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Background/Aim: Leukodystrophies comprise a group of genetic white matter disorders that lead to progressive motor and cognitive impairment. Recent development of novel therapies has led to an increase in clinical trials for leukodystrophies. To enable recruitment of individuals with a leukodystrophy into clinical trials, clinical trial acceptability should be ascertained. We sought therefore, to identify the motivations for and barriers to clinical trial participation in addition to clinical trial features that may be of concern to individuals with a leukodystrophy and/or their carers. Methods: Adults with a leukodystrophy and parents/carers of individuals with a leukodystrophy were recruited through the Australian Leukodystrophy Registry and through online advertisements. Qualitative semi-structured interviews were used to explore participants views on what clinical trials involve, the perceived risks and benefits of clinical trials, their desire to participate in clinical trials and their personal experience with leukodystrophy. Thematic analysis of data was performed with co-coding of interview transcripts. Results: 5 interviews were held with parents of children with leukodystrophy, 4 with parents of adults with leukodystrophy and 3 with adults diagnosed with leukodystrophy. Motivations for clinical trial enrolment include access to potentially lifesaving novel treatments and improved prognostic outcomes. Participants were concerned about adverse clinical trial outcomes, including side effects and exacerbation of illness. Despite this, majority of participants were willing to try anything in clinical trials, demonstrating a high tolerance for first in human trials and trials utilising invasive treatment options. Conclusions: Interviewees communicated a strong desire to participate in interventional clinical trials involving novel therapies. To support enrolment into future leukodystrophy clinical trials we suggest the provision of transparent information regarding clinical trial treatments, consideration of alternative trial control measures, and inclusion of treating clinicians in the trial recruitment process. Clinicians play an integral role in initiating transparent conversations regarding trial risks and adverse outcomes. [ABSTRACT FROM AUTHOR]

Abstract Background/Aim Leukodystrophies comprise a group of genetic white matter disorders that lead to progressive motor and cognitive impairment. Recent development of novel therapies has led to an increase in clinical trials for leukodystrophies. To enable recruitment of individuals with a leukodystrophy into clinical trials, clinical trial acceptability should be ascertained. We sought therefore, to identify the motivations for and barriers to clinical trial participation in addition to clinical trial features that may be of concern to individuals with a leukodystrophy and/or their carers. Methods Adults with a leukodystrophy and parents/carers of individuals with a leukodystrophy were recruited through the Australian Leukodystrophy Registry and through online advertisements. Qualitative semi-structured interviews were used to explore participants views on what clinical trials involve, the perceived risks and benefits of clinical trials, their desire to participate in clinical trials and their personal experience with leukodystrophy. Thematic analysis of data was performed with co-coding of interview transcripts. Results 5 interviews were held with parents of children with leukodystrophy, 4 with parents of adults with leukodystrophy and 3 with adults diagnosed with leukodystrophy. Motivations for clinical trial enrolment include access to potentially lifesaving novel treatments and improved prognostic outcomes. Participants were concerned about adverse clinical trial outcomes, including side effects and exacerbation of illness. Despite this, majority of participants were willing to try anything in clinical trials, demonstrating a high tolerance for first in human trials and trials utilising invasive treatment options. Conclusions Interviewees communicated a strong desire to participate in interventional clinical trials involving novel therapies. To support enrolment into future leukodystrophy clinical trials we suggest the provision of transparent information regarding clinical trial treatments, consideration of alternative trial control measures, and inclusion of treating clinicians in the trial recruitment process. Clinicians play an integral role in initiating transparent conversations regarding trial risks and adverse outcomes.

Shivani Srivastava,1,* Anuradha Tyagi,2,* Vishakha Anand Pawar,3,* Nawaid Hussain Khan,4,* Kavita Arora,5,6 Chaitenya Verma,7,8 Vinay Kumar9 1Department of Pathology, School of Medicine, Yale University, New Haven, CT, USA; 2Department of cBRN, Institute of Nuclear Medicine and Allied Science, Delhi, India; 3The University of Texas MD Anderson Cancer Center, Houston, TX, USA; 4Faculty of Medicine, Ala-Too International University, Bishkek, Kyrgyz Republic; 5Advanced Instrumentation Research Facility, Jawaharlal Nehru University, New Delhi, India; 6School of Computational & Integrative Sciences, Jawaharlal Nehru University, New Delhi, India; 7Department of Pathology, Wexner Medical Center, Ohio State University, Columbus, OH, USA; 8Department of Biotechnology, SSET, Sharda University, Greater Noida, 201306, India; 9Pennsylvania State University Hershey Medical Center, 500 University Dr, Heshey, PA, USA*These authors contributed equally to this workCorrespondence: Chaitenya Verma; Vinay Kumar, Email chaitenya999@gmail.com; vinayktyagi07@gmail.comAbstract: The CAR-T cell therapy has marked the dawn of new era in the cancer therapeutics and cell engineering techniques. The review emphasizes on the challenges that obstruct the therapeutic efficiency caused by cell toxicities, immunosuppressive tumor environment, and decreased T cell infiltration. In the interest of achieving the overall survival (OS) and event-free survival (EFS) of patients, the conceptual background of potential target selection and various CAR-T cell design techniques are described which can minimize the off-target effects, reduce toxicity, and thus increase the resilience of CAR-T cell treatment in the haematological malignancies as well as in solid tumors. Furthermore, it delves into cutting-edge technologies like gene editing and synthetic biology, providing new opportunities to enhance the functionality of CAR-T cells and overcome mechanisms of immune evasion. This review provides a comprehensive understanding of the complex and diverse aspects of CAR-T cell-based gene treatments, including both scientific and clinical aspects. By effectively addressing the obstacles and utilizing the capabilities of cutting-edge technology, CAR-T cell therapy shows potential in fundamentally changing immunotherapy and reshaping the approach to cancer treatment.Keywords: CAR-T cells, immune checkpoint inhibitors, gene therapies, gene editing, predictive biomarkers

To illustrate the financial consequences of implementing different managed entry agreements (managed entry agreements for the Dutch healthcare system for autologous gene therapy atidarsagene autotemcel [Libmeldy]), while also providing a first systematic guidance on how to construct managed entry agreements to aid future reimbursement decision making and create patient access to high-cost, one-off potentially curative therapies. Three payment models were compared: (1) an arbitrary 60% price discount, (2) an outcome-based spread payment with discounts, and (3) an outcome-based spread payment linked to a willingness to pay model with discounts. Financial consequences were estimated for full responders (A), patients responding according to the predicted clinical pathway presented in health technology assessment reports (B), and unstable responders (C). The associated costs for an average patient during the time frame of the payment agreement, the total budget impact, and associated benefits expressed in quality-adjusted life-years of the patient population were calculated. When patients responded according to the predicted clinical pathway presented in health technology assessment reports (scenario B), implementing outcome-based reimbursement models (models 2 and 3) had lower associated budget impacts while gaining similar benefits compared with the discount (scenario 1, €8.9 million to €6.6 million vs €9.2 million). In the case of unstable responders (scenario C), costs for payers are lower in the outcome-based scenarios (€4.1 million and €3.0 million, scenario 2C and 3C, respectively) compared with implementing the discount (€9.2 million, scenario 1C). Outcome-based models can mitigate the financial risk of reimbursing atidarsagene autotemcel. This can be considerably beneficial over simple discounts when clinical performance was similar to or worse than predicted. • High-priced one-off gene therapies, such as atidarsagene autotemcel (AA, Libmeldy), are innovative treatments that often fulfill an unmet medical need. However, they represent a reimbursement challenge to many healthcare systems because of substantial upfront costs, which are often incurred all at once, with the claim of durability of effects. • More guidance is needed to inform decision makers and healthcare payers which type of reimbursement and payment model is suitable. Therefore, a framework and calculation tool were used to help decision makers weigh the different payment scenarios for AA and help them negotiate and implement an outcome-based spread payment model. • The results from this calculation tool demonstrated that for AA, outcome-based models could considerably mitigate the financial risks for the payer in cases when clinical performance was similar or worse than predicted. The exact outcomes of the calculations should be treated with caution as the discount rates used are arbitrary and should be updated with values from decision makers. [ABSTRACT FROM AUTHOR]

Abstract Drug exceptional access programs (DEAPs) exist across Canada to address gaps in access to pharmaceuticals. These programs circumvent standard procedures, raising epistemic, economic, social and political issues. This commentary provides insights into these issues by revealing the context and procedures on which these programs depend.

Abstract Background The emergence of high-priced potential cures has sparked significant health policy discussions in South Korea, where the healthcare system is funded through a single-payer National Health Insurance model. We conducted focus group interviews (FGIs) and accompanying surveys with diverse stakeholders to comprehensively understand related issues and find better solutions to the challenges brought by these technologies. Methods From October to November 2022, 11 FGIs were conducted with stakeholders from various sectors, including government payers, policy and clinical experts, civic and patient organisations, and the pharmaceutical industry, involving a total of 25 participants. These qualitative discussions were supplemented by online surveys to effectively capture and synthesise stakeholder perspectives. Results Affordability was identified as a critical concern by 84% of stakeholders, followed by clinical uncertainty (76%) and limited value for money (72%). Stakeholders expressed a preference for both financial-based controls and outcome-based pricing strategies to mitigate these challenges. Despite the support for outcome-based refunds, payers raised concerns about the feasibility of instalment payment models, whether linked to outcomes or not, due to the specific challenges of the Korean reimbursement system and the potential risk of ‘cumulative liabilities’ from ongoing payments for previously administered treatments. In addition, the FGIs highlighted the need for clear budgetary limits for drugs with high uncertainties, with mixed opinions on the creation of special silo funds (64.0% agreement). Less than half (48%) endorsed the use of external reference pricing, currently applied to such essential drugs in South Korea. A significant majority (84%), predominantly non-pharma stakeholders, advocated for addressing cost-effectiveness uncertainty through re-assessment once long-term clinical data become available. Conclusions This study uncovers a broad agreement among stakeholders on the need for more effective value assessment methodologies for high-priced potential cures, stressing the importance of more robust and comprehensive re-assessment supported by long-term data collection, rather than primarily relying on external reference pricing. Each type of stakeholders exhibited a cautious approach to their specific uncertainties, suggesting that new funding strategies should accommodate these uncertainties with predefined guidelines and agreements prior to the initiation of managed entry agreements.

Refractory hypercholesterolemia (RH) is characterized by the failure of patients to achieve therapeutic targets for low-density lipoprotein-cholesterol (LDL-C) despite receiving maximal tolerable doses of standard lipid-lowering treatments. It predominantly impacts individuals with familial hypercholesterolemia (FH), thereby elevating the risk of cardiovascular complications. The prevalence of RH is now recognized to be substantially greater than previously thought. This review provides a comprehensive insight into current and emerging therapies for RH patients, including groundbreaking genetic-based therapeutic approaches. The review places emphasis on the dependency of therapies on low-density lipoprotein receptors (LDLRs) and highlights the critical role of considering LDLR activity in RH patients for individualization of the treatment. Refractory hypercholesterolemia (RH) is a condition where patients are unable to get below target levels of 'bad' cholesterol despite receiving maximum doses of standard treatments. It is commonly present in those with a genetic disorder, called familial hypercholesterolemia (FH), known to increase the risk of heart complications. RH's prevalence is now understood to be higher than previously believed and this review offers insights into current and emerging therapies for RH, including genetic-based treatments. It stresses the importance of the mechanistic pathways behind cholesterol clearance, particularly low-density lipoprotein receptor (LDLR) activity, in RH treatment customization. Article highlights Refractory hypercholesterolemia – definition, epidemiological data. Therapeutic targets for the treatment of refractory hypercholesterolemiaLow-density lipoprotein receptor (LDLR)-dependent therapies targeting cholesterol production and upregulating LDLR The efficacy of lipid-lowering treatments that depend on low-density lipoprotein receptor (LDLR) activity may be limited in patients with importantly reduced LDLR function, particularly among homozygous familial hypercholesterolemia (HoFH) patients with very low or no residual LDLR activity. 3-Hydroxy-3-Methylglutaryl-Coenzyme A (HMG-CoA) inhibitors (statins) Statins as first-line lipid-lowering drugs, mechanism, efficacy, side effects. Adenosine triphosphate (ATP)-citrate lyase inhibitor Bempedoic acid is a good therapeutic option for statin-intolerant patients. Mechanism of action, efficacy, side effects. PCSK9 inhibitors Review of therapeutic options aimed at PCSK9 inhibition including monoclonal antibodies, siRNA, and therapeutic genome editing. LDLR gene replacement therapy and gene editing strategies Clinical trial of LDLR gene replacement therapy in HoFH, potential of clustered regularly interspaced short palindromic repeats (CRISPR)-based methods. LDLR-independent therapiesAngiopoietin-like 3 inhibition Angiopoietin-like 3 (ANGPTL3) inhibition as a therapeutic target which is LDLR independent. Efficacy of monoclonal antibodies, siRNA, and therapeutic genome editing. MTP inhibition Mechanism of action, efficacy, and side effects of lomitapide. CETP inhibition Drug development history, efficacy, and limitations of use. Inhibition of apolipoprotein B (apoB) formation Mechanism of action, efficacy, and side effects leading to Mipomersen cessation. Cholesterol absorption inhibition: ezetimibe Mechanism of action, efficacy, and side effects of ezetimibe. Agents targeting Lipoprotein (a) (Lp[a]) Atherogenic mechanisms of Lipoprotein (a) (Lp[a]). Lp(a) lowering the potential of currently available drugs. Novel therapies aimed at Lp(a) reduction are available within clinical trials. Combination of therapies Summary of lipid-lowering potential of drug combinations. LDL and Lp(a) apheresis Types of aphereses, indications, limitations of use. High-density lipoprotein (HDL) autotransfusion The efficacy of plasma delipidation system (PDS-2TM) in patients with atherosclerosis, who do not respond adequately to available pharmacological options. Refractory hypercholesterolemia beyond LDL-cholesterol: residual cardiovascular risk associated with remnant cholesterol The role of remnant cholesterol in triglyceride-rich lipoproteins in residual cardiovascular risk and potential therapeutic role of anti-apolipoprotein C-III (APOC3) therapy. Refractory hypercholesterolemia in the pediatric population Summary of available therapeutic options for pediatric population with severe hypercholesterolemia. Conclusion Refractory hypercholesterolemia appears to be a more prevalent condition than might be initially perceived. In terms of its management, it is of particular importance to custom-tailor the appropriate treatment regimen depending on the underlying etiology. The principal determinant for therapy selection should be based on LDL receptor activity. [ABSTRACT FROM AUTHOR]

The etiology of sensorineural hearing loss is heavily influenced by genetic mutations, with approximately 80% of cases attributed to genetic causes and only 20% to environmental factors. Over 100 non-syndromic deafness genes have been identified in humans thus far. In non-syndromic sensorineural hearing impairment, around 75–85% of cases follow an autosomal recessive inheritance pattern. In recent years, groundbreaking advancements in molecular gene therapy for inner-ear disorders have shown promising results. Experimental studies have demonstrated improvements in hearing following a single local injection of adeno-associated virus-derived vectors carrying an additional normal gene or using ribozymes to modify the genome. These pioneering approaches have opened new possibilities for potential therapeutic interventions. Following the PRISMA criteria, we summarized the AAV gene therapy experiments showing hearing improvement in the preclinical phases of development in different animal models of DFNB deafness and the AAV gene therapy programs currently in clinical phases targeting autosomal recessive non syndromic hearing loss. A total of 17 preclinical studies and 3 clinical studies were found and listed. Despite the hurdles, there have been significant breakthroughs in the path of HL gene therapy, holding great potential for providing patients with novel and effective treatment. [ABSTRACT FROM AUTHOR]

Drug exceptional access programs (DEAPs) exist across Canada to address gaps in access to pharmaceuticals. These programs circumvent standard procedures, raising epistemic, economic, social and political issues. This commentary provides insights into these issues by revealing the context and procedures on which these programs depend. [ABSTRACT FROM AUTHOR]

Background: The emergence of high-priced potential cures has sparked significant health policy discussions in South Korea, where the healthcare system is funded through a single-payer National Health Insurance model. We conducted focus group interviews (FGIs) and accompanying surveys with diverse stakeholders to comprehensively understand related issues and find better solutions to the challenges brought by these technologies. Methods: From October to November 2022, 11 FGIs were conducted with stakeholders from various sectors, including government payers, policy and clinical experts, civic and patient organisations, and the pharmaceutical industry, involving a total of 25 participants. These qualitative discussions were supplemented by online surveys to effectively capture and synthesise stakeholder perspectives. Results: Affordability was identified as a critical concern by 84% of stakeholders, followed by clinical uncertainty (76%) and limited value for money (72%). Stakeholders expressed a preference for both financial-based controls and outcome-based pricing strategies to mitigate these challenges. Despite the support for outcome-based refunds, payers raised concerns about the feasibility of instalment payment models, whether linked to outcomes or not, due to the specific challenges of the Korean reimbursement system and the potential risk of 'cumulative liabilities' from ongoing payments for previously administered treatments. In addition, the FGIs highlighted the need for clear budgetary limits for drugs with high uncertainties, with mixed opinions on the creation of special silo funds (64.0% agreement). Less than half (48%) endorsed the use of external reference pricing, currently applied to such essential drugs in South Korea. A significant majority (84%), predominantly non-pharma stakeholders, advocated for addressing cost-effectiveness uncertainty through re-assessment once long-term clinical data become available. Conclusions: This study uncovers a broad agreement among stakeholders on the need for more effective value assessment methodologies for high-priced potential cures, stressing the importance of more robust and comprehensive re-assessment supported by long-term data collection, rather than primarily relying on external reference pricing. Each type of stakeholders exhibited a cautious approach to their specific uncertainties, suggesting that new funding strategies should accommodate these uncertainties with predefined guidelines and agreements prior to the initiation of managed entry agreements. [ABSTRACT FROM AUTHOR]

Adeno‐associated virus (AAV)‐based therapies are recognized as one of the most potent next‐generation treatments for inherited and genetic diseases. However, several biological and technological aspects of AAV vectors remain a critical issue for their widespread clinical application. Among them, the limited capacity of the AAV genome significantly hinders the development of AAV‐based gene therapy. In this context, genetically modified transgenes compatible with AAV are opening up new opportunities for unlimited gene therapies for many genetic disorders. Recent advances in de novo protein design and remodelling are paving the way for new, more efficient and targeted gene therapeutics. Using computational and genetic tools, AAV expression cassette and transgenic DNA can be split, miniaturized, shuffled or created from scratch to mediate efficient gene transfer into targeted cells. In this review, we highlight recent advances in AAV‐based gene therapy with a focus on its use in translational research. We summarize recent research and development in gene therapy, with an emphasis on large transgenes (>4.8 kb) and optimizing strategies applied by biomedical companies in the research pipeline. We critically discuss the prospects for AAV‐based treatment and some emerging challenges. We anticipate that the continued development of novel computational tools will lead to rapid advances in basic gene therapy research and translational studies. [ABSTRACT FROM AUTHOR]

The etiology of sensorineural hearing loss is heavily influenced by genetic mutations, with approximately 80% of cases attributed to genetic causes and only 20% to environmental factors. Over 100 non-syndromic deafness genes have been identified in humans thus far. In non-syndromic sensorineural hearing impairment, around 75–85% of cases follow an autosomal recessive inheritance pattern. In recent years, groundbreaking advancements in molecular gene therapy for inner-ear disorders have shown promising results. Experimental studies have demonstrated improvements in hearing following a single local injection of adeno-associated virus-derived vectors carrying an additional normal gene or using ribozymes to modify the genome. These pioneering approaches have opened new possibilities for potential therapeutic interventions. Following the PRISMA criteria, we summarized the AAV gene therapy experiments showing hearing improvement in the preclinical phases of development in different animal models of DFNB deafness and the AAV gene therapy programs currently in clinical phases targeting autosomal recessive non syndromic hearing loss. A total of 17 preclinical studies and 3 clinical studies were found and listed. Despite the hurdles, there have been significant breakthroughs in the path of HL gene therapy, holding great potential for providing patients with novel and effective treatment.

Background: Gene replacement therapy (GRT) is a treatment method used to combat or prevent various diseases. Its high one-off cost constitutes a major obstacle for successful market access. This paper aims to assess and discuss the applicability of amortization in models, such as costeffectiveness models (CEMs) and budget impact models (BIMs) informing HTA recommendations and reimbursement decisions. Methods and findings: A hypothetical CEA and BIA were considered. The objective was to compare the GRT with and without amortization. A straight-line amortization model was used. The CEM and BIM were considered and assessed based on two set of scenarios: considering different amortization duration or different discounting rate. The impact of amortization against the total cost of gene therapy was assessed for all the scenarios. The cost difference between GRT with and without amortization in relation to its total cost was -$58,855, thus amortization does not have a significant impact on the results and conclusions of the cost-effectiveness analysis. For BIM in the base case, amortization had no impact on the results. Conclusion: Amortization has negligible impact on the results of CEM and total BIM and no impact on the conclusions from the model. One exception is the budget impact in case of an amortization period longer than the time horizon of BIM, where a half of the GRT price is moved beyond the model time horizon. Amortization has a distinguishing effect from an accounting perspective, but it does not have any implication for payers. [ABSTRACT FROM AUTHOR]

Summary: We review the evidence for the presence of stem/progenitor cells in the heart and the preclinical and clinical data using diverse cell types for the therapy of cardiac diseases. We highlight the failure of adult stem/progenitor cells to ameliorate heart function in most cardiac diseases, with the possible exception of refractory angina. The use of pluripotent stem cell-derived cardiomyocytes is analysed as a viable alternative therapeutic option but still needs further research at preclinical and clinical stages. We also discuss the use of direct reprogramming of cardiac fibroblasts into cardiomyocytes and the use of extracellular vesicles as therapeutic agents in ischemic and non-ischemic cardiac diseases. Finally, gene therapies and genome editing for the treatment of hereditary cardiac diseases, ablation of genes responsible for atherosclerotic disease, or modulation of gene expression in the heart are discussed.

Abstract Adeno‐associated virus (AAV)‐based therapies are recognized as one of the most potent next‐generation treatments for inherited and genetic diseases. However, several biological and technological aspects of AAV vectors remain a critical issue for their widespread clinical application. Among them, the limited capacity of the AAV genome significantly hinders the development of AAV‐based gene therapy. In this context, genetically modified transgenes compatible with AAV are opening up new opportunities for unlimited gene therapies for many genetic disorders. Recent advances in de novo protein design and remodelling are paving the way for new, more efficient and targeted gene therapeutics. Using computational and genetic tools, AAV expression cassette and transgenic DNA can be split, miniaturized, shuffled or created from scratch to mediate efficient gene transfer into targeted cells. In this review, we highlight recent advances in AAV‐based gene therapy with a focus on its use in translational research. We summarize recent research and development in gene therapy, with an emphasis on large transgenes (>4.8 kb) and optimizing strategies applied by biomedical companies in the research pipeline. We critically discuss the prospects for AAV‐based treatment and some emerging challenges. We anticipate that the continued development of novel computational tools will lead to rapid advances in basic gene therapy research and translational studies.

ABSTRACTBackground: Gene replacement therapy (GRT) is a treatment method used to combat or prevent various diseases. Its high one-off cost constitutes a major obstacle for successful market access. This paper aims to assess and discuss the applicability of amortization in models, such as cost-effectiveness models (CEMs) and budget impact models (BIMs) informing HTA recommendations and reimbursement decisions.Methods and findings: A hypothetical CEA and BIA were considered. The objective was to compare the GRT with and without amortization. A straight-line amortization model was used. The CEM and BIM were considered and assessed based on two set of scenarios: considering different amortization duration or different discounting rate. The impact of amortization against the total cost of gene therapy was assessed for all the scenarios.The cost difference between GRT with and without amortization in relation to its total cost was -$58,855, thus amortization does not have a significant impact on the results and conclusions of the cost-effectiveness analysis. For BIM in the base case, amortization had no impact on the results.Conclusion: Amortization has negligible impact on the results of CEM and total BIM and no impact on the conclusions from the model. One exception is the budget impact in case of an amortization period longer than the time horizon of BIM, where a half of the GRT price is moved beyond the model time horizon. Amortization has a distinguishing effect from an accounting perspective, but it does not have any implication for payers.

Positron emission tomography (PET) is a noninvasive modality for in vivo assessment of pathophysiological processes in living subjects. PET imaging detects γ-rays produced by the decay of a radioactive compound (radiotracer) to infer the location of the binding of that compound within the brain, thus revealing the location of the receptor to which it bound. PET reporter systems are used to monitor the progression of disease and the expression of therapeutic transgenes, for instance in the context of stem cell and molecular genetic therapies. Successful PET reporter systems for the brain are improving the treatment of neurological diseases, and hold promise for the advancement of novel treatments for neuropsychiatric disorders. Positron emission tomography (PET) can be used as a noninvasive method to longitudinally monitor and quantify the expression of proteins in the brain in vivo. It can be used to monitor changes in biomarkers of mental health disorders, and to assess therapeutic interventions such as stem cell and molecular genetic therapies. The utility of PET monitoring depends on the availability of a radiotracer with good central nervous system (CNS) penetration and high selectivity for the target protein. This review evaluates existing methods for the visualization of reporter proteins and/or protein function using PET imaging, focusing on engineered systems, and discusses possible approaches for future success in the development of high-sensitivity and high-specificity PET reporter systems for the brain. [ABSTRACT FROM AUTHOR]

One of the main causes of heart failure is cardiomyopathies. Among them, the most common is hypertrophic cardiomyopathy (HCM), characterized by thickening of the left ventricular muscle. This article focuses on HCM and other cardiomyopathies with myocardial hypertrophy, including Fabry disease, Pompe disease, and Danon disease. The genetics and pathogenesis of these diseases are described, as well as current and experimental treatment options, such as pharmacological intervention and the potential of gene therapies. Although genetic approaches are promising and have the potential to become the best treatments for these diseases, further research is needed to evaluate their efficacy and safety. This article describes current knowledge and advances in the treatment of the aforementioned cardiomyopathies. [ABSTRACT FROM AUTHOR]

Genetic diseases cause numerous complex and intractable pathologies. DNA sequences encoding each human's complexity and many disease risks are contained in the mitochondrial genome, nuclear genome, and microbial metagenome. Diagnosis of these diseases has unified around applications of next-generation DNA sequencing. However, translating specific genetic diagnoses into targeted genetic therapies remains a central goal. To date, genetic therapies have fallen into three broad categories: bulk replacement of affected genetic compartments with a new exogenous genome, nontargeted addition of exogenous genetic material to compensate for genetic errors, and most recently, direct correction of causative genetic alterations using gene editing. Generalized methods of diagnosis, therapy, and reagent delivery into each genetic compartment will accelerate the next generations of curative genetic therapies. We discuss the structure and variability of the mitochondrial, nuclear, and microbial metagenomic compartments, as well as the historical development and current practice of genetic diagnostics and gene therapies targeting each compartment.

Heart failure is a cardiovascular condition, leading to fatigue, breathlessness, and fluid retention. It affects around 56 million people globally and is a leading cause of hospitalization and mortality. Its prevalence is rising due to aging populations and lifestyle factors. Managing heart failure demands a multidisciplinary approach, encompassing medications, lifestyle modifications, and often medical devices or surgeries. The treatment burden is substantial, impacting patients’ daily lives and straining healthcare systems. Improving early detection, novel therapies, and patient education are crucial for alleviating the burden and enhancing the quality of life. There are notable advancements in the field of heart failure treatment and prevention. We will discuss significant pharmacological and device advances related to heart failure, including angiotensin receptor–neprilysin inhibitor, sodium–glucose co-transporter inhibition, glucagon-like peptide-1 agonist, cardiac resynchronization therapy, cardiac contractility modulation, mechanical circulatory support devices, and transcatheter valve interventions. We will also review novel therapies on the horizon, emerging technologies like CRISPR-based treatments for genetic anomalies, and the involvement of artificial intelligence in heart failure detection and management.

Cell and gene therapies promise durable benefits but face financial challenges from the uncertainty in their performance. Value-based purchasing arrangements (VBPAs) can address uncertainty but have been inhibited in the US by the Medicaid Drug Rebate Program (MDRP) approach to determining Medicaid Best Price (MBP) rebates. The likely effectiveness of MDRP reform proposals enabling VBPAs is examined in this study for durable cell and gene therapies. Monte Carlo simulations examined three potential reforms (Multiple Best Prices, Bundled Sales, and National Pooling) to determine the impact on payment misalignment, the required payer size to participate, and the percentage of total lives covered by a VBPA. Simulation results suggest that 11% to 54% of commercial US lives would be feasibly covered by a VBPA depending on reform type and condition size. MPB reform achieved the highest commercial contracted percentage and lowest misalignment for commercial payers compared to National Pooling and Bundled Sales. State Medicaid plan results suggest lower extreme misalignment across all successfully contracted instances than commercial payers. The Multiple Best Prices will likely enable VBPAs for many durable cell and gene therapies and larger payers. Further reforms may be needed to extend VBPAs to ultra-orphan conditions. [ABSTRACT FROM AUTHOR]

Despite the success of severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) vaccines, there remains a clear need for new classes of preventatives for respiratory viral infections due to vaccine hesitancy, lack of sterilizing immunity, and for at‐risk patient populations, including the immunocompromised. While many neutralizing antibodies have been identified, and several approved, to treat COVID‐19, systemic delivery, large doses, and high costs have the potential to limit their widespread use, especially in low‐ and middle‐income countries. To use these antibodies more efficiently, an inhalable formulation is developed that allows for the expression of mRNA‐encoded, membrane‐anchored neutralizing antibodies in the lung to mitigate SARS‐CoV‐2 infections. First, the ability of mRNA‐encoded, membrane‐anchored, anti‐SARS‐CoV‐2 antibodies to prevent infections in vitro is demonstrated. Next, it is demonstrated that nebulizer‐based delivery of these mRNA‐expressed neutralizing antibodies potently abrogates disease in the hamster model. Overall, these results support the use of nebulizer‐based mRNA expression of neutralizing antibodies as a new paradigm for mitigating respiratory virus infections. [ABSTRACT FROM AUTHOR]

Neurodegenerative disorders (NDDs), such as Alzheimer's disease (AD) and Parkinson's Disease (PD), are a group of heterogeneous diseases that mainly affect central nervous system (CNS) functions. A subset of NDDs exhibit CNS dysfunction and muscle degeneration, as observed in Gangliosidosis 1 (GM1) and late stages of PD. Neuromuscular disorders (NMDs) are a group of diseases in which patients show primary progressive muscle weaknesses, including Duchenne Muscular Dystrophy (DMD), Pompe disease, and Spinal Muscular Atrophy (SMA). NDDs and NMDs typically have a genetic component, which affects the physiological functioning of critical cellular processes, leading to pathogenesis. Currently, there is no cure or efficient treatment for most of these diseases. More than 200 clinical trials have been completed or are currently underway in order to establish safety, tolerability, and efficacy of promising gene therapy approaches. Thus, gene therapy-based therapeutics, including viral or non-viral delivery, are very appealing for the treatment of NDDs and NMDs. In particular, adeno-associated viral vectors (AAV) are an attractive option for gene therapy for NDDs and NMDs. However, limitations have been identified after systemic delivery, including the suboptimal capacity of these therapies to traverse the blood–brain barrier (BBB), degradation of the particles during the delivery, high reactivity of the patient's immune system during the treatment, and the potential need for redosing. To circumvent these limitations, several preclinical and clinical studies have suggested intrathecal (IT) delivery to target the CNS and peripheral organs via cerebrospinal fluid (CSF). CSF administration can vastly improve the delivery of small molecules and drugs to the brain and spinal cord as compared to systemic delivery. Here, we review AAV biology and vector design elements, different therapeutic routes of administration, and highlight CSF delivery as an attractive route of administration. We discuss the different aspects of neuromuscular and neurodegenerative diseases, such as pathogenesis, the landscape of mutations, and the biological processes associated with the disease. We also describe the hallmarks of NDDs and NMDs as well as discuss current therapeutic approaches and clinical progress in viral and non-viral gene therapy and enzyme replacement strategies for those diseases. [ABSTRACT FROM AUTHOR]

Abstract Despite the success of severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2) vaccines, there remains a clear need for new classes of preventatives for respiratory viral infections due to vaccine hesitancy, lack of sterilizing immunity, and for at‐risk patient populations, including the immunocompromised. While many neutralizing antibodies have been identified, and several approved, to treat COVID‐19, systemic delivery, large doses, and high costs have the potential to limit their widespread use, especially in low‐ and middle‐income countries. To use these antibodies more efficiently, an inhalable formulation is developed that allows for the expression of mRNA‐encoded, membrane‐anchored neutralizing antibodies in the lung to mitigate SARS‐CoV‐2 infections. First, the ability of mRNA‐encoded, membrane‐anchored, anti‐SARS‐CoV‐2 antibodies to prevent infections in vitro is demonstrated. Next, it is demonstrated that nebulizer‐based delivery of these mRNA‐expressed neutralizing antibodies potently abrogates disease in the hamster model. Overall, these results support the use of nebulizer‐based mRNA expression of neutralizing antibodies as a new paradigm for mitigating respiratory virus infections.

Simple Summary: Despite the success in hematology, chimeric antigen receptor T cell therapies have shown, to date, unsatisfactory results in other clinical settings. A remarkable number of different CAR-based approaches have been developed, varying not only the specific antigen to be targeted, but also the type of cell to be modified, the costimulatory domain, and the additional signals incorporated to overcome solid-tumor-specific challenges. This variety of options has created a broad diversification of CAR approaches that, on one hand, may accelerate the identification of successful strategies, but on the other hand, may hamper the interpretation of clinical results and the overall advancement of the field. In this review, we present the most promising approaches under development and discuss their specific advantages and challenges to facilitate the identification of winning strategies. Chimeric antigen receptor T cell therapies are revolutionizing the clinical practice of hematological tumors, whereas minimal progresses have been achieved in the solid tumor arena. Multiple reasons have been ascribed to this slower pace: The higher heterogeneity, the hurdles of defining reliable tumor antigens to target, and the broad repertoire of immune escape strategies developed by solid tumors are considered among the major ones. Currently, several CAR therapies are being investigated in preclinical and early clinical trials against solid tumors differing in the type of construct, the cells that are engineered, and the additional signals included with the CAR constructs to overcome solid tumor barriers. Additionally, novel approaches in development aim at overcoming some of the limitations that emerged with the approved therapies, such as large-scale manufacturing, duration of manufacturing, and logistical issues. In this review, we analyze the advantages and challenges of the different approaches under development, balancing the scientific evidences supporting specific choices with the manufacturing and regulatory issues that are essential for their further clinical development. [ABSTRACT FROM AUTHOR]

A persistent barrier to the cure and treatment of neurological diseases is the limited ability of the central and peripheral nervous systems to undergo neuroregeneration and repair. Recent efforts have turned to regeneration of various cell types through cellular reprogramming of native cells as a promising therapy to replenish lost or diminished cell populations in various neurological diseases. This review provides an in-depth analysis of the current viral vectors, genes of interest, and target cellular populations that have been studied, as well as the challenges and future directions of these novel therapies. Furthermore, the mechanisms by which cellular reprogramming could be optimized as treatment in neurological diseases and a review of the most recent cellular reprogramming in vitro and in vivo studies will also be discussed. [ABSTRACT FROM AUTHOR]

The number of gene therapies in clinical trials and moving toward licensure is increasing. Most gene therapies are designed to achieve long-term effects, but at licensure the data to support claims of long-term durability are often limited, as long-term monitoring studies are often part of post-approval commitments by companies. Health technology assessors must therefore assess the potential for the long-term durability of a product and the potential cost–effectiveness based on the data available. The authors explored the benefit of strengthening the ability to infer durability of effect using analogue category data. Different analogue categories were assessed for the potential to substantiate claims of sustainability of effect for gene therapies by leveraging biological plausibility arguments. The authors propose a pathway for identifying potential analogues. Such a pathway should help establish plausible or theoretical long-term outcomes that can be considered in value assessments of gene therapies. Many diseases, affecting all parts of the body, can be treated with gene therapy. Gene therapies make changes to a person's genes by either replacing or inactivating a gene that is causing disease or by adding new genes that can fight diseases such as cancers. These therapies have the potential to cure patients of the disease for their lifetime. When decisions are being made over whether gene therapies are safe and work well in patients, it can be difficult to understand if they will maintain their benefits to a person over a lifetime, as they have only been studied in clinical trials for a much shorter amount of time. In this paper, the authors explore whether information around the benefits of therapies that work in a similar way, or target similar diseases, can be used to strengthen an understanding of how well newer therapies work over a long period of time. The authors propose a pathway that can be followed to identify the suitability of a comparison between different therapies and how the evidence of benefit over time can be interpreted. This information will be useful for developers of gene therapies who are trying to generate evidence of long-term benefit to patients, as well as for decision makers who need to understand how well these gene therapies will work over a patient's lifetime. [ABSTRACT FROM AUTHOR]

Objectives: X-linked retinitis pigmentosa (XLRP) is a rare inherited retinal disease with no available treatment. Gene therapies in clinical trials will pose challenges for health technology assessment (HTA) if found to be safe and effective. We evaluated 2 of these challenges, namely acceptability and difficulties in assessing value beyond short-term patient health and healthcare savings and discounting in economic evaluation., Methods: We conducted a narrative literature review on the socioeconomic burden of XLRP to identify relevant components of value for a hypothetical gene therapy from a societal perspective and to assess their relative importance. We compared the resulting value profile against the value frameworks of three European HTA agencies. We also reviewed their guidelines on discounting and potential discounting issues specific to XLRP., Results: Much of the societal value of an XLRP gene therapy is likely to originate from productivity effects, carer spillovers, and value elements related to patient uncertainty. The evidence on these effects, however, is often limited, making it difficult for HTA agencies to assess them. Cost-effectiveness results are likely to be highly sensitive to the discount rate, and discounting will compound the effects of omitting important sources of value., Conclusions: We have identified and detailed important components of societal value, key evidence gaps, and potential discounting issues for an XLRP gene therapy, which can inform future value assessments. Many of these may apply to gene therapies in other disease areas. Revisiting existing HTA approaches is recommended to ensure these are fit for purpose for such new classes of treatment., Competing Interests: Author Disclosures Author disclosure forms can be accessed below in the Supplemental Material section., (Copyright © 2024. Published by Elsevier Inc.)

Abstract Cellular therapies have become an important part of clinical care. The treatment of patients with cell therapies often involves the collection of autologous cells at the medical center treating the patient, the shipment of these cells to a centralized manufacturing site, and the return of the cryopreserved clinical cell therapy to the medical center treating the patient for storage until infusion. As this activity grows, cell processing laboratories at many academic medical centers are involved with many different autologous products manufactured by several different centralized laboratories. The handling of these products by medical center-based cell therapy laboratories is complicated and resource-intensive since each centralized manufacturing laboratory has unique methods for labeling, storing, shipping, receiving, thawing, and infusing the cells. The field would benefit from the development of more uniform practices. The development of a coordinating center similar to those established to facilitate the collection, shipping, and transplantation of hematopoietic stem cells from unrelated donors would also be beneficial. In summary, the wide range of practices involved with labeling, shipping, freezing, thawing, and infusing centrally manufactured autologous cellular therapies lack efficiency and consistency and puts patients at risk. More uniform practices are needed.

Introduction: With the development of gene therapy for people with haemophilia (PWH), it is important to understand how people impacted by haemophilia (PIH) and clinicians prioritise haemophilia treatment attributes to support informed treatment decisions. Objective: To examine the treatment attribute preferences of PIH and clinical experts in the United Kingdom (UK) and to develop a profile of gene therapy characteristics fit for use in future discrete choice experiments (DCEs). Methods: Semi‐structured interviews were conducted with PIH (n = 14) and clinical experts (n = 6) who ranked pre‐defined treatment attributes by importance. Framework analysis was conducted to identify key themes and treatment attributes; points were allocated based on the rankings. Synthesis of results by a multidisciplinary group informed development of a profile of gene therapy characteristics for use in future research. Results: Key themes identified by PIH and clinical experts included patient relevant features and the importance of 'informed decision making'. The six top‐ranked treatment attributes were 'effect on factor level' (79 points), 'uncertainty regarding long‐term risks' (57 points), 'impact on daily life' (41 points), 'frequency of monitoring' (33 points), 'impact on ability to participate in physical activity' (29 points), and 'uncertainty regarding long‐term benefits' (28 points). The final treatment characteristics were categorised as therapeutic option, treatment effectiveness, safety concerns, impact on self‐management and quality of life (role limitations). Conclusion: We identified several gene therapy characteristics important to PIH and clinicians in the UK. These characteristics will be used in a future DCE to further investigate patient preferences for gene therapy. [ABSTRACT FROM AUTHOR]

The optimization of upstream and downstream processes for production of recombinant adeno-associated virus (rAAV) with consistent quality depends on the ability to rapidly characterize critical quality attributes (CQAs). In the context of rAAV production, the virus titer, capsid content, and aggregation are identified as potential CQAs, affecting the potency, purity, and safety of rAAV-mediated gene therapy products. Analytical methods to measure these attributes commonly suffer from long turnaround times or low throughput for process development, although rapid, high-throughput methods are beginning to be developed and commercialized. These methods are not yet well established in academic or industrial practice, and supportive data are scarce. Here, we review both established and upcoming analytical methods for the quantification of rAAV quality attributes. In assessing each method, we highlight the progress toward rapid, at-line characterization of rAAV. Furthermore, we identify that a key challenge for transitioning from traditional to newer methods is the scarcity of academic and industrial experience with the latter. This literature review serves as a guide for the selection of analytical methods targeting quality attributes for rapid, high-throughput process characterization during process development of rAAV-mediated gene therapies.

Advanced therapy medicinal products (ATMPs) constitute therapeutic agents based on obtained cells, tissues or genes representing a novel treatment opportunity in medicine. In addition, ATMPs are administered into the cells or tissues of humans from the patient's own cells, donors, or genetically modified cells. Recently, the field of developing ATMPs has become a point of attention due to the clinical efficacy expected in defeating incurable diseases such as cancers and neurodegenerative disorders. Currently, there are two modes regarding the distribution of ATMPs. First, ATMPs that might be legally authorized for marketing. Second, the patients are able to access unapproved ATMPs through the hospital exemption (HE) or clinical practice program or through the compassionate use and expanded access program. The aim of this review is to discuss state-of-the-art knowledge on the regulation of ATMPs and provide regulatory recommendations. [ABSTRACT FROM AUTHOR]

Parkinson’s disease (PD) is one of the most debilitating brain diseases. Despite the availability of symptomatic treatments, response towards the health of PD patients remains scarce. To fulfil the medical needs of the PD patients, an efficacious and etiological treatment is required. In this review, we have compiled the information covering limitations of current therapeutic options in PD, novel drug targets for PD, and finally, the role of some critical beneficial natural products to control the progression of PD.

Introduction: The limited evidence in the clinical trials of gene therapies (GTs) posed substantial challenges for a reliable health technology assessment (HTA). This paper provides insights into the relationship between the background of diseases and the health economics assessment of GTs.Areas covered: The impacts of differentiated severity and unmet needs of genetic diseases, on the economic analysis of GTs, were discussed.Expert opinion: GTs offer a potential cure or significant clinical improvement, while limitations in clinical evidence constitute major obstacles for a robust assessment of clinical effectiveness and economic outcomes. This uncertainty may be balanced by the severity of the targeted condition and the associated unmet needs, thus leading to a relatively higher acceptance for GTs. Overtime, HTA agencies will become more demanding on comprehensive evidence of long-term effectiveness. With a growing number of GTs on the horizon, to what extent the unmet needs of previously devastating diseases will be fulfilled remain unclear. Nonetheless, comparative studies, either with a historical control group or existing treatments, will be necessary to demonstrate the additional benefits associated with GTs. [ABSTRACT FROM AUTHOR]

Gene therapies (GTs) are considered to be a paradigm-shifting class of treatments with the potential to treat previously incurable diseases or those with significant unmet treatment needs. However, considerable challenges remain in their health technology assessment (HTA), mainly stemming from the inability to perform robust clinical trials to convince decision-makers to pay the high prices for the potential long-term treatment benefits provided. This article aims to review the recommendations that have been published for evidence generation and economic analysis for GTs against the feasibility of their implementation within current HTA decision analysis frameworks. After reviewing the systematically identified literature, we found that questions remain on the appropriateness of GT evidence generation, considering that additional, broader values brought by GTs seem insufficiently incorporated within proposed analytic methods. In cases where innovative methods are proposed, HTA organizations remain highly conservative and resistant to change their reference case and decision analysis framework. Such resistances are largely attributed to the substantial evidence uncertainty, resource-consuming administration process, and the absence of consensus on the optimized methodology to balance all the advantages and potential pitfalls of GTs.

Treating neuroinflammation‐related injuries and disorders through manipulation of neuroinflammation functions is being heralded as a new therapeutic strategy. In this study, a novel pectic galactan (PG) polysaccharide based gene therapy approach is developed for targeting reactive gliosis in neuroinflammation. Galectin‐3 (Gal‐3) is a cell protein with a high affinity to β‐galactoside sugars and is highly expressed in reactive gliosis. Since PG carries galactans, it can target reactive gliosis via specific carbohydrate interaction between galactan and Gal‐3 on the cell membrane, and therefore can be utilized as a carrier for delivering genes to these cells. The carrier is synthesized by modifying quaternary ammonium groups on the PG. The resulting quaternized PG (QPG) is found to form complexes with plasmid DNA with a mean diameter of 100 nm and have the characteristics required for targeted gene therapy. The complexes efficiently condense large amounts of plasmid per particle and successfully bind to Gal‐3. The in vivo study shows that the complexes are biocompatible and safe for administration and can selectively transfect reactive glial cells of an induced cortical lesion. The results confirm that this PG‐based delivery system is a promising platform for targeting Gal‐3 overexpressing neuroinflammation cells for treating neuroinflammation‐related injuries and neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

A persistent barrier to the cure and treatment of neurological diseases is the limited ability of the central and peripheral nervous systems to undergo neuroregeneration and repair. Recent efforts have turned to regeneration of various cell types through cellular reprogramming of native cells as a promising therapy to replenish lost or diminished cell populations in various neurological diseases. This review provides an in-depth analysis of the current viral vectors, genes of interest, and target cellular populations that have been studied, as well as the challenges and future directions of these novel therapies. Furthermore, the mechanisms by which cellular reprogramming could be optimized as treatment in neurological diseases and a review of the most recent cellular reprogramming in vitro and in vivo studies will also be discussed.

Parkinson’s disease (PD) is a common neurodegenerative disease typified by a movement disorder consisting of bradykinesia, rest tremor, rigidity, and postural instability. Treatment options for PD are limited, with most of the current approaches based on restoration of dopaminergic tone in the striatum. However, these do not alter disease course and do not treat the non-dopamine-dependent features of PD such as freezing of gait, cognitive impairment, and other non-motor features of the disorder, which often have the greatest impact on quality of life. As understanding of PD pathogenesis grows, novel therapeutic avenues are emerging. These include treatments that aim to control the symptoms of PD without the problematic side effects seen with currently available treatments and those that are aimed towards slowing pathology, reducing neuronal loss, and attenuating disease course. In this latter regard, there has been much interest in drug repurposing (the use of established drugs for a new indication), with many drugs being reported to affect PD-relevant intracellular processes. This approach offers an expedited route to the clinic, given that pharmacokinetic and safety data are potentially already available. In terms of better symptomatic therapies that are also regenerative, gene therapies and cell-based treatments are beginning to enter clinical trials, and developments in other neurosurgical strategies such as more nuanced deep brain stimulation approaches mean that the landscape of PD treatment is likely to evolve considerably over the coming years. In this review, we provide an overview of the novel therapeutic approaches that are close to, or are already in, clinical trials.

Cellular therapies have become an important part of clinical care. The treatment of patients with cell therapies often involves the collection of autologous cells at the medical center treating the patient, the shipment of these cells to a centralized manufacturing site, and the return of the cryopreserved clinical cell therapy to the medical center treating the patient for storage until infusion. As this activity grows, cell processing laboratories at many academic medical centers are involved with many different autologous products manufactured by several different centralized laboratories. The handling of these products by medical center-based cell therapy laboratories is complicated and resource-intensive since each centralized manufacturing laboratory has unique methods for labeling, storing, shipping, receiving, thawing, and infusing the cells. The field would benefit from the development of more uniform practices. The development of a coordinating center similar to those established to facilitate the collection, shipping, and transplantation of hematopoietic stem cells from unrelated donors would also be beneficial. In summary, the wide range of practices involved with labeling, shipping, freezing, thawing, and infusing centrally manufactured autologous cellular therapies lack efficiency and consistency and puts patients at risk. More uniform practices are needed. [ABSTRACT FROM AUTHOR]

Thalassemia is one of the important challenges of the health system in Iran. Recently the medicinal drug of luspatercept and gene therapy have opened new horizons for thalassemia treatment. The present article aims to evaluate the attitude of thalassemics in Iran about the new treatments. In this research, data collection through the virtual space has been practiced. The patients were required to declare their opinion on the aforementioned treatments. Finally, 128 male and 204 female plus 1 who did not specify their gender answered the questions. The results showed that despite patients' positive attitude towards new treatments, their treatment experiences as well as the expenses of the new treatment practices are cause of concern. Moreover, the social problems like unemployment among thalassemics place impact on their perspective about treatment changes. Based on the findings of the present research, providing patients with more information about new treatment regimen and making the their expenses compatible with the economic status of the developing countries would be effective in making the new treatments accessible to all eligible patients. [ABSTRACT FROM AUTHOR]