Treatment Of Rare Diseases Research Articles

Current Status and Prospects of Viral Vector-Based Gene Therapy to Treat Kidney Diseases.

Inherited kidney diseases are among the leading causes of chronic kidney disease, reducing the quality of life and resulting in substantial socioeconomic impact. The advent of early genetic testing and the growing understanding of the molecular basis and pathophysiology of these disorders have opened avenues for novel treatment strategies. Viral vector-based gene therapies have evolved from experimental treatments for rare diseases to potent platforms that carry the intrinsic potential to provide a cure with a single application. Several gene therapy products have reached the market, and the numbers are only expected to increase. Still, none target inherited kidney diseases. Gene transfer to the kidney has lagged when compared to other tissue-directed therapies such as hepatic, neuromuscular, and ocular tissues. Systemic delivery of genetic information to tackle kidney disease is challenging. The pharma industry is taking steps to take on kidney disease and to translate the current research into the therapeutic arena. In this review, we provide an overview of the current viral vector-based approaches and their potential. We discuss advances in platforms and injection routes that have been explored to enhance gene delivery toward kidney cells in animal models, and how these can fuel the development of viable gene therapy products for humans.

Current situation and prospect for the diagnosis and treatment of pediatric critical rare diseases in China.

The onset of critical rare diseases (RDs) in children is rapid and dangerous, accompanied by a high mortality rate, which brings a heavy burden to both families and society. Multiple malformations, neuromuscular diseases, metabolic diseases, and heart diseases are the most common types of RDs in children of China, often manifesting with multiple organ dysfunction. At present, the diagnosis and treatment of critical RDs in children face challenges such as prolonged diagnosis time, a high misdiagnosis rate, limited treatment modalities, and a significant disease burden. However, with the progress in genetic testing technology, the establishment of multidisciplinary diagnosis and treatment platforms, and the implementation of relevant RD policies in China, children with critical RDs will received enhanced medical services, experience improved prognoses, and reintegrate into social life.

Non-viral delivery of nucleic acid for treatment of rare diseases of the muscle

Non-viral delivery of nucleic acid for treatment of rare diseases of the muscle

The role of early-phase trials and real-world evidence in drug development.

Phase 3 randomized controlled trials (RCTs), while the gold standard for treatment efficacy and safety, are not always feasible, are expensive, can be prolonged and can be limited in generalizability. Other under-recognized sources of evidence can also help advance drug development. Basic science, proof-of-concept studies and early-phase RCTs can provide evidence regarding the potential for clinical benefit. Real-world evidence generated from registries or observational datasets can provide insights into the treatment of rare diseases that often pose a challenge for trial recruitment. Pragmatic trials embedded in healthcare systems can assess the treatment effects in clinical settings among patient populations sometimes excluded from trials. This Perspective discusses potential sources of evidence that may be used to complement explanatory phase 3 RCTs and to speed the development of new cardiovascular medications. Content is derived from the 19th Global Cardiovascular Clinical Trialists meeting (December 2022), involving clinical trialists, patients, clinicians, regulators, funders and industry representatives.

The Italian breakthrough in CRISPR trials for rare diseases: a focus on beta-thalassemia and sickle cell disease treatment.

The development of gene therapy and the current advantageous method of clustered regularly interspaced short palindromic repeats (CRISPRs) has allowed the implementation of several clinical trials aimed at studying the possible efficacy of gene therapy for rare diseases. Rare diseases pose a global challenge, in that their collective impact on health systems is considerable, whereas their individually rare occurrence hinders research and development of efficient therapies. Despite the low prevalence of individual rare diseases, there are more than 7,000 defined rare diseases affecting 3.5–5.9% of the global population. Rare diseases are mostly chronic and approximately 80% are caused by genetic mutation with an early-life onset. In Italy, in 2021 were recorded more than 400,000 people with rare disease. Because of its location and history, Italy has an unfortunate statistic regarding the presence and prevalence of two rare genetic diseases, namely beta-thalassemia, of which there are about 90 million carriers worldwide, 400,000 of whom are actually affected, and sickle cell disease, with about 300 million carriers and 6.5 million people affected worldwide. Advancements in genomic studies allowed Italy to join clinical trials to study effective and resolving gene therapies for BT and SCD. This study reports on the impact of rare diseases in Italy, ongoing studies, and recent achievements in BT and SCD trials using the CRISPR method and remaining hurdles in the application of CRISPR technology to rare diseases, also taking a glimpse at the newest challenges and future opportunities in the genetic treatment for rare diseases.

Next-generation therapeutics for rare genetic disorders.

The therapeutic potential of the human genome has been explored through the development of next-generation therapeutics, which have had a high impact on treating genetic disorders. Classical treatments have traditionally focused on common diseases that require repeated treatments. However, with the recent advancements in the development of nucleic acids, utilizing DNA and RNA to modify or correct gene expression in genetic disorders, there has been a paradigm shift in the treatment of rare diseases, offering more potential one-time cure options. Advanced technologies that use CRISPR-Cas 9, antisense oligonucleotides, siRNA, miRNA, and aptamers are promising tools that have achieved successful breakthroughs in the treatment of various genetic disorders. The advancement in the chemistry of these molecules has improved their efficacy, reduced toxicity, and expanded their clinical use across a wide range of tissues in various categories of human disorders. However, challenges persist regarding the safety and efficacy of these advanced technologies in translating into clinical practice. This review mainly focuses on the potential therapies for rare genetic diseases and considers how next-generation techniques enable drug development to achieve long-lasting curative effects through gene inhibition, replacement, and editing.

Real-world evidence for coverage determination of treatments for rare diseases

Health technology assessment (HTA) decisions for pharmaceuticals are complex and evolving. New rare disease treatments are often approved more quickly through accelerated approval schemes, creating more uncertainties about clinical evidence and budget impact at the time of market entry. The use of real-world evidence (RWE), including early coverage with evidence development, has been suggested as a means to support HTA decisions for rare disease treatments. However, the collection and use of RWE poses substantial challenges. These challenges are compounded when considered in the context of treatments for rare diseases. In this paper, we describe the methodological challenges to developing and using prospective and retrospective RWE for HTA decisions, for rare diseases in particular. We focus attention on key elements of study design and analyses, including patient selection and recruitment, appropriate adjustment for confounding and other sources of bias, outcome selection, and data quality monitoring. We conclude by offering suggestions to help address some of the most vexing challenges. The role of RWE in coverage and pricing determination will grow. It is, therefore, necessary for researchers, manufacturers, HTA agencies, and payers to ensure that rigorous and appropriate scientific principles are followed when using RWE as part of decision-making.

Estimating rare disease prevalence and costs in the USA: a cohort study approach using the Healthcare Cost Institute claims data

ObjectiveThe study capitalised on national insurance claims data to gather information on patient characteristics and associated costs to better understand the diagnosis and treatment of rare diseases (RDs).Materials and methodsData...

Methodological and regulatory aspects of pharmaceutical development of biological products

The aim of the work was to conduct an analysis of the current state and current trends in the approval of drugs, as well as some aspects of the methodology for their development based on biological molecules and registration.Materials and methods. The material for the analysis was taken from the abstract databases of PubMed, Google Scholar and e-library.ru. The search was carried out using publications for the period from 2008 to 2023, the keywords were as follows: “biologicals”, “new drug approval”, “drug authorization”, “drug development”, “biosimilar”, taking into account various spellings.Results. Over the past 15 years, scientists have been observing revolutionary trends and processes in the field of the drug development, especially biopharmaceuticals. Significant advances have been made in gene, immune and cell therapies, resulting in the approval of such drugs more than doubling over the past ten years. The development of biological drugs includes the identification and testing of molecular targets and requires a deep understanding of the structure and functioning of the polypeptides involved in the development of the effect. The features of these active pharmaceutical substances are a high molecular weight, a complex three-dimensional structure and a high immunogenic potential. Preclinical and clinical studies of biologics have unique challenges. Selecting appropriate animal species, understanding the immunogenicity, and assessing pharmacodynamics and toxicological properties require a multilevel, detailed approach. The article discusses the regulatory framework under which these drugs are registered, summarizing the guidelines provided by international organizations such as the International Council for Harmonization and various national agencies.Conclusion. The analysis highlights the current advances and prospects in the development of biologics, highlighting their key role in future transformations in the treatment of rare diseases and oncology, approaching the era of personalized medicine. Monitoring the development directions and technological approaches, as well as the commitment to global methodological and regulatory aspects can become a catalyst in the development of the Russian pharmacology.

Utilization of Bacteriophage phi6 for the Production of High-Quality Double-Stranded RNA Molecules.

Double-stranded RNA (dsRNA) molecules are mediators of RNA interference (RNAi) in eukaryotic cells. RNAi is a conserved mechanism of post-transcriptional silencing of genes cognate to the sequences of the applied dsRNA. RNAi-based therapeutics for the treatment of rare hereditary diseases have recently emerged, and the first sprayable dsRNA biopesticide has been proposed for registration. The range of applications of dsRNA molecules will likely expand in the future. Therefore, cost-effective methods for the efficient large-scale production of high-quality dsRNA are in demand. Conventional approaches to dsRNA production rely on the chemical or enzymatic synthesis of single-stranded (ss)RNA molecules with a subsequent hybridization of complementary strands. However, the yield of properly annealed biologically active dsRNA molecules is low. As an alternative approach, we have developed methods based on components derived from bacteriophage phi6, a dsRNA virus encoding RNA-dependent RNA polymerase (RdRp). Phi6 RdRp can be harnessed for the enzymatic production of high-quality dsRNA molecules. The isolated RdRp efficiently synthesizes dsRNA in vitro on a heterologous ssRNA template of any length and sequence. To scale up dsRNA production, we have developed an in vivo system where phi6 polymerase complexes produce target dsRNA molecules inside Pseudomonas cells.

Development of trofinetide for the treatment of Rett syndrome: from bench to bedside.

Rett syndrome (RTT) is rare neurodevelopmental disorder caused by mutations in the MECP2 gene that encodes methyl-CpG-binding protein 2 (MeCP2), a DNA-binding protein with roles in epigenetic regulation of gene expression. Functional loss of MeCP2 results in abnormal neuronal maturation and plasticity, characterized by loss of verbal communication and loss of fine and gross motor function, among others. Trofinetide, a synthetic analog of glycine-proline-glutamate, was approved by the US Food and Drug Administration for the treatment of RTT in adult and pediatric patients aged 2years and older. Here, we present the development of trofinetide from bench research to clinical studies and emphasize how the collaboration between academia, the pharmaceutical industry, and patient advocacy led to the recent approval. The bench-to-bedside development of trofinetide underscores the value of collaboration between these groups in the development and approval of treatments for rare diseases.

Tofacitinib for the treatment of severe rare skin diseases: a narrative review.

Autoimmune bullous diseases, connective tissue diseases, and vasculitis represent a group of severe rare skin diseases. While glucocorticoids and immunosuppressive agents serve as standard treatments for these diseases, their efficacy is limited due to adverse side effects, indicating the need for alternative approaches. Biologics have been used in the management of some rare skin diseases. However, the use of biologics is associated with concerns, such as infection risk and high costs, prompting the quest for efficacious and cost-effective alternatives. This study discusses the safety issues associated with tofacitinib and its potential in treating rare skin diseases. This narrative review focuses on the pharmacodynamic properties of tofacitinib and its impact on the JAK/STAT pathway. In addition, we present a comprehensive discussion of the effects and mechanism of action of tofacitinib for each severe rare skin disease. This role of tofacitinib in treating severe rare skin diseases has been discussed, shedding light on its promising prospects as a treatment modality. Few reports of serious adverse events are available in patients treated with tofacitinib. We explored the mechanism of action, efficacy, and safety considerations of tofacitinib and found that it can be used as a treatment option for rare skin diseases. However, multicenter clinical studies are needed to confirm the efficacy and safety of JAK inhibitors.

Use of Mexiletine in Children: A Minireview

AbstractMexiletine is well-established sodium channel blocker that acts on cardiac myocytes and neurons. It has recently been repositioned as an orphan drug in the treatment of rare neuromuscular diseases in adults with nondystrophic myotonia. It has also long been used in some rare pediatric diseases in the areas of cardiopathy, epilepsy, neuromuscular diseases, and pain disorders. Here, we review the different uses of mexiletine reported in pediatrics, stating indications, efficacy, and tolerance. Special attention by health authorities to maintain access to mexiletine in rare pediatric diseases and further pediatric research in these rare syndromes are required.

Rare and complex diseases in focus: ChatGPT's role in improving diagnosis and treatment.

Rare and complex diseases pose significant challenges to both patients and healthcare providers. These conditions often present with atypical symptoms, making diagnosis and treatment a formidable task. In recent years, artificial intelligence and natural language processing technologies have shown great promise in assisting medical professionals in diagnosing and managing such conditions. This paper explores the role of ChatGPT, an advanced artificial intelligence model, in improving the diagnosis and treatment of rare and complex diseases. By analyzing its potential applications, limitations, and ethical considerations, we demonstrate how ChatGPT can contribute to better patient outcomes and enhance the healthcare system's overall effectiveness.

Identifying and Extracting Rare Diseases and Their Phenotypes with Large Language Models

PurposePhenotyping is critical for informing rare disease diagnosis and treatment, but disease phenotypes are often embedded in unstructured text. While natural language processing (NLP) can automate extraction, a major bottleneck is developing annotated corpora. Recently, prompt learning with large language models (LLMs) has been shown to lead to generalizable results without any (zero-shot) or few annotated samples (few-shot), but none have explored this for rare diseases. Our work is the first to study prompt learning for identifying and extracting rare disease phenotypes in the zero- and few-shot settings.MethodsWe compared the performance of prompt learning with ChatGPT and fine-tuning with BioClinicalBERT. We engineered novel prompts for ChatGPT to identify and extract rare diseases and their phenotypes (e.g., diseases, symptoms, and signs), established a benchmark for evaluating its performance, and conducted an in-depth error analysis.ResultsOverall, fine-tuning BioClinicalBERT resulted in higher performance (F1 of 0.689) than ChatGPT (F1 of 0.472 and 0.610 in the zero- and few-shot settings, respectively). However, ChatGPT achieved higher accuracy for rare diseases and signs in the one-shot setting (F1 of 0.778 and 0.725). Conversational, sentence-based prompts generally achieved higher accuracy than structured lists.ConclusionPrompt learning using ChatGPT has the potential to match or outperform fine-tuning BioClinicalBERT at extracting rare diseases and signs with just one annotated sample. Given its accessibility, ChatGPT could be leveraged to extract these entities without relying on a large, annotated corpus. While LLMs can support rare disease phenotyping, researchers should critically evaluate model outputs to ensure phenotyping accuracy.

Long-term efficacies of selective vasodilators in pulmonary arterial hypertension: a comprehensive comparison using a spontaneous reporting database.

There is no clinical evidence of differences in drugs associated with long-term survival in patients with pulmonary arterial hypertension (PAH) due to the small population and lack of information on death in Japanese medical database systems. This study evaluated whether patient data from a spontaneous reporting database could be used for comparing the effects of pulmonary vasodilators on long-term survival in PAH patients. PAH patient data reported in the Japanese Adverse Drug Event Report (JADER) database from April 2004 to July 2022 were extracted. Kaplan-Meier curves were used to compare survival times. Adjusted hazard ratios (aHRs) for all-cause mortality were determined using Cox proportional hazards models. Of 1969 PAH patients reported in the JADER database, 1208 were included in the survival analyses. The patient demographics were similar to those of the PAH population reported in the Japan Pulmonary Hypertension Registry. Among drugs targeting the prostacyclin pathway, epoprostenol was most associated with long-term survival (aHR, 0.38; 95% confidence interval (CI), 0.23-0.64). The PAH patients treated with endothelin receptor antagonists had improved survival, especially among the macitentan users (aHR, 0.30; 95% CI, 0.22-0.42). Sildenafil was associated with a poor prognosis in the PAH patients (aHR, 1.56; 95% CI, 1.19-2.04). Although our results must be interpreted with caution due to several limitations inherent to spontaneous reporting databases, our approach using the JADER database for survival analysis may provide useful information in limited situations such as the treatment of rare diseases including PAH.

Using automated text classification to explore uncertainty in NICE appraisals for drugs for rare diseases.

This study examined the application, feasibility, and validity of supervised learning models for text classification in appraisals for rare disease treatments (RDTs) in relation to uncertainty, and analyzed differences between appraisals based on the classification results. We analyzed appraisals for RDTs (n=94) published by the National Institute for Health and Care Excellence (NICE) between January 2011 and May 2023. We used Naïve Bayes, Lasso, and Support Vector Machine models in a binary text classification task (classifying paragraphs as either referencing uncertainty in the evidence base or not). To illustrate the results, we tested hypotheses in relation to the appraisal guidance, advanced therapy medicinal product (ATMP) status, disease area, and age group. The best performing (Lasso) model achieved 83.6 percent classification accuracy (sensitivity=74.4 percent, specificity=92.6 percent). Paragraphs classified as referencing uncertainty were significantly more likely to arise in highly specialized technology (HST) appraisals compared to appraisals from the technology appraisal (TA) guidance (adjusted odds ratio=1.44, 95 percent CI 1.09, 1.90, p=0.004). There was no significant association between paragraphs classified as referencing uncertainty and appraisals for ATMPs, non-oncology RDTs, and RDTs indicated for children only or adults and children. These results were robust to the threshold value used for classifying paragraphs but were sensitive to the choice of classification model. Using supervised learning models for text classification in NICE appraisals for RDTs is feasible, but the results of downstream analyses may be sensitive to the choice of classification model.

EVENT STUDY ON DRUG APPROVALS - IMPACT OF ORPHAN DRUG APPROVALS ON THE SHAREHOLDER VALUE OF PHARMACEUTICAL COMPANIES

The pharmaceutical industry is controversially discussed. Nevertheless, there is a con-sensus that the need for new medicines is undeniable. In particular, the treatment of rare diseases with orphan drugs is characterized by a high unmet medical need. Regulatory incentive schemes seek to stimulate orphan drug research and development (R&D). This is also reflected in the increasing approvals during the last two decades. Orphan drugs have gained relevance and become a more attractive business for pharmaceutical compa-nies (Blonda et al., 2021, p. 2)

Metabolic bone diseases : what's new in 2023

The sequential effects of romosozumab and denosumab in osteoporosis are shown in real-life, while the mechanisms of post-denosumab rebound are reviewed extensively. A network meta-analysis confirms the superiority of anabolics vs anti-resorptives on fracture reduction, while the latter shown a reduction of mortality in a large population-based study. Fracture risk prediction by FRAXPlus is improved. New meta-analyses confirm the benefits of Vitamin D on fractures and falls. Finally, multiples trials with new molecules for the treatment of rare bone diseases, including osteogenesis imperfecta, fibrous dysplasia and hypoparathyroidism, shown promising results.

Adeno-Associated Virus Engineering and Load Strategy for Tropism Modification, Immune Evasion and Enhanced Transgene Expression.

Gene therapy aims to add, replace or turn off genes to help treat disease. To date, the US Food and Drug Administration (FDA) has approved 14 gene therapy products. With the increasing interest in gene therapy, feasible gene delivery vectors are necessary for inserting new genes into cells. There are different kinds of gene delivery vectors including viral vectors like lentivirus, adenovirus, retrovirus, adeno-associated virus et al, and non-viral vectors like naked DNA, lipid vectors, polymer nanoparticles, exosomes et al, with viruses being the most commonly used. Among them, the most concerned vector is adeno-associated virus (AAV) because of its safety, natural ability to efficiently deliver gene into cells and sustained transgene expression in multiple tissues. In addition, the AAV genome can be engineered to generate recombinant AAV (rAAV) containing transgene sequences of interest and has been proven to be a safe gene vector. Recently, rAAV vectors have been approved for the treatment of various rare diseases. Despite these approvals, some major limitations of rAAV remain, namely nonspecific tissue targeting and host immune response. Additional problems include neutralizing antibodies that block transgene delivery, a finite transgene packaging capacity, high viral titer used for per dose and high cost. To deal with these challenges, several techniques have been developed. Based on differences in engineering methods, this review proposes three strategies: gene engineering-based capsid modification (capsid modification), capsid surface tethering through chemical conjugation (surface tethering), and other formulations loaded with AAV (virus load). In addition, the major advantages and limitations encountered in rAAV engineering strategies are summarized.