Advances and Challenges in Gene Therapy for Alzheimer's Disease.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and behavioral impairments. Despite extensive research efforts, effective treatment options for AD remain limited. Recently, gene therapy has emerged as a promising avenue for targeted intervention in the pathogenesis of AD. This review will provide an overview of clinical and preclinical studies where gene therapy techniques have been utilized in the context of AD, highlighting their potential as novel therapeutic strategies. While challenges remain, ongoing research and technological advancement continue to enhance the potential of gene therapy as a targeted and personalized therapeutic approach for AD.

An algorithm for discontinuing mechanical ventilation in boys with x-linked myotubular myopathy after positive response to gene therapy: the ASPIRO experience.

X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital myopathy. Most (80%) children with XLMTM have profound muscle weakness and hypotonia at birth resulting in severe respiratory insufficiency, the inability to sit up, stand or walk, and early mortality. At birth, 85-90% of children with XLMTM require mechanical ventilation, with more than half requiring invasive ventilator support. Historically, ventilator-dependent children with neuromuscular-derived respiratory failure of this degree and nature, static or progressive, are not expected to achieve complete independence from mechanical ventilator support. In the ASPIRO clinical trial (NCT03199469), participants receiving a single intravenous dose of an investigational gene therapy (resamirigene bilparvovec) started showing significant improvements in daily hours of ventilation support compared with controls by 24 weeks post-dosing, and 16 of 24 dosed participants achieved ventilator independence between 14 and 97 weeks after dosing. At the time, there was no precedent or published guidance for weaning chronically ventilated children with congenital neuromuscular diseases off mechanical ventilation. When the first ASPIRO participants started showing dramatically improved respiratory function, the investigators initiated efforts to safely wean them off ventilator support, in parallel with primary protocol respiratory outcome measures. A group of experts in respiratory care and physiology and management of children with XLMTM developed an algorithm to safely wean children in the ASPIRO trial off mechanical ventilation as their respiratory muscle strength increased. The algorithm developed for this trial provides recommendations for assessing weaning readiness, a stepwise approach to weaning, and monitoring of children during and after the weaning process.

A comprehensive review of AAV-mediated strategies targeting microglia for therapeutic intervention of neurodegenerative diseases.

Neurodegenerative diseases pose a significant health burden globally, with limited treatment options available. Among the various cell types involved in the pathogenesis of these disorders, microglia, the resident immune cells of the central nervous system, play a pivotal role. Dysregulated microglial activation contributes to neuroinflammation and neuronal damage, making them an attractive target for therapeutic intervention. Adeno-associated virus (AAV) vectors have emerged as powerful tools for delivering therapeutic genes to specific cell types in the central nervous system with remarkable precision and safety. In the current review, we discuss the strategies employed to achieve selective transduction of microglia, including the use of cell-specific promoters, engineered capsids, and microRNA (miRNA) strategies. Additionally, we address the challenges and future directions in the development of AAV-based therapies targeting microglia. Overall, AAV-mediated targeting of microglia holds promise as a novel therapeutic approach for neurodegenerative diseases, offering the potential to modify disease progression and improve patient outcomes.

The principles and promising future of sonogenetics for precision medicine.

Sonogenetics is an emerging medical technology that uses acoustic waves to control cells through sonosensitive mediators (SSMs) that are genetically encoded, thus remotely and non-invasively modulating specific molecular events and/or biomolecular functions. Sonogenetics has opened new opportunities for targeted spatiotemporal manipulation in the field of gene and cell-based therapies due to its inherent advantages, such as its noninvasive nature, high level of safety, and deep tissue penetration. Sonogenetics holds impressive potential in a wide range of applications, from tumor immunotherapy and mitigation of Parkinsonian symptoms to the modulation of neural reward pathway, and restoration of vision. This review provides a detailed overview of the mechanisms and classifications of established sonogenetics systems and summarizes their applications in disease treatment and management. The review concludes by highlighting the challenges that hinder the further progress of sonogenetics, paving the way for future advances.

Clinical decision making around commercial use of gene and genetic therapies for spinal muscular atrophy.

Spinal muscular atrophy is no longer a leading cause of inherited infant death in the United States. Since 2016, three genetic therapies have been approved for the treatment of spinal muscular atrophy. Each therapy has been well studied with robust data for both safety and efficacy. However, there are no head-to-head comparator studies to inform clinical decision making. Thus, treatment selection, timing, and combination therapy is largely up to clinician preference and insurance policies. As the natural history of spinal muscular atrophy continues to change, more data is needed to assist in evidence-based and cost-effective clinical decision making.

Hematopoietic stem cell gene therapy to halt neurodegeneration.

Microglia play fundamental roles in multiple pathological primary and secondary processes affecting the central nervous system that ultimately result in neurodegeneration and for this reason they are considered as a key therapeutic target in several neurodegenerative diseases. Microglia-targeted therapies are directed at either restoring or modulating microglia function, to redirect their functional features toward neuroprotection. Among these strategies, hematopoietic stem cell gene therapy have proven to be endowed with a unique potential for replacing diseased microglia with engineered, transplant progeny cells that can integrate and exert relevant beneficial effects in the central nervous system of patients affected by inherited and acquired neurodegenerative conditions.

Gene therapy for the leukodystrophies: From preclinical animal studies to clinical trials.

Leukodystrophies are progressive single gene disorders affecting the white matter of the brain. Several gene therapy trials are in progress to address the urgent unmet need for this patient population. We performed a comprehensive literature review of all gene therapy clinical trials listed in www.clinicaltrials.gov through August 2024, and the relevant preclinical studies that enabled clinical translation. Of the approximately 50 leukodystrophies described to date, only eight have existing gene therapy clinical trials: metachromatic leukodystrophy, X-linked adrenoleukodystrophy, globoid cell leukodystrophy, Canavan disease, giant axonal neuropathy, GM2 gangliosidoses, Alexander disease and Pelizaeus-Merzbacher disease. What led to the emergence of gene therapy trials for these specific disorders? What preclinical data or disease context was enabling? For each of these eight disorders, we first describe its pathophysiology and clinical presentation. We discuss the impact of gene therapy delivery route, targeted cell type, delivery modality, dosage, and timing on therapeutic efficacy. We note that use of allogeneic hematopoietic stem cell transplantation in some leukodystrophies allowed for an accelerated path to clinic even in the absence of available animal models. In other leukodystrophies, small and large animal model studies enabled clinical translation of experimental gene therapies. Human clinical trials for the leukodystrophies include ex vivo lentiviral gene delivery, in vivo AAV-mediated gene delivery, and intrathecal antisense oligonucleotide approaches. We outline adverse events associated with each modality focusing specifically on genotoxicity and immunotoxicity. We review monitoring and management of events related to insertional mutagenesis and immune responses. The data presented in this review show that gene therapy, while promising, requires systematic monitoring to account for the precarious disease biology and the adverse events associated with new technology.

Neurological glycogen storage diseases and emerging therapeutics.

Glycogen storage diseases (GSDs) comprise a group of inherited metabolic disorders characterized by defects in glycogen metabolism, leading to abnormal glycogen accumulation in multiple tissues, most notably affecting the liver, skeletal muscle, and heart. Recent findings have uncovered the importance of glycogen metabolism in the brain, sustaining a myriad of physiological functions and linking its perturbation to central nervous system (CNS) pathology. This link resulted in classification of neurological-GSDs (n-GSDs), a group of diseases with shared deficits in neurological glycogen metabolism. The n-GSD patients exhibit a spectrum of clinical presentations with common etiology while requiring tailored therapeutic approaches from the traditional GSDs. Recent research has elucidated the genetic and biochemical mechanisms and pathophysiological basis underlying different n-GSDs. Further, the last decade has witnessed some promising developments in novel therapeutic approaches, including enzyme replacement therapy (ERT), substrate reduction therapy (SRT), small molecule drugs, and gene therapy targeting key aspects of glycogen metabolism in specific n-GSDs. This preclinical progress has generated noticeable success in potentially modifying disease course and improving clinical outcomes in patients. Herein, we provide an overview of current perspectives on n-GSDs, emphasizing recent advances in understanding their molecular basis, therapeutic developments, underscore key challenges and the need to deepen our understanding of n-GSDs pathogenesis to develop better therapeutic strategies that could offer improved treatment and sustainable benefits to the patients.

[A modular approach to in vivo gene therapy]. / Thérapie génique in vivo : une approche modulaire.

In vivo inactivation of a deleterious gene has been achieved in a small trial, with excellent clinical results. Interestingly, the delivery and editing system is the same as in previous work on a different disease, and the new therapy required simply changing the guide RNA used to target the Cas9 nuclease. This modular approach could be extended to a number of other genetic diseases.

Gene therapy clinical trials worldwide to 2023-an update.

To date, 3,900 gene therapy clinical trials have been completed, are ongoing or have been approved worldwide. Our database brings together global information on gene therapy clinical activity from trial databases, official agency sources, published literature, conference presentations and posters kindly provided to us by individual investigators or trial sponsors. This review presents our analysis of clinical trials that, to the best of our knowledge, have been or are being performed worldwide. As of our March 2023 update, we have entries on 3,900 trials undertaken in 46 countries. We have analyzed the geographical distribution of trials, the disease indications (or other reasons) for trials, the proportions to which different vector types are used, and which genes have been transferred. Details of the analyses presented, and our searchable database are on The Journal of Gene Medicine Gene Therapy Clinical Trials Worldwide website at https://a873679.fmphost.com/fmi/webd/GTCT. We also provide an overview of the progress being made around the world, and discuss key trends since the previous review, namely the unprecedented increase in gene therapy clinical trial activity, including the implementation of genome editing technology with the potential to transform the field moving forward.

Stem cell therapeutics and gene therapy for neurologic disorders.

Rapid advances in biological knowledge and technological innovation have greatly advanced the fields of stem cell and gene therapies to combat a broad spectrum of neurologic disorders. Researchers are currently exploring a variety of stem cell types (e.g., embryonic, progenitor, induced pluripotent) and various transplantation strategies, each with its own advantages and drawbacks. Similarly, various gene modification techniques (zinc finger, TALENs, CRISPR-Cas9) are employed with various delivery vectors to modify underlying genetic contributors to neurologic disorders. While these two individual fields continue to blaze new trails, it is the combination of these technologies which enables genetically engineered stem cells and vastly increases investigational and therapeutic opportunities. The capability to culture and expand stem cells outside the body, along with their potential to correct genetic abnormalities in patient-derived cells or enhance cells with extra gene products, unleashes the full biological potential for innovative, multifaceted approaches to treat complex neurological disorders. In this review, we provide an overview of stem cell and gene therapies in the context of neurologic disorders, highlighting recent advances and current shortcomings, and discuss prospects for future therapies in clinical settings.

A roadmap for affordable genetic medicines.

Twenty genetic therapies have been approved by the US Food and Drug Administration to date, a number that now includes the first CRISPR genome-editing therapy for sickle cell disease-CASGEVY (exagamglogene autotemcel, Vertex Pharmaceuticals). This extraordinary milestone is widely celebrated owing to the promise for future genome-editing treatments of previously intractable genetic disorders and cancers. At the same time, such genetic therapies are the most expensive drugs on the market, with list prices exceeding US$4 million per patient. Although all approved cell and gene therapies trace their origins to academic or government research institutions, reliance on for-profit pharmaceutical companies for subsequent development and commercialization results in prices that prioritize recouping investments, paying for candidate product failures and meeting investor and shareholder expectations. To increase affordability and access, sustainable discovery-to-market alternatives are needed that address system-wide deficiencies. Here we present recommendations of a multidisciplinary task force assembled to chart such a path. We describe a pricing structure that, once implemented, could reduce per-patient cost tenfold and propose a business model that distributes responsibilities while leveraging diverse funding sources. We also outline how academic licensing provisions, manufacturing innovation and supportive regulations can reduce cost and enable broader patient treatment.

Current Trends and Innovative Approaches in Cancer Immunotherapy.

Immunotherapy is one of the most promising therapeutic approaches in the field of cancer treatment. As a tumor progresses, tumor cells employ an array of immune-regulatory mechanisms to suppress immune responses within the tumor microenvironment. Using our understanding of these mechanisms, cancer immunotherapy has been developed to enhance the immune system's effectiveness in treating cancer. Numerous cancer immunotherapies are currently in clinical use, yet many others are either in different stages of development or undergoing clinical studies. In this paper, we briefly discuss the features and current status of cancer immunotherapies. This includes the application of monoclonal antibodies, immune checkpoint inhibitors, adoptive cell therapy, cytokine therapy, cancer vaccines, and gene therapy, all of which have gained significant recognition in clinical practice. Additionally, we discuss limitations that may hinder successful clinical utilization and promising strategies, such as combining immunotherapy with nanotechnology.

The potential of gene delivery for the treatment of traumatic brain injury.

Therapeutics for traumatic brains injuries constitute a global unmet medical need. Despite the advances in neurocritical care, which have dramatically improved the survival rate for the ~ 70 million patients annually, few treatments have been developed to counter the long-term neuroinflammatory processes and accompanying cognitive impairments, frequent among patients. This review looks at gene delivery as a potential therapeutic development avenue for traumatic brain injury. We discuss the capacity of gene delivery to function in traumatic brain injury, by producing beneficial biologics within the brain. Gene delivery modalities, promising vectors and key delivery routes are discussed, along with the pathways that biological cargos could target to improve long-term outcomes for patients. Coupling blood-brain barrier crossing with sustained local production, gene delivery has the potential to convert proteins with useful biological properties, but poor pharmacodynamics, into effective therapeutics. Finally, we review the limitations and health economics of traumatic brain injury, and whether future gene delivery approaches will be viable for patients and health care systems.