Search Results (24)

The hypertrophic cardiomyopathy (HCM) clinical phenotype includes sarcomeric HCM, which is the most common form of inherited cardiomyopathy with a population prevalence of 1:500, and phenocopies such as cardiac amyloidosis and Anderson–Fabry disease, which are considered rare diseases. Identification of cardiac and non-cardiac red flags in the context of multi-organ syndrome, multimodality imaging, including echocardiography, cardiac magnetic resonance, and genetic testing, has a central role in the diagnostic pathway. Identifying the specific disease underlying the hypertrophic phenotype is very important since many disease-modifying therapies are currently available, and phase 3 trials for new treatments have been completed or are ongoing. In particular, many chemotherapy agents (alkylating agents, proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies targeting clonal cells) allowing one to treat AL amyloidosis, transthyretin stabilizers (tafamidis and acoramidis), and gene silencers (patisiran and vutrisiran) are available in transthyretin cardiac amyloidosis, and enzyme replacement therapies (agalsidase-alpha, agalsidase-beta, and pegunigalsidase-alpha) or oral chaperone therapy (migalastat) can be used in Anderson–Fabry disease. In addition, the introduction of cardiac myosin inhibitors (mavacamten and aficamten) has deeply modified the treatment of hypertrophic obstructive cardiomyopathy. The aim of this review is to describe the new disease-modifying treatments available in HCM and phenocopies in light of current scientific evidence. Full article

Transthyretin (TTR) amyloid cardiomyopathy (ATTR-CM) is a progressive disease that has emerged as a significant cause of heart failure. Advances in the understanding of ATTR-CM pathophysiology have revolutionised its therapeutic landscape over the past decade, with the development of targeted therapies that are able to improve survival and quality of life. TTR stabilizers, such as tafamidis and acoramidis, can reduce TTR instability and subsequent amyloid fibril formation. Clinical trials have demonstrated their efficacy both in improving survival and quality of life in patients with ATTR-CM. Gene-silencing therapies using small interfering RNAs (siRNAs), such as patisiran and vutrisiran, or antisense oligonucleotide inhibitors (ASOs), such as inotersen and eplontersen, serve as powerful therapeutic options by decreasing TTR production; trials on patients with ATTR-CM have been recently published or are ongoing. Novel, emerging therapies aim to enhance fibril clearance using monoclonal antibodies, such as NI006, that target amyloid deposits in the myocardium, promoting their depletion, plausibly with regression of the structural and functional impairments caused by the disease. Concurrently, advancements in diagnostic modalities have facilitated earlier detection of this disease, allowing the timely initiation of treatment with a more significant impact on patients’ survival and quality of life. Despite these strides, challenges remain, including the high cost of disease-modifying therapy and the need for response criteria to monitor treatment’s efficacy. Future directions will involve improving patients’ screening to achieve earlier diagnoses, optimising patients’ selection for disease-modifying therapy and identifying criteria for the treatment’s response or lack thereof to possibly consider therapy switch or associations. In this review, we will explore the more recent therapeutic advancements in ATTR-CM, starting from traditional heart failure therapies and moving to disease-modifying therapies with a detailed evaluation of the registration trials to explore the strengths and shortcomings of each treatment. 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

Biological barriers remain a major obstacle for the development of innovative therapeutics. Depending on a disease’s pathophysiology, the involved tissues, cell populations, and cellular components, drugs often have to overcome several biological barriers to reach their target cells and become effective in a specific cellular compartment. Human biological barriers are incredibly diverse and include multiple layers of protection and obstruction. Importantly, biological barriers are not only found at the organ/tissue level, but also include cellular structures such as the outer plasma membrane, the endolysosomal machinery, and the nuclear envelope. Nowadays, clinicians have access to a broad arsenal of therapeutics ranging from chemically synthesized small molecules, biologicals including recombinant proteins (such as monoclonal antibodies and hormones), nucleic-acid-based therapeutics, and antibody-drug conjugates (ADCs), to modern viral-vector-mediated gene therapy. In the past decade, the therapeutic landscape has been changing rapidly, giving rise to a multitude of innovative therapy approaches. In 2018, the FDA approval of patisiran paved the way for small interfering RNAs (siRNAs) to become a novel class of nucleic-acid-based therapeutics, which—upon effective drug delivery to their target cells—allow to elegantly regulate the post-transcriptional gene expression. The recent approvals of valoctocogene roxaparvovec and etranacogene dezaparvovec for the treatment of hemophilia A and B, respectively, mark the breakthrough of viral-vector-based gene therapy as a new tool to cure disease. A multitude of highly innovative medicines and drug delivery methods including mRNA-based cancer vaccines and exosome-targeted therapy is on the verge of entering the market and changing the treatment landscape for a broad range of conditions. In this review, we provide insights into three different disease entities, which are clinically, scientifically, and socioeconomically impactful and have given rise to many technological advancements: acquired immunodeficiency syndrome (AIDS) as a predominant infectious disease, pancreatic carcinoma as one of the most lethal solid cancers, and hemophilia A/B as a hereditary genetic disorder. Our primary objective is to highlight the overarching principles of biological barriers that can be identified across different disease areas. Our second goal is to showcase which therapeutic approaches designed to cross disease-specific biological barriers have been promising in effectively treating disease. In this context, we will exemplify how the right selection of the drug category and delivery vehicle, mode of administration, and therapeutic target(s) can help overcome various biological barriers to prevent, treat, and cure disease. Full article

Background: In recent years, many advances have been made in the treatment of hereditary transthyretin amyloidosis (ATTRv). Patisiran is a small-interfering RNA used to treat ATTRv with only polyneuropathy or polyneuropathy and cardiomyopathy. The aim of our study was to assess the effect of patisiran on cardiac function in ATTRv patients using speckle tracking echocardiography (STE) analysis. Methods: A single-center prospective study was performed enrolling 21 patients with ATTRv (11 M—52% of the population; 10 F—48% of the population; median age 66 ± 8.4 years old). A total of 7 patients had cardiac amyloidosis and polyneuropathy, and 14 patients had only polyneuropathy without cardiac involvement. Cardiological evaluation including electrocardiograms, echocardiography with STE, and assessment of myocardial work parameters was performed in all patients before starting patisiran and after 9–18 months. Functional capacity was assessed using the 6 min walk test; quality of life was assessed using the Kansas City Cardiomyopathy Questionnaire (KCCQ). Results: We did not find a significant difference in gender prevalence of ATTR amyloidosis in all of the population (p-value 0.79), but we found that cardiac amyloidosis significantly predominated in the male sex compared to patients with only neuropathy. In all patients, we found a slight improvement in functional capacity and quality of life. We did not find significant changes in left ventricular ejection fraction (LVEF), but we found a significant improvement in left ventricular global longitudinal strain (GLS), global work waste (GWW), and global work efficiency (GWE), especially in patients with cardiac amyloidosis; E/e’ average and left atrial stiffness also improved significantly in patients with cardiac amyloidosis. Conclusions: Our study confirms a positive effect of patisiran on cardiac function, particularly the absence of signs of subclinical deterioration as detected by very sensitive STE parameters such as GLS, MW, and atrial stiffness during follow up in patients treated with patisiran. Full article

Hereditary transthyretin amyloidosis (hATTR) is a multisystemic, rare, inherited, progressive and adult-onset disease, affecting the sensory-motor nerves, heart, autonomic function, and other organs. There are over 130 mutations known in the TTR gene. The His90Asn mutation has been previously reported in several reports, but its pathogenetic role is still debated. We report two sporadic cases of adult women with a heterozygous His90Asn mutation in TTR gene and neurological involvement extensively investigated. A typical Congo red-positive pathologic deposition of amyloid fibrils in the salivary glands was documented in one subject. Patients were successfully treated with patisiran with a good clinical outcome. These data support a pathogenetic role of His90Asn mutation in hATTR, and suggest early treatment in symptomatic carriers of His90Asn mutation. Full article

Small interfering RNA (siRNA)-based medications offer the ability to target previously undruggable targets and have now received FDA approval in five instances for orphan or uncommon diseases. The current siRNA “-sirans” are directed towards hepatic molecular targets. Because they are not conventional drug formulae, their ultimate clinical success will require overcoming multiple barriers beyond their pharmacology. The minimal patient numbers leave fewer patients to bear the costs of R&D and manufacture; therefore, the cost of these drugs, questionable third-party reimbursement, and competition from other drug classes for the same low number of patients are impediments to patient access. The parenteral route of administration, as well as emerging safety restrictions, are also drawbacks to siRNA. With this review, we document currently approved siRNA drugs by condition, approval date, administration route and frequencies. We have estimated the available patient populations for siran therapies using the U.S. Medicaid and Medicare populations and sought to identify the frequency with which large Medicaid formularies list siRNA drugs. Current comparative costs between the siRNA drugs and alternatives have been presented, and the review summarizes current adverse events as reported to the FDA’s Adverse Event Reporting System. Our review and data indicate that sirans are extremely expensive and seldom recognized in posted Medicaid formularies. However, alternative treatments for these conditions are no less costly, usually do not have significantly different adverse events, and are often less convenient for the patient. Full article

The global statistics of bone disorders, skeletal defects, and fractures are frightening. Several therapeutic strategies are being used to fix them; however, RNAi-based siRNA therapy is starting to prove to be a promising approach for the prevention of bone disorders because of its advanced capabilities to deliver siRNA or siRNA drug conjugate to the target tissue. Despite its ‘bench-to-bedside’ usefulness and approval by food and drug administration for five siRNA-based therapeutic medicines: Patisiran, Vutrisiran, Inclisiran, Lumasiran, and Givosiran, its use for the other diseases still remains to be resolved. By correcting the complications and complexities involved in siRNA delivery for its sustained release, better absorption, and toxicity-free activity, siRNA therapy can be harnessed as an experimental tool for the prevention of complex and undruggable diseases with a personalized medicine approach. The present review summarizes the findings of notable research to address the implications of siRNA in bone health for the restoration of bone mass, recovery of bone loss, and recuperation of bone fractures. Full article

Small interfering RNA (siRNA) represents a novel, fascinating therapeutic strategy that allows for selective reduction in the production of a specific protein through RNA interference. In the cardiovascular (CV) field, several siRNAs have been developed in the last decade. Inclisiran has been shown to significantly reduce low-density lipoprotein cholesterol (LDL-C) circulating levels with a reassuring safety profile, also in older patients, by hampering proprotein convertase subtilisin/kexin type 9 (PCSK9) production. Olpasiran, directed against apolipoprotein(a) mRNA, prevents the assembly of lipoprotein(a) [Lp(a)] particles, a lipoprotein linked to an increased risk of ischemic CV disease and heart valve damage. Patisiran, binding transthyretin (TTR) mRNA, has demonstrated an ability to improve heart failure and polyneuropathy in patients with TTR amyloidosis, even in older patients with wild-type form. Zilebesiran, designed to reduce angiotensinogen secretion, significantly decreases systolic and diastolic blood pressure (BP). Thanks to their effectiveness, safety, and tolerability profile, and with a very low number of administrations in a year, thus overcoming adherence issues, these novel drugs are the leaders of a new era in molecular therapies for CV diseases. Full article

In the realm of gene therapy, a pivotal moment arrived with Paul Berg’s groundbreaking identification of the first recombinant DNA in 1972. This achievement set the stage for future breakthroughs. Conditions once considered undefeatable, like melanoma, pancreatic cancer, and a host of other ailments, are now being addressed at their root cause—the genetic level. Presently, the gene therapy landscape stands adorned with 22 approved in vivo and ex vivo products, including IMLYGIC, LUXTURNA, Zolgensma, Spinraza, Patisiran, and many more. In this comprehensive exploration, we delve into a rich assortment of 16 drugs, from siRNA, miRNA, and CRISPR/Cas9 to DNA aptamers and TRAIL/APO2L, as well as 46 carriers, from AAV, AdV, LNPs, and exosomes to naked mRNA, sonoporation, and magnetofection. The article also discusses the advantages and disadvantages of each product and vector type, as well as the current challenges faced in the practical use of gene therapy and its future potential. Full article

Gene therapy has emerged as a powerful tool to treat various diseases, such as cardiovascular diseases, neurological diseases, ocular diseases and cancer diseases. In 2018, the FDA approved Patisiran (the siRNA therapeutic) for treating amyloidosis. Compared with traditional drugs, gene therapy can directly correct the disease-related genes at the genetic level, which guarantees a sustained effect. However, nucleic acids are unstable in circulation and have short half-lives. They cannot pass through biological membranes due to their high molecular weight and massive negative charges. To facilitate the delivery of nucleic acids, it is crucial to develop a suitable delivery strategy. The rapid development of delivery systems has brought light to the gene delivery field, which can overcome multiple extracellular and intracellular barriers that prevent the efficient delivery of nucleic acids. Moreover, the emergence of stimuli-responsive delivery systems has made it possible to control the release of nucleic acids in an intelligent manner and to precisely guide the therapeutic nucleic acids to the target site. Considering the unique properties of stimuli-responsive delivery systems, various stimuli-responsive nanocarriers have been developed. For example, taking advantage of the physiological variations of a tumor (pH, redox and enzymes), various biostimuli- or endogenous stimuli-responsive delivery systems have been fabricated to control the gene delivery processes in an intelligent manner. In addition, other external stimuli, such as light, magnetic fields and ultrasound, have also been employed to construct stimuli-responsive nanocarriers. Nevertheless, most stimuli-responsive delivery systems are in the preclinical stage, and some critical issues remain to be solved for advancing the clinical translation of these nanocarriers, such as the unsatisfactory transfection efficiency, safety issues, complexity of manufacturing and off-target effects. The purpose of this review is to elaborate the principles of stimuli-responsive nanocarriers and to emphasize the most influential advances of stimuli-responsive gene delivery systems. Current challenges of their clinical translation and corresponding solutions will also be highlighted, which will accelerate the translation of stimuli-responsive nanocarriers and advance the development of gene therapy. 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

Background and aims. Hereditary transthyretin amyloidosis with polyneuropathy (ATTRv) is caused by mutations in the TTR gene, leading to misfolded monomers that aggregate generating amyloid fibrils. The clinical phenotype is heterogeneous, characterized by a multisystemic disease affecting the sensorimotor, autonomic functions along with other organs. Patisiran is a small interfering RNA acting as a TTR silencer approved for the treatment of ATTRv. Punctual and detailed instrumental biomarkers are on demand for ATTRv to measure the severity of the disease and monitor progression and response to treatment. Methods. Fifteen patients affected by ATTRv amyloidosis (66.4 ± 7.8 years, six males) were evaluated before the start of therapy with patisiran and after 9-months of follow-up. The clinical and instrumental evaluation included body weight and height; Coutinho stage; Neuropathy Impairment Score (NIS); Karnofsky performance status (KPS); Norfolk QOL Questionnaire; Six-minute walking test (6 MWT); nerve conduction studies; handgrip strength (HGS); and bioimpedance analysis (BIA). Results. Body composition significantly changed following the 9-months pharmacological treatment. In particular, the patients exhibited an increase in fat free mass, body cell mass, and body weight with a decrease in fat mass. A significant increase after 9 months of treatment was observed for the 6 MWT. Coutinho stage, KPS, NIS, NIS-W, nerve conduction studies, Norfolk, COMPASS-31 scale, and HGS remained unchanged. Conclusions. BIA might represent a useful tool to assess the effects of multiorgan damage in ATTRv and to monitor disease progression and response to treatments. More evidence is still needed for HGS. Patisiran stabilizes polyneuropathy and preserves motor strength by increasing muscle mass after 9 months of treatment. Full article

The aim of this research was to develop a simple and efficient ion-pair reagent-free chromatographic method for the separation and qualitative determination of oligonucleotide impurities, exemplified by synthesis of raw products of the two single strands of patisiran siRNA. The stationary phases with mixed hydrophobic/hydrophilic properties (cholesterol and alkylamide) were firstly used for this purpose with reversed-phased high-performance liquid chromatography. Several different chromatographic parameters were tested for their impact on impurities separation: type, concentration, pH of salt, as well as organic solvent type in the mobile phase. The pH was the most influential factor on the separation and signal intensities in mass spectrometry detection. Finally, the optimized method included the application of cholesterol stationary phase, with mobile phase containing 20 mM ammonium formate (pH 6.5) and methanol. It allowed good separation and the identification of most impurities within 25 min. Since not all closely related impurities could be fully resolved from the main peak in this oligonucleotide impurity profiling, two-dimensional liquid chromatography was used for peak purity determination of the target oligonucleotides. The Ethylene Bridged Hybrid (BEH) Amide column in hydrophilic interaction liquid chromatography was applied in the second dimension, allowing additional separation of three closely related impurities. Full article

Hereditary transthyretin amyloidosis (ATTRv; v for “variant”) is the most common form of hereditary amyloidosis, with an autosomal dominant inheritance and a variable penetrance. This disease has a significant variability in clinical presentation and multiorgan involvement. While kidney involvement in early-onset ATTRv has been reported in one-third of patients, in late-onset ATTRv it has generally been considered rare. In the present study, we describe trajectories of kidney function over time before and after treatment with gene silencing therapies in a cohort of 17 ATTRv patients with different mutations, coming from Italy (nine subjects treated with inotersen and eight patients treated with patisiran). The analysis of estimated glomerular filtration rate (eGFR) slopes revealed that the average change in eGFR was 0.01 mL/min/1.73 m² per month before initiation and −0.23 mL/min/1.73 m² per month during follow-up for inotersen and −0.62 mL/min/1.73 m² per month before initiation and −0.20 mL/min/1.73 m² per month during follow-up for patisiran. In conclusion, we did not observe any significant difference either between the two groups of treatment or within-group before and after therapy, so gene-silencing therapies may be considered safe for renal function in ATTRv and are not associated with a worsening of eGFR slope. Full article