Community consensus for Heparan sulfate as a biomarker to support accelerated approval in Neuronopathic Mucopolysaccharidoses.

Mucopolysaccharidoses (MPS) disorders are a group of ultra-rare, inherited, lysosomal storage diseases caused by enzyme deficiencies that result in accumulation of glycosaminoglycans (GAGs) in cells throughout the body including the brain, typically leading to early death. Current treatments do not address the progressive cognitive impairment observed in patients with neuronopathic MPS disease. The rarity and clinical heterogeneity of these disorders as well as pre-existing brain disease in clinically diagnosed patients make the development of new therapeutics utilizing a traditional regulatory framework extremely challenging. Children with neuronopathic MPS disorders will likely sustain irreversible brain damage if randomized to a placebo or standard-of-care treatment arm that does not address brain disease. The United States Food and Drug Administration (FDA) recognized these challenges, and, in 2020, issued final guidance for industry on slowly progressive, low-prevalence, rare diseases with substrate deposition that result from single enzyme defects, outlining a path for generating evidence of effectiveness to support accelerated approval based on reduction of substrate accumulation [1]. Neuronopathic MPS disorders, which are characterized by the accumulation of the GAG heparan sulfate (HS) in the brain, fit the intended disease characteristics for which this guidance was written, but to date, this guidance has not yet been applied to any therapeutic candidate for MPS. In February 2024, the Reagan-Udall Foundation for the FDA convened a public workshop for representatives from the FDA, patient advocacy groups, clinical and basic science research, and industry to explore a case study of using cerebrospinal fluid (CSF) HS as a relevant biomarker to support accelerated approval of new therapeutics for neuronopathic MPS disorders. This review provides a summary of the MPS presentations at the workshop and perspective on the path forward for neuronopathic MPS disorders.

Advancements in CRISPR-Based Therapies for Genetic Modulation in Neurodegenerative Disorders.

: Neurodegenerative disorders pose significant challenges in the realm of healthcare, as these conditions manifest in complex, multifaceted ways, often attributed to genetic anomalies. With the emergence of CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) technology, a new frontier has been unveiled in the quest for targeted, precise genetic manipulation. This abstract explores the recent advancements and potential applications of CRISPR-based therapies in addressing genetic components contributing to various neurodegenerative disorders. The review delves into the foundational principles of CRISPR technology, highlighting its unparalleled ability to edit genetic sequences with unprecedented precision. In addition, it talks about the latest progress in using CRISPR to target specific genetic mutations linked to neurodegenerative diseases like Huntington's disease, Alzheimer's disease, amyotrophic lateral sclerosis (ALS), and Parkinson's disease. It talks about the most important studies and trials that show how well and safely CRISPR-based therapies work. This shows how this technology can change genetic variants that cause diseases. Notably, the discussion emphasizes the challenges and ethical considerations associated with the implementation of CRISPR in clinical settings, including off-target effects, delivery methods, and long-term implications. Furthermore, the article explores the prospects and potential hurdles in the widespread application of CRISPR technology for treating neurodegenerative disorders. It touches upon the need for continued research, improved delivery mechanisms, and ethical frameworks to ensure responsible and equitable access to these groundbreaking therapies.

Use of biomarkers in clinical trials and future developments that will help identify novel biomarkers.

Engineering new solutions for therapeutic benefit in Amyotrophic Lateral Sclerosis (ALS) has proved a difficult task to accomplish. This is largely the reflection of complexities at multiple levels, that require solutions to improve cost-effectiveness and outcomes. The main obstacle related to the condition's clinical heterogeneity, chiefly the broad difference in survival observed among ALS patients, imposes large populations studies and long follow-up to evaluate any efficacy. The emerging solution is composite clinical and biological parameters enabling prognostic stratification into homogeneous phenotypes for more affordable studies. From a therapeutic development perspective, the choice of a medicinal product requires the availability of treatment-specific biomarkers of target engagement to identify off-target effects based on the compound's putative modality of action. More importantly, there are no established biomarkers of treatment response that can complement clinical outcome measures and support futility and end of treatment analyses of efficacy. Ultimately the onus rests on the development of biomarkers encompassing the unmet needs of clinical trial design, from inclusion to efficacy. These readouts of the pathological process may be used in combination with clinical and paraclinical outcome measured, significantly reducing the time and financial burden of clinical studies. Progress towards a biomarker-driven clinical trial design in ALS has been possible thanks to the accurate detection of neurofilaments and of other immunological mediators in biological fluids with the disease progression, a step change enabling the testing of novel therapeutic agents in a new clinical trial setting. However, further progress remains to be made to find treatment specific target engagement biomarkers along with readouts of treatment response that can be reliably applied to all emerging therapies and clinical studies. Here we will cover the basic notions of biomarker development in ALS clinical trials, the most crucial unanswered questions and the unmet needs in the ALS biomarkers space.

Microphysiological systems as models for immunologically 'cold' tumors.

The tumor microenvironment (TME) is a diverse milieu of cells including cancerous and non-cancerous cells such as fibroblasts, pericytes, endothelial cells and immune cells. The intricate cellular interactions within the TME hold a central role in shaping the dynamics of cancer progression, influencing pivotal aspects such as tumor initiation, growth, invasion, response to therapeutic interventions, and the emergence of drug resistance. In immunologically 'cold' tumors, the TME is marked by a scarcity of infiltrating immune cells, limited antigen presentation in the absence of potent immune-stimulating signals, and an abundance of immunosuppressive factors. While strategies targeting the TME as a therapeutic avenue in 'cold' tumors have emerged, there is a pressing need for novel approaches that faithfully replicate the complex cellular and non-cellular interactions in order to develop targeted therapies that can effectively stimulate immune responses and improve therapeutic outcomes in patients. Microfluidic devices offer distinct advantages over traditional in vitro 3D co-culture models and in vivo animal models, as they better recapitulate key characteristics of the TME and allow for precise, controlled insights into the dynamic interplay between various immune, stromal and cancerous cell types at any timepoint. This review aims to underscore the pivotal role of microfluidic systems in advancing our understanding of the TME and presents current microfluidic model systems that aim to dissect tumor-stromal, tumor-immune and immune-stromal cellular interactions in various 'cold' tumors. Understanding the intricacies of the TME in 'cold' tumors is crucial for devising effective targeted therapies to reinvigorate immune responses and overcome the challenges of current immunotherapy approaches.

Defining clinical endpoints in limb girdle muscular dystrophy: a GRASP-LGMD study.

BACKGROUND: The Limb Girdle Muscular Dystrophies (LGMDs) are characterized by progressive weakness of the shoulder and hip girdle muscles as a result of over 30 different genetic mutations. This study is designed to develop clinical outcome assessments across the group of disorders. METHODS/DESIGN: The primary goal of this study is to evaluate the utility of a set of outcome measures on a wide range of LGMD phenotypes and ability levels to determine if it would be possible to use similar outcomes between individuals with different phenotypes. We will perform a multi-center, 12-month study of 188 LGMD patients within the established Genetic Resolution and Assessments Solving Phenotypes in LGMD (GRASP-LGMD) Research Consortium, which is comprised of 11 sites in the United States and 2 sites in Europe. Enrolled patients will be clinically affected and have mutations in CAPN3 (LGMDR1), ANO5 (LGMDR12), DYSF (LGMDR2), DNAJB6 (LGMDD1), SGCA (LGMDR3), SGCB (LGMDR4), SGCD (LGMDR6), or SGCG (LGMDR5, or FKRP-related (LGMDR9). DISCUSSION: To the best of our knowledge, this will be the largest consortium organized to prospectively validate clinical outcome assessments (COAs) in LGMD at its completion. These assessments will help clinical trial readiness by identifying reliable, valid, and responsive outcome measures as well as providing data driven clinical trial decision making for future clinical trials on therapeutic agents for LGMD. The results of this study will permit more efficient clinical trial design. All relevant data will be made available for investigators or companies involved in LGMD therapeutic development upon conclusion of this study as applicable. TRIAL REGISTRATION: Clinicaltrials.gov NCT03981289; Date of registration: 6/10/2019.

TET2 mutation as prototypic clonal hematopoiesis lesion.

Loss of function TET2 mutation (TET2MT) is one of the most frequently observed lesions in clonal hematopoiesis (CH). TET2 a member TET-dioxygenase family of enzymes that along with TET1 and TET3, progressively oxidize 5-methyl cytosine (mC) resulting in regulated demethylation of promoter, enhancer and silencer elements of the genome. This process is critical for efficient transcription that determine cell lineage fate, proliferation and survival and the maintenance of the genomic fidelity with aging of the organism. Partial or complete loss-of-function TET2 mutations create regional and contextual DNA hypermethylation leading to gene silencing or activation that result in skewed myeloid differentiation and clonal expansion. In addition to myeloid skewing, loss of TET2 creates differentiation block and provides proliferative advantage to hematopoietic stem and progenitor cells (HSPCs). TET2MT is a prototypical lesion in CH, since the mutant clones dominate during stress hematopoiesis and often associates with evolution of myeloid malignancies. TET2MT clones has unique privilege to create and persist in pro-inflammatory milieu. Despite extensive knowledge regarding biochemical mechanisms underlying distorted myeloid differentiation, and enhanced self-replication of TET2MT HSPC, the mechanistic link of various pathogenesis associated with TET2 loss in CHIP is less understood. Here we review the recent development in TET2 biology and its probable mechanistic link in CH with aging and inflammation. We also explored the therapeutic strategies of targeting TET2MT associated CHIP and the utility of targeting TET2 in normal hematopoiesis and somatic cell reprograming. We explore the biochemical mechanisms and candidate therapies that emerged in last decade of research.

Defining Clinical Endpoints in Limb Girdle Muscular Dystrophy: A GRASP-LGMD study.

Background: The Limb Girdle Muscular Dystrophies (LGMDs) are characterized by progressive weakness of the shoulder and hip girdle muscles as a result of over 30 different genetic mutations. This study is designed to develop clinical outcome assessments across the group of disorders. Methods/design: The primary goal of this study is to evaluate the utility of a set of outcome measures on a wide range of LGMD phenotypes and ability levels to determine if it would be possible to use similar outcomes between individuals with different phenotypes. We will perform a multi-center, 12-month study of 188 LGMD patients within the established Genetic Resolution and Assessments Solving Phenotypes in LGMD (GRASP-LGMD) Research Consortium, which is comprised of 11 sites in the United States and 2 sites in Europe. Enrolled patients will be clinically affected and have mutations in CAPN3 (LGMDR1), ANO5 (LGMDR12), DYSF (LGMDR2), DNAJB6 (LGMDD1), SGCA (LGMDR3), SGCB (LGMDR4), SGCD (LGMDR6), or SGCG (LGMDR5, or FKRP-related (LGMDR9). Discussion: To the best of our knowledge, this will be the largest consortium organized to prospectively validate clinical outcome assessments (COAs) in LGMD at its completion. These assessments will help clinical trial readiness by identifying reliable, valid, and responsive outcome measures as well as providing data driven clinical trial decision making for future clinical trials on therapeutic agents for LGMD. The results of this study will permit more efficient clinical trial design. All relevant data will be made available for investigators or companies involved in LGMD therapeutic development upon conclusion of this study as applicable. Trial registration: clinicaltrials.gov NCT03981289; Date of registration: 6/10/2019.

Particulate matter exposure and neurodegenerative diseases: A comprehensive update on toxicity and mechanisms.

Exposure to particulate matter (PM) has been associated with a range of health impacts, including neurological abnormalities that affect neurodevelopment, neuroplasticity, and behavior. Recently, there has been growing interest in investigating the possible relationship between PM exposure and the onset and progression of neurodegenerative diseases, such as Alzheimer's disease, Parkinson's disease, Huntington's disease, and multiple sclerosis. However, the precise mechanism by which PM affects neurodegeneration is still unclear, even though several epidemiological and animal model studies have provided mechanistic insights. This article presents a review of the current research on the neurotoxicity of PM and its impact on neurodegenerative diseases. This review summarizes findings from epidemiological and animal model studies collected through searches in Google Scholar, PubMed, Web of Science, and Scopus. This review paper also discusses the reported effects of PM exposure on the central nervous system and highlights research gaps and future directions. The information presented in this review may inform public health policies aimed at reducing PM exposure and may contribute to the development of new treatments for neurodegenerative diseases. Further mechanistic and therapeutic research will be needed to fully understand the relationship between PM exposure and neurodegenerative diseases.

Multifaceted Roles of ALK Family Receptors and Augmentor Ligands in Health and Disease: A Comprehensive Review.

This review commemorates the 10-year anniversary of the discovery of physiological ligands Augα (Augmentor α; ALKAL2; Fam150b) and Augß (Augmentor ß; ALKAL1; Fam150a) for anaplastic lymphoma kinase (ALK) and leukocyte tyrosine kinase (LTK), previously considered orphan receptors. This manuscript provides an in-depth review of the biophysical and cellular properties of ALK family receptors and their roles in cancer, metabolism, pain, ophthalmology, pigmentation, central nervous system (CNS) function, and reproduction. ALK and LTK receptors are implicated in the development of numerous cancers, and targeted inhibition of their signaling pathways can offer therapeutic benefits. Additionally, ALK family receptors are involved in regulating body weight and metabolism, modulating pain signaling, and contributing to eye development and pigmentation. In the CNS, these receptors play a role in synapse modulation, neurogenesis, and various psychiatric pathologies. Lastly, ALK expression is linked to reproductive functions, with potential implications for patients undergoing ALK inhibitor therapy. Further research is needed to better understand the complex interactions of ALK family receptors and Aug ligands and to repurpose targeted therapy for a wide range of human diseases.

Data Mining of Microarray Datasets in Translational Neuroscience.

Data mining involves the computational analysis of a plethora of publicly available datasets to generate new hypotheses that can be further validated by experiments for the improved understanding of the pathogenesis of neurodegenerative diseases. Although the number of sequencing datasets is on the rise, microarray analysis conducted on diverse biological samples represent a large collection of datasets with multiple web-based programs that enable efficient and convenient data analysis. In this review, we first discuss the selection of biological samples associated with neurological disorders, and the possibility of a combination of datasets, from various types of samples, to conduct an integrated analysis in order to achieve a holistic understanding of the alterations in the examined biological system. We then summarize key approaches and studies that have made use of the data mining of microarray datasets to obtain insights into translational neuroscience applications, including biomarker discovery, therapeutic development, and the elucidation of the pathogenic mechanisms of neurodegenerative diseases. We further discuss the gap to be bridged between microarray and sequencing studies to improve the utilization and combination of different types of datasets, together with experimental validation, for more comprehensive analyses. We conclude by providing future perspectives on integrating multi-omics, to advance precision phenotyping and personalized medicine for neurodegenerative diseases.

A Comprehensive Review on Neuroimmunology: Insights from Multiple Sclerosis to Future Therapeutic Developments.

This review delves into neuroimmunology, focusing on its relevance to multiple sclerosis (MS) and potential treatment advancements. Neuroimmunology explores the intricate relationship between the immune system and the central nervous system (CNS). Understanding these mechanisms is vital for grasping the pathophysiology of diseases like MS and for devising innovative treatments. This review introduces foundational neuroimmunology concepts, emphasizing the role of immune cells, cytokines, and blood-brain barrier in CNS stability. It highlights how their dysregulation can contribute to MS and discusses genetic and environmental factors influencing MS susceptibility. Cutting-edge research methods, from omics techniques to advanced imaging, have revolutionized our understanding of MS, offering valuable diagnostic and prognostic tools. This review also touches on the intriguing gut-brain axis, examining how gut microbiota impacts neuroimmunological processes and its potential therapeutic implications. Current MS treatments, from immunomodulatory drugs to disease-modifying therapies, are discussed alongside promising experimental approaches. The potential of personalized medicine, cell-based treatments, and gene therapy in MS management is also explored. In conclusion, this review underscores neuroimmunology's significance in MS research, suggesting that a deeper understanding could pave the way for more tailored and effective treatments for MS and similar conditions. Continued research and collaboration in neuroimmunology are essential for enhancing patient outcomes.

Omics-based deep learning approaches for lung cancer decision-making and therapeutics development.

Lung cancer has been the most common and the leading cause of cancer deaths globally. Besides clinicopathological observations and traditional molecular tests, the advent of robust and scalable techniques for nucleic acid analysis has revolutionized biological research and medicinal practice in lung cancer treatment. In response to the demands for minimally invasive procedures and technology development over the past decade, many types of multi-omics data at various genome levels have been generated. As omics data grow, artificial intelligence models, particularly deep learning, are prominent in developing more rapid and effective methods to potentially improve lung cancer patient diagnosis, prognosis and treatment strategy. This decade has seen genome-based deep learning models thriving in various lung cancer tasks, including cancer prediction, subtype classification, prognosis estimation, cancer molecular signatures identification, treatment response prediction and biomarker development. In this study, we summarized available data sources for deep-learning-based lung cancer mining and provided an update on recent deep learning models in lung cancer genomics. Subsequently, we reviewed the current issues and discussed future research directions of deep-learning-based lung cancer genomics research.

Hepatitis Delta Virus-Host Protein Interactions: From Entry to Egress.

Hepatitis delta virus (HDV) is the smallest known human virus and causes the most severe form of human viral hepatitis, yet it is still not fully understood how the virus replicates and how it interacts with many host proteins during replication. This review aims to provide a systematic review of all the host factors currently known to interact with HDV and their mechanistic involvement in all steps of the HDV replication cycle. Finally, we discuss implications for therapeutic development based on our current knowledge of HDV-host protein interactions.

Targeting shared molecular etiologies to accelerate drug development for rare diseases.

Rare diseases affect over 400 million people worldwide and less than 5% of rare diseases have an approved treatment. Fortunately, the number of underlying disease etiologies is far less than the number of diseases, because many rare diseases share a common molecular etiology. Moreover, many of these shared molecular etiologies are therapeutically actionable. Grouping rare disease patients for clinical trials based on the underlying molecular etiology, rather than the traditional, symptom-based definition of disease, has the potential to greatly increase the number of patients gaining access to clinical trials. Basket clinical trials based on a shared molecular drug target have become common in the field of oncology and have been accepted by regulatory agencies as a basis for drug approvals. Implementation of basket clinical trials in the field of rare diseases is seen by multiple stakeholders-patients, researchers, clinicians, industry, regulators, and funders-as a solution to accelerate the identification of new therapies and address patient's unmet needs.

Exosome and epithelial-mesenchymal transition: A complex secret of cancer progression.

This short communication will enlighten the readers about the exosome and the epithelial-mesenchymal transition (EMT) related to several complicated events. It also highlighted the therapeutic potential of exosomes against EMT. Exosome toxicology, exosome heterogeneity, and a single exosome profiling approach are also covered in this article. In the future, exosomes could help us get closer to cancer vaccine and precision oncology.

Heparan sulfate proteoglycans in cancer: Pathogenesis and therapeutic potential.

The heparan sulfate proteoglycans (HSPGs) are glycoproteins that consist of a proteoglycan "core" protein and covalently attached heparan sulfate (HS) chain. HSPGs are ubiquitously expressed in mammalian cells on the cell surface and in the extracellular matrix (ECM) and secretory vesicles. Within HSPGs, the protein cores determine when and where HSPG expression takes place, and the HS chains mediate most of HSPG's biological roles through binding various protein ligands, including cytokines, chemokines, growth factors and receptors, morphogens, proteases, protease inhibitors, and ECM proteins. Through these interactions, HSPGs modulate cell proliferation, adhesion, migration, invasion, and angiogenesis to display essential functions in physiology and pathology. Under physiological conditions, the expression and localization of HSPGs are finely regulated to orchestrate their physiological functions, and this is disrupted in cancer. The HSPG dysregulation elicits multiple oncogenic signaling, including growth factor signaling, ECM and Integrin signaling, chemokine and immune signaling, cancer stem cell, cell differentiation, apoptosis, and senescence, to prompt cell transformation, proliferation, tumor invasion and metastasis, tumor angiogenesis and inflammation, and immunotolerance. These oncogenic roles make HSPGs an attractive pharmacological target for anti-cancer therapy. Several therapeutic strategies have been under development, including anti-HSPG antibodies, peptides and HS mimetics, synthetic xylosides, and heparinase inhibitors, and shown promising anti-cancer efficacy. Therefore, much progress has been made in this line of study. However, it needs to bear in mind that the roles of HSPGs in cancer can be either oncogenic or tumor-suppressive, depending on the HSPG and the cancer cell type with the underlying mechanisms that remain obscure. Further studies need to address these to fill the knowledge gap and rationalize more efficient therapeutic targeting.

Chronic graft-versus-host disease in pediatric patients: Differences and challenges.

Despite the use of high-resolution molecular techniques for tissue typing, chronic graft-versus-host disease (cGVHD) remains a major complication following allogeneic hematopoietic stem cell transplant. cGVHD adversely affects the life-expectancy and quality of life. The latter is particularly important and functionally relevant in pediatric patients who have a longer life-expectancy than adults. Current laboratory evidence suggests that there is not any difference in the pathophysiology of cGVHD between adults and pediatric patients. However, there are some clinical features and complications of the disease that are different in pediatric patients. There are also challenges in the development of new therapeutics for this group of patients. In this review, we will discuss the epidemiology, pathophysiology, clinical features and consequences of the disease, and highlight the differences between pediatric and adult patients. We will examine the current treatment options for pediatric patients with moderate to severe cGVHD and discuss the challenges facing therapeutic development for cGVHD in the pediatric population.

Therapeutics for flaviviral infections.

Flaviviruses are vector-borne pathogens capable of causing devastating human diseases. The re-emergence of Zika in 2016 notoriously led to a widescale epidemic in the Americas. New daunting evidence suggests that a single mutation in Zika virus genome may increase transmission and pathogenesis, further highlighting the need to be prepared for flavivirus outbreaks. Dengue, in particular infects about 400 million people each year, leading to reoccurring local outbreaks. Public health efforts to mitigate flavivirus transmission is largely dependent on vector control strategies, as only a limited number of flavivirus vaccines have been developed thus far. There are currently no commercially available antivirals for flaviviruses, leaving supportive care as the primary treatment option. In this review, we will briefly paint a broad picture of the flavivirus landscape in terms of therapeutics, with particular focus on viral targets, promising novel compounds entering the drug discovery pipeline, as well as model systems for evaluating drug efficacy.

The Blood-Brain Barrier: Implications for Experimental Cancer Therapeutics.

The blood-brain barrier is critically important for the treatment of both primary and metastatic cancers of the central nervous system (CNS). Clinical outcomes for patients with primary CNS tumors are poor and have not significantly improved in decades. As treatments for patients with extracranial solid tumors improve, the incidence of CNS metastases is on the rise due to suboptimal CNS exposure of otherwise systemically active agents. Despite state-of-the art surgical care and increasingly precise radiation therapy, clinical progress is limited by the ability to deliver an effective dose of a therapeutic agent to all cancerous cells. Given the tremendous heterogeneity of CNS cancers, both across cancer subtypes and within a single tumor, and the range of diverse therapies under investigation, a nuanced examination of CNS drug exposure is needed. With a shared goal, common vocabulary, and interdisciplinary collaboration, the field is poised for renewed progress in the treatment of CNS cancers.