Search Results (17)

Background/Objectives: Hereditary transthyretin-mediated amyloidosis (ATTRv) is a rare disease characterized by the deposition of amyloid in the heart and peripheral nerves, particularly affecting small fibers. This study aims to evaluate autonomic cardiac involvement in ATTRv. Methods: Twelve patients with ATTRv and twelve sex- and age-matched healthy subjects underwent ¹²³I-mIBG scintigraphy to evaluate the early and late heart-to-mediastinum ratio (eH/M and lH/M), ^99mTc-HDP bone scan scintigraphy, and neurophysiological assessments. Data were analyzed in relation to functional cardiac and neurologic scales (NYHA and FAP scales). Results: Patients with ATTRv exhibited significant cardiac denervation, as demonstrated by the reduction in early and late H/M ratios compared to the control group (eH/M: 1.48 ± 0.08 vs. 1.89 ± 0.05, p < 0.001; lH/M: 1.39 ± 0.08 vs. 2.01 ± 0.05, p < 0.001). Values of eH/M and lH/M < 1.6 effectively differentiated patients with ATTRv from the healthy controls. Cardiac denervation correlated with interventricular septal thickness and the Perugini score but was not related to neurophysiological assessments or NYHA and FAP scales. Conclusions: Ultimately, ¹²³I-mIBG scintigraphy is an effective tool for assessing cardiac denervation in patients with ATTRv. Full article

Small interfering RNAs (siRNAs) are short, double-stranded RNA molecules that play a crucial role in the regulation of gene expression, particularly through a natural process called RNA interference (RNAi). Their discovery, about 25 years ago, paved the way for a whole series of research leading to synthetic molecules. The gene silencing potential of these siRNAs was initially oriented towards diseases resulting from genetic dysfunctions. This led to the development of the first synthetic siRNAs approved for human use in hereditary transthyretin amyloidosis. Subsequently, the field of application expanded beyond the confines of genetic diseases. The refinement of pharmacological techniques has led to the synthesis of a variety of siRNAs capable of blocking the production of individual proteins responsible for various disease conditions, thus expanding their field of therapeutic application. The kidney has also been affected by this new therapeutic tool, largely indirectly but also, with some difficulty, directly. The structural complexity of the kidney has made the search for siRNAs targeting its individual components very challenging. Nevertheless, the first results of the application of this new therapeutic technology to the kidney are beginning to be seen in experimental animals and in humans. siRNAs have been approved for the treatment of amyloidosis with patisiran and oxalosis with lumasiran and nedosiran. Studies are ongoing for the use of siRNAs as anti-complement drugs in IgA nephropathy, as angiotensinogen inhibitors in hypertension, or against some mediators of acute kidney injury. In this review, the biological mechanisms underlying the use of siRNAs are briefly exposed. The results of the therapeutic application of RNA interference to the kidney and its diseases are also analyzed and discussed. Full article

RNA therapeutics have undergone remarkable evolution since their inception in the late 1970s, revolutionizing medicine by offering new possibilities for treating previously intractable diseases. The field encompasses various modalities, including antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), microRNAs (miRNAs), and messenger RNAs (mRNAs), each with unique mechanisms and applications. The foundation was laid in 1978 with the discovery that synthetic oligonucleotides could inhibit viral replication, followed by pivotal developments such as RNA interference’s discovery in 1998. The COVID-19 pandemic marked a crucial turning point, demonstrating the potential of mRNA vaccines and accelerating interest in RNA-based approaches. However, significant challenges remain, including stability issues, delivery to target tissues, potential off-target effects, and immunogenicity concerns. Recent advancements in chemical modifications, delivery systems, and the integration of AI technologies are addressing these challenges. The field has seen notable successes, such as approved treatments for spinal muscular atrophy and hereditary transthyretin-mediated amyloidosis. Looking ahead, RNA therapeutics show promise for personalized medicine approaches, particularly in treating genetic disorders and cancer. The continued evolution of this field, driven by technological innovations and deeper understanding of RNA biology, suggests a transformative impact on future medical treatments. The purpose of this review is to provide a comprehensive overview of the evolution, current state, and prospects of RNA therapeutics. Full article

Transthyretin-mediated amyloidosis (ATTR) is a systemic disease with protein precipitation in many tissues, mainly the peripheral nerve and heart. Both genetic (ATTRv, “v” for variant) and wild-type (ATTRwt) forms are known. Beyond the steric encumbrance, precipitated transthyretin seems to have a toxic effect. In this study carried out in men, we recruited 15 ATTRv patients, 7 ATTRv asymptomatic carriers, 14 ATTRwt patients and 10 young and 13 old healthy controls to evaluate the oxidative stress using FORD (Free Oxygen Radicals Defense) and FORT (Free Oxygen Radicals Test) analyses. ATTRv patients showed reduced FORD compared to ATTRwt and ATTRv asymptomatic carriers. FORD independently predicted the disease stage, with the early stages characterized by the highest consumption. These findings suggest a role for oxidative stress in the early stages of ATTRv. Full article

A total of nine TIDES (pepTIDES and oligonucleoTIDES) were approved by the FDA during 2023. The four approved oligonucleotides are indicated for various types of disorders, including amyotrophic lateral sclerosis, geographic atrophy, primary hyperoxaluria type 1, and polyneuropathy of hereditary transthyretin-mediated amyloidosis. All oligonucleotides show chemically modified structures to enhance their stability and therapeutic effectiveness as antisense or aptamer oligomers. Some of them demonstrate various types of conjugation to driving ligands. The approved peptides comprise various structures, including linear, cyclic, and lipopeptides, and have diverse applications. Interestingly, the FDA has granted its first orphan drug designation for a peptide-based drug as a highly selective chemokine antagonist. Furthermore, Rett syndrome has found its first-ever core symptoms treatment, which is also peptide-based. Here, we analyze the TIDES approved in 2023 on the basis of their chemical structure, medical target, mode of action, administration route, and common adverse effects. Full article

Transthyretin amyloidosis (ATTR) is a progressive and systemic disease caused by the misfolding and amyloid aggregation of transthyretin (TTR). Stabilizing the TTR tetramers and disrupting the formed TTR aggregation are treated as a promising strategy for the treatment of ATTR. Previous studies have reported that epigallocatechin gallate (EGCG) can participate in the whole process of TTR aggregation to prevent ATTR. However, the interaction mechanism of EGCG in this process is still obscure. In this work, we performed molecular dynamics simulations to investigate the interactions between EGCG and TTR tetramers, and between EGCG and TTR aggregates formed by the V30M mutation. The obtained results suggest that EGCG at the binding site of the V30M TTR tetramer can form stable hydrogen bonds with residues in the flexible AB-loop and EF-helix-loop, which reduces the structural mobility of these regions significantly. Additionally, the polyaromatic property of EGCG contributes to the increasement of hydrophobicity at the binding site and thus makes the tetramer difficult to be solvated and dissociated. For V30M-TTR-generated aggregates, EGCG can promote the dissociation of boundary β-strands by destroying key residue interactions of TTR aggregates. Moreover, EGCG is capable of inserting into the side-chain of residues of neighboring β-strands and disrupting the highly structured aggregates. Taken together, this study elucidates the role of EGCG in preventing TTR amyloidosis, which can provide important theoretical support for the future of drug design for ATTR. Full article

Waste of high-cost medicines, such as orphan drugs, is a major problem in healthcare, which leads to excessive costs for treatments. The main objective of this study was to evaluate the impact of a vial-sharing strategy for patisiran, an orphan drug used for the treatment of hereditary transthyretin-mediated amyloidosis, in terms of a reduction in the discarded drug amount and cost savings. The retrospective observational study was conducted in a tertiary referral center (Emilia-Romagna, Italy), between February 2021 and November 2022. Data on drug waste were calculated as “(mg used–mg prescribed)/mg prescribed” for each session. We found a statistically significant (−9.14%, p < 0.001, 95% CI 5.87–12.41) absolute difference in mean discarded drug rates per session based on the study phase (before and after vial-sharing introduction) at the two-sample t-test. The absolute difference corresponded to a percentage decrease in the average reduction in the discarded drug rate with vial sharing of 82.96% per session. On an annual scale, the estimated cost savings was EUR 26,203.80/year for a patient with a standard body weight of 70 kg. In conclusion, we demonstrated that a patisiran vial-sharing program undoubtedly offsets some of the high costs associated with this treatment. We suggest that this easy-to-introduce and cost-effective approach can be applied to the administration of other high-cost drugs. Full article

Heart failure (HF) is associated with endothelial dysfunction. Vascular function per se plays an important role in cardiac function, whether it is a cause or consequence. However, there is no information on vascular function in patients with wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM). The purpose of this study was to evaluate vascular function in patients with ATTRwt-CM. We measured flow-mediated vasodilation (FMD) as an index of endothelial function and nitroglycerine-induced vasodilation (NID) as an index of vascular smooth muscle function and brachial artery intima-media thickness (bIMT) and brachial-ankle pulse wave velocity (baPWV) as indices of arterial stiffness in 22 patients with ATTRwt-CM and in 22 one-by-one matched control patients using vascular function confounding factors. FMD was significantly greater in patients with ATTRwt-CM than in the controls (5.4 ± 3.4% versus 3.5 ± 2.4%, p = 0.038) and the N-terminal pro-brain natriuretic peptide (NT-proBNP) level was significantly greater in patients with ATTRwt-CM than in the controls (2202 ± 1478 versus 470 ± 677 pg/mL, p < 0.001). There were no significant differences in NID, bIMT or baPWV between the two groups. There was a significant relationship between NT-proBNP and FMD in patients with ATTRwt-CM (r = 0.485, p = 0.022). NT-proBNP showed no significant relationships with NID, bIMT or baPWV. Conclusions: Endothelial function was preserved in patients with ATTRwt-CM. Patients with ATTRwt-CM may have compensatory effects with respect to endothelial function through elevation of BNP. Full article

Background and aims: Orphan diseases, or rare diseases, are defined in Europe as diseases that affect less than 5 out of every 10,000 citizens. Given the small number of cases and the lack of profit potential, pharmaceutical companies have not invested much in the development of possible treatments. However, over the last few years, new therapies for rare diseases have emerged, giving physicians a chance to offer personalized treatment. With this paper, we aim to present some of the orphan neurological diseases for which new drugs have been developed lately. Methods: We have conducted a literature review of the papers concerning rare diseases and their treatment, and we have analyzed the existing studies for each orphan drug. For this purpose, we have used the Google Scholar search engine and the Orphanet. We have selected the studies published in the last 15 years. Results. Since the formation of the National Organization for Rare Diseases, the Orphan Drug Act, and the National Institutes of Health Office of Rare Diseases, pharmacological companies have made a lot of progress concerning the development of new drugs. Therefore, diseases that until recently were without therapeutic solutions benefit today from personalized treatment. We have detailed in our study over 15 neurological and systemic diseases with neurological implications, for which the last 10–15 years have brought important innovations regarding their treatment. Conclusions: Many steps have been taken towards the treatment of these patients, and the humanity and professionalism of the pharmaceutical companies, along with the constant support of the patient’s associations for rare diseases, have led to the discovery of new treatments and useful future findings. Full article

Transthyretin (TTR) aggregation and amyloid formation are associated with several ATTR diseases, such as senile systemic amyloidosis (SSA) and familial amyloid polyneuropathy (FAP). However, the mechanism that triggers the initial pathologic aggregation process of TTR remains largely elusive. Lately, increasing evidence has suggested that many proteins associated with neurodegenerative diseases undergo liquid–liquid phase separation (LLPS) and subsequent liquid-to-solid phase transition before the formation of amyloid fibrils. Here, we demonstrate that electrostatic interactions mediate LLPS of TTR, followed by a liquid-solid phase transition, and eventually the formation of amyloid fibrils under a mildly acidic pH in vitro. Furthermore, pathogenic mutations (V30M, R34T, and K35T) of TTR and heparin promote the process of phase transition and facilitate the formation of fibrillar aggregates. In addition, S-cysteinylation, which is a kind of post-translational modification of TTR, reduces the kinetic stability of TTR and increases the propensity for aggregation, while another modification, S-sulfonation, stabilizes the TTR tetramer and reduces the aggregation rate. Once TTR was S-cysteinylated or S-sulfonated, they dramatically underwent the process of phase transition, providing a foundation for post-translational modifications that could modulate TTR LLPS in the context of pathological interactions. These novel findings reveal molecular insights into the mechanism of TTR from initial LLPS and subsequent liquid-to-solid phase transition to amyloid fibrils, providing a new dimension for ATTR therapy. Full article

Lipid nanoparticles (LNPs) are an emerging vehicle for gene delivery that accommodate both nucleic acid and protein. Based on the experience of therapeutic liposomes, current LNPs have been developed based on the chemistry of lipids and RNA and on the biology of human disease. LNPs have been used for the development of Onpattro, an siRNA drug for transthyretin-mediated amyloidosis, in 2018. The subsequent outbreak of COVID-19 required a vaccine for its suppression. LNP-based vaccine production received much attention for this and resulted in great success. In this review, the essential technology of LNP gene delivery has been described according to the chemistry for LNP production and biology for its clinical application. Full article

ATTR amyloidosis comprises a spectrum of multiple clinical presentations, including, predominantly, neuropathy and cardiomyopathy. The common triggering pathogenic protein is misfolded transthyretin, a carrier protein that destabilizes misfolds and assembles into mature amyloid fibrils. The current management of ATTR amyloidosis includes the use of agents that stabilize TTR or attenuate its liver inducible production. Herein, we tested the hypothesis that a monoclonal antibody targeting the soluble oligomeric as well as the aggregated TTR would influence experimental neuropathy. We have shown that Ab-A, our previously described humanized IgG monoclonal antibody, dose-dependently ameliorates the toxicity to neurons triggered by misfolded TTR oligomers. Furthermore, the antibody that exhibits wide misTTR epitope recognition that includes the oligomeric and aggregated forms of the protein dose-dependently enhances the uptake of misfolded TTR to microglia, the resident predominant cells of the innate immune system within the CNS. These in vitro mechanistic properties of the antibody were corroborated by experimental in vivo data showing that the antibody rapidly clears human TTR amyloid extracts infiltrated to the sciatic nerves of rats. Thus, the monoclonal antibody targeting soluble and aggregated TTR is effective in experimental neuropathy, likely due its ability to act as a neuroprotective agent, as well its misTTR-mediated clearance via microglia. Full article

Background: Transthyretin-mediated amyloidosis (ATTR) is a rare multisystemic disease involving the peripheral nervous system and heart. Autonomic and small fiber involvement is one of the hallmarks of ATTR, and many tools have been proposed to assess this aspect. Aim: The aim of this study was to investigate cutaneous and mixed nerve silent periods (CSP and MnSP) as instruments for small fiber assessment. Methods: A total of 21 ATTR patients, 20 healthy controls, and 18 asymptomatic carriers underwent a sensory conduction study from the right sural and non-dominant ulnar nerves. A motor conduction study from the right deep peroneal and non-dominant ulnar nerves, with their F waves, CSPs, and MnSPs, was performed. Results: The amplitudes of the sural and ulnar sensory nerves and of the peroneal and ulnar motor nerves were reduced in ATTR patients compared to the other groups. F waves from the ulnar and peroneal nerves showed no differences between the three groups. The CSP and MnSP latency, but not amplitude, were increased in both the ulnar and peroneal nerves of ATTR patients. Conclusions: ATTR patients showed axonal involvement of large sensory and motor nerve fibers and demyelinating features of small sensory fibers. Full article

Transthyretin (TTR) proteolysis has been recognized as a complementary mechanism contributing to transthyretin-related amyloidosis (ATTR amyloidosis). Accordingly, amyloid deposits can be composed mainly of full-length TTR or contain a mixture of both cleaved and full-length TTR, particularly in the heart. The fragmentation pattern at Lys48 suggests the involvement of a serine protease, such as plasmin. The most common TTR variant, TTR V30M, is susceptible to plasmin-mediated proteolysis, and the presence of TTR fragments facilitates TTR amyloidogenesis. Recent studies revealed that the serine protease inhibitor, SerpinA1, was differentially expressed in hepatocyte-like cells (HLCs) from ATTR patients. In this work, we evaluated the effects of SerpinA1 on in vitro and in vivo modulation of TTR V30M proteolysis, aggregation, and deposition. We found that plasmin-mediated TTR proteolysis and aggregation are partially inhibited by SerpinA1. Furthermore, in vivo downregulation of SerpinA1 increased TTR levels in mice plasma and deposition in the cardiac tissue of older animals. The presence of TTR fragments was observed in the heart of young and old mice but not in other tissues following SerpinA1 knockdown. Increased proteolytic activity, particularly plasmin activity, was detected in mice plasmas. Overall, our results indicate that SerpinA1 modulates TTR proteolysis and aggregation in vitro and in vivo. Full article

The homotetrameric plasma protein transthyretin (TTR), is responsible for a series of debilitating and often fatal disorders in humans known as transthyretin amyloidosis. Currently, there is no cure for TTR amyloidosis and treatment options are rare. Thus, the identification and development of effective and safe therapeutic agents remain a research imperative. The objective of this study was to determine the effectiveness of Bacopa monnieri extract (BME) in the modulation of TTR amyloidogenesis and disruption of preformed fibrils. Using aggregation assays and transmission electron microscopy, it was found that BME abrogated the formation of human TTR aggregates and mature fibrils but did not dis-aggregate pre-formed fibrils. Through acid-mediated and urea-mediated denaturation assays, it was revealed that BME mitigated the dissociation of folded human TTR and L55P TTR into monomers. ANS binding and glutaraldehyde cross-linking assays showed that BME binds at the thyroxine-binding site and possibly enhanced the quaternary structural stability of native TTR. Together, our results suggest that BME bioactives prevented the formation of TTR fibrils by attenuating the disassembly of tetramers into monomers. These findings open up the possibility of further exploration of BME as a potential resource of valuable anti-TTR amyloidosis therapeutic ingredients. Full article