifespan over ramipril alone [67]. Metformin, normally used to treat diabetes, showed a 25% increase in lifespan compared with losartan in the 129 Sv ARAS mouse but no additive benefit in the Bl/6 XLAS mouse [68]. ...
The standard of care for patients with Alport syndrome (AS) is angiotensin‐converting enzyme (ACE) inhibitors. In autosomal recessive Alport (ARAS) mice, ACE inhibitors double lifespan. We previously showed that deletion of Itga1 in Alport mice [double‐knockout (DKO) mice] increased lifespan by 50%. This effect seemed dependent on the prevention of laminin 211‐mediated podocyte injury. Here, we treated DKO mice with vehicle or ramipril starting at 4 weeks of age. Proteinuria and glomerular filtration rates were measured at 5‐week intervals. Glomeruli were analyzed for laminin 211 deposition in the glomerular basement membrane (GBM) and GBM ultrastructure was analyzed using transmission electron microscopy (TEM). RNA sequencing (RNA‐seq) was performed on isolated glomeruli at all time points and the results were compared with cultured podocytes overlaid (or not) with recombinant laminin 211. Glomerular filtration rate declined in ramipril‐treated DKO mice between 30 and 35 weeks. Proteinuria followed these same patterns with normalization of foot process architecture in ramipril‐treated DKO mice. RNA‐seq revealed a decline in the expression of Foxc2 , nephrin ( Nphs1 ), and podocin ( Nphs2 ) mRNAs, which was delayed in the ramipril‐treated DKO mice. GBM accumulation of laminin 211 was delayed in ramipril‐treated DKO mice, likely due to a role for α1β1 integrin in CDC42 activation in Alport mesangial cells, which is required for mesangial filopodial invasion of the subendothelial spaces of the glomerular capillary loops. Ramipril synergized with Itga1 knockout, tripling lifespan compared with untreated ARAS mice. © 2023 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
... Increased levels of MicroRNA-21 are associated with increased gene expression modulating the initial tissue repair response following acute/chronic kidney injury, followed by inflammation and subsequent fibrosis in the tubulointerstitium in the kidney. In Col4a3 −/− Alport syndrome mice, the anti-fibrotic effects of anti-microRNA-21 were demonstrated, these protective effects were increased further when combined with ACE inhibitor therapy [39]. ...
Alport syndrome is a rare genetic disease that results in disordered basement membrane type IV collagen resulting in haematuria, proteinuria and often development of renal fibrosis leading to progressive kidney disease. The therapeutic blockage of the renin-angiotensin-aldosterone system, which slows the progression to kidney failure, is supported by strong evidence. Recent clinical trials using sodium-glucose co-transporter-2 (SGLT2) inhibitors and mineralocorticoid receptor antagonists (MRA) in patients with chronic kidney disease have changed the therapeutic landscape. Patients with Alport syndrome and progressive kidney disease may benefit from treatment with MRAs because research has shown that these drugs are nephroprotective through a variety of mechanisms, including by preventing fibrosis. Ongoing clinical trials show great promise in order to help establish the long-term safety and efficacy of Finerenone, a MRA. This review discusses the evidence for the use of MRAs as a potential treatment in Alport syndrome that may slow the progression of chronic kidney disease and prevent patients reaching kidney failure.
... This intervention led to a lowering of albuminuria and attenuation of glomerulosclerosis and interstitial fibrosis. In another animal study that evaluated the individual and combined effects of anti-miR-21 ASOs (Lademirsen) with angiotensin I-converting enzyme inhibitor therapy (ramipril) in Alport syndrome mice models; anti-miR-21 therapy was found to have both individual and additive benefits in delaying kidney damage [64]. Lademirsen also underwent a phase 1 clinical trial for its safety and pharmacodynamic and pharmacokinetic profile in Alport syndrome patients but its phase 2 clinical trial was terminated by the sponsor because it failed to meet the pre-defined futility criteria [65]. ...
In diabetes, possibly the most significant site of microvascular damage is the kidney. Due to diabetes and/or other co-morbidities, such as hypertension and age-related nephron loss, a significant number of people with diabetes suffer from kidney diseases. Improved diabetic care can reduce the prevalence of diabetic nephropathy (DN); however, innovative treatment approaches are still required. MicroRNA-21 (miR-21) is one of the most studied multipotent microRNAs (miRNAs), and it has been linked to renal fibrosis and exhibits significantly altered expression in DN. Targeting miR-21 offers an advantage in DN. Currently, miR-21 is being pharmacologically silenced through various methods, all of which are in early development. In this review, we summarize the role of miR-21 in the molecular pathogenesis of DN and several therapeutic strategies to use miR-21 as a therapeutic target in DN. The existing experimental interventions offer a way to rectify the lower miRNA levels as well as to reduce the higher levels. Synthetic miRNAs also referred to as miR-mimics, can compensate for abnormally low miRNA levels. Furthermore, strategies like oligonucleotides can be used to alter the miRNA levels. It is reasonable to target miR-21 for improved results because it directly contributes to the pathological processes of kidney diseases, including DN.
... One of the ncRNA compounds, which entered the clinical phase, is an inhibitor against miR-92a (MRG-110) [256,257] that was shown to exhibit beneficial effects in wound healing and CVDs such as LI, MI (NCT03603431, NCT03494712). Another example is anti-miR-21, which was evaluated for its capability to reduce kidney fibrosis in patients with Alport syndrome (NCT03373786) and will be further examined in a clinical phase II study (NCT02855268) [258]. Moreover, CDR132L, a synthetic oligonucleotide inhibiting miR-132 indicated as a key regulator in cardiac remodeling processes [259,260], entered recent clinical study phase II (NCT04045405, NCT05350969) for safety and efficacy assessment in ischemic HF patients. ...
Diabetes mellitus, a group of metabolic disorders characterized by high levels of blood glucose caused by insulin defect or impairment, is a major risk factor for cardiovascular diseases and related mortality. Patients with diabetes experience a state of chronic or intermittent hyperglycemia resulting in damage to the vasculature, leading to micro- and macro-vascular diseases. These conditions are associated with low-grade chronic inflammation and accelerated atherosclerosis. Several classes of leukocytes have been implicated in diabetic cardiovascular impairment. Although the molecular pathways through which diabetes elicits an inflammatory response have attracted significant attention, how they contribute to altering cardiovascular homeostasis is still incompletely understood. In this respect, non-coding RNAs (ncRNAs) are a still largely under-investigated class of transcripts that may play a fundamental role. This review article gathers the current knowledge on the function of ncRNAs in the crosstalk between immune and cardiovascular cells in the context of diabetic complications, highlighting the influence of biological sex in such mechanisms and exploring the potential role of ncRNAs as biomarkers and targets for treatments. The discussion closes by offering an overview of the ncRNAs involved in the increased cardiovascular risk suffered by patients with diabetes facing Sars-CoV-2 infection.
Graphical Abstract
... The antifibrotic effect of anti-miR-21 oligonucleotides was described in Col4a3 −/− Alport mice. Significant additive effects were found for a combination of anti-miR-21 and ACEI therapies on kidney function and survival in Alport mouse models, especially in the fast-progression model [33]. ...
Alport syndrome (AS) is a hereditary kidney disease caused by pathogenic variants in COL4A3 and COL4A4 genes with autosomal recessive or autosomal dominant transmission or in the COL4A5 gene with X-linked inheritance. Digenic inheritance was also described. Clinically it is associated with microscopic hematuria, followed by proteinuria and chronic renal insufficiency with end-stage renal disease in young adults. Nowadays, there is no curative treatment available. The inhibitors of RAS (renin-angiotensin system) since childhood slow the progression of the disease. Sodium-glucose cotransporter-2 inhibitors seem to be promising drugs from DAPA-CKD (dapagliflozin–chronic kidney disease) study, but only a limited number of patients with Alport syndrome was included. Endothelin type A receptor and angiotensin II type 1 receptor combined inhibitors, and lipid-lowering agents are used in ongoing studies in patients with AS and focal segmental glomerulosclerosis (FSGS). Hydroxychloroquine in AS is studied in a clinical trial in China. Molecular genetic diagnosis of AS is crucial not only for prognosis prediction but also for future therapeutic options. Different types of mutations will require various types of gene, RNA, or protein therapy to improve the function, the of final protein product.
... Therefore, pathomechanisms-like transcriptome alteration might be similar, or closely related, for both genes. The mild consequences of NUP133 mutant variants (as observed in cell culture) probably translate into severe phenotypes in more complex model systems, such as organoids, drosophila melanogaster, or mus musculus [72][73][74][75]. Further studies, using these models, might evaluate the therapeutic approaches for targeting small RhoGTPase signaling or the inhibition of proteasomal degradation (e.g., NUP107) [26,76,77]. ...
Steroid-resistant nephrotic syndrome (SRNS) frequently leads to end-stage renal disease, ultimately requiring kidney replacement therapies. SRNS is often caused by hereditary monogenic mutations, specifically affecting specialized epithelial cells (podocytes) of the glomerular filtration barrier. Mutations in several components of the nuclear pore complex, including NUP133 and NUP107, have been recently identified to cause hereditary SRNS. However, underlying pathomechanisms, eliciting podocyte-specific manifestations of these nucleoporopathies, remained largely elusive. Here, we generated an in vitro model of NUP133-linked nucleoporopathies using CRISPR/Cas9-mediated genome editing in human podocytes. Transcriptome, nuclear pore assembly, and cytoskeleton regulation of NUP133 loss-of-function, mutant, and wild-type podocytes were analyzed. Loss of NUP133 translated into a disruption of the nuclear pore, alterations of the podocyte-specific transcriptome, and impaired cellular protrusion generation. Surprisingly, comparative analysis of the described SRNS-related NUP133 mutations revealed only mild defects. Am impaired protein interaction in the Y-complex and decrease of NUP133 protein levels might be the primary and unifying consequence of mutant variants, leading to a partial loss-of-function phenotype and disease manifestation in susceptible cell types, such as podocytes.
