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1
Ramón, Javier, Ferran Vila-Julià, David Molina-Granada, Miguel Molina-Berenguer, Maria Jesús Melià, Elena García-Arumí, Javier Torres-Torronteras, Yolanda Cámara, and Ramon Martí. "Therapy Prospects for Mitochondrial DNA Maintenance Disorders." International Journal of Molecular Sciences 22, no. 12 (June 16, 2021): 6447. http://dx.doi.org/10.3390/ijms22126447.
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Mitochondrial DNA depletion and multiple deletions syndromes (MDDS) constitute a group of mitochondrial diseases defined by dysfunctional mitochondrial DNA (mtDNA) replication and maintenance. As is the case for many other mitochondrial diseases, the options for the treatment of these disorders are rather limited today. Some aggressive treatments such as liver transplantation or allogeneic stem cell transplantation are among the few available options for patients with some forms of MDDS. However, in recent years, significant advances in our knowledge of the biochemical pathomechanisms accounting for dysfunctional mtDNA replication have been achieved, which has opened new prospects for the treatment of these often fatal diseases. Current strategies under investigation to treat MDDS range from small molecule substrate enhancement approaches to more complex treatments, such as lentiviral or adenoassociated vector-mediated gene therapy. Some of these experimental therapies have already reached the clinical phase with very promising results, however, they are hampered by the fact that these are all rare disorders and so the patient recruitment potential for clinical trials is very limited.
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Chojdak-Łukasiewicz, Justyna, Edyta Dziadkowiak, and Sławomir Budrewicz. "Monogenic Causes of Strokes." Genes 12, no. 12 (November 23, 2021): 1855. http://dx.doi.org/10.3390/genes12121855.
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Strokes are the main cause of death and long-term disability worldwide. A stroke is a heterogeneous multi-factorial condition, caused by a combination of environmental and genetic factors. Monogenic disorders account for about 1% to 5% of all stroke cases. The most common single-gene diseases connected with strokes are cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) Fabry disease, mitochondrial myopathy, encephalopathy, lactacidosis, and stroke (MELAS) and a lot of single-gene diseases associated particularly with cerebral small-vessel disease, such as COL4A1 syndrome, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), and Hereditary endotheliopathy with retinopathy, nephropathy, and stroke (HERNS). In this article the clinical phenotype for the most important single-gene disorders associated with strokes are presented. The monogenic causes of a stroke are rare, but early diagnosis is important in order to provide appropriate therapy when available.
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Mishra, Ratnakar, Benson S. Chen, Prachi Richa, and Patrick Yu-Wai-Man. "Wolfram syndrome: new pathophysiological insights and therapeutic strategies." Therapeutic Advances in Rare Disease 2 (January 2021): 263300402110395. http://dx.doi.org/10.1177/26330040211039518.
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Wolfram Syndrome (WS) is an ultra-rare, progressive neurodegenerative disease characterized by early-onset diabetes mellitus and irreversible loss of vision, secondary to optic nerve degeneration. Visual loss in WS is an important cause of registrable blindness in children and young adults and the pathological hallmark is the preferential loss of retinal ganglion cells within the inner retina. In addition to optic atrophy, affected individuals frequently develop variable combinations of neurological, endocrinological, and psychiatric complications. The majority of patients carry recessive mutations in the WFS1 (4p16.1) gene that encodes for a multimeric transmembrane protein, wolframin, embedded within the endoplasmic reticulum (ER). An increasingly recognised subgroup of patients harbor dominant WFS1 mutations that usually cause a milder phenotype, which can be limited to optic atrophy. Wolframin is a ubiquitous protein with high levels of expression in retinal, neuronal, and muscle tissues. It is a multifunctional protein that regulates a host of cellular functions, in particular the dynamic interaction with mitochondria at mitochondria-associated membranes. Wolframin has been implicated in several crucial cellular signaling pathways, including insulin signaling, calcium homeostasis, and the regulation of apoptosis and the ER stress response. There is currently no cure for WS; management remains largely supportive. This review will cover the clinical, genetic, and pathophysiological features of WS, with a specific focus on disease models and the molecular pathways that could serve as potential therapeutic targets. The current landscape of therapeutic options will also be discussed in the context of the latest evidence, including the pipeline for repurposed drugs and gene therapy. Plain language summary Wolfram syndrome – disease mechanisms and treatment options Wolfram syndrome (WS) is an ultra-rare genetic disease that causes diabetes mellitus and progressive loss of vision from early childhood. Vision is affected in WS because of damage to a specialized type of cells in the retina, known as retinal ganglion cells (RGCs), which converge at the back of the eye to form the optic nerve. The optic nerve is the fast-conducting cable that transmits visual information from the eye to the vision processing centers within the brain. As RGCs are lost, the optic nerve degenerates and it becomes pale in appearance (optic atrophy). Although diabetes mellitus and optic atrophy are the main features of WS, some patients can develop more severe problems because the brain and other organs, such as the kidneys and the bladder, are also affected. The majority of patients with WS carry spelling mistakes (mutations) in the WFS1 gene, which is located on the short arm of chromosome 4 (4p16.1). This gene is highly expressed in the eye and in the brain, and it encodes for a protein located within a compartment of the cell known as the endoplasmic reticulum. For reasons that still remain unclear, WFS1 mutations preferentially affect RGCs, accounting for the prominent visual loss in this genetic disorder. There is currently no effective treatment to halt or slow disease progression and management remains supportive, including the provision of visual aids and occupational rehabilitation. Research into WS has been limited by its relative rarity and the inability to get access to eye and brain tissues from affected patients. However, major advances in our understanding of this disease have been made recently by making use of more accessible cells from patients, such as skin cells (fibroblasts), or animal models, such as mice and zebrafish. This review summarizes the mechanisms by which WFS1 mutations affect cells, impairing their function and eventually leading to their premature loss. The possible treatment strategies to block these pathways are also discussed, with a particular focus on drug repurposing (i.e., using drugs that are already approved for other diseases) and gene therapy (i.e., replacing or repairing the defective WFS1 gene).
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Albiges, Laurence, Ronan Flippot, Nathalie Rioux-Leclercq, and Toni K. Choueiri. "Non–Clear Cell Renal Cell Carcinomas: From Shadow to Light." Journal of Clinical Oncology 36, no. 36 (December 20, 2018): 3624–31. http://dx.doi.org/10.1200/jco.2018.79.2531.
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Non–clear cell renal cell carcinomas (RCCs) account for up to 25% of kidney cancers and encompass distinct diseases with distinct pathologic features, different molecular alterations, and various patterns of response to systemic therapies. Recent advances in molecular biology and large collaborative efforts helped to better define the oncogenic mechanisms at play in papillary, chromophobe, collecting duct, medullary, translocation, and sarcomatoid RCCs. Papillary RCCs are divided into several subsets of tumors characterized by distinct gene expression profiles, chromatin remodeling genes, cell cycle changes, and alterations of the MET pathway. Chromophobe RCC genomic analysis revealed mostly metabolic pathway alterations with mitochondrial dysfunctions. Translocation RCCs are characterized by MITF fusions and wide genomic reprogramming. Collecting duct carcinomas are distinct entities from upper tract urothelial carcinomas associated with high T-cell infiltration and metabolic alterations. Medullary RCCs present alterations of the INI1 gene and rhabdoid features at pathologic analysis. Finally, sarcomatoid RCCs represent sarcomatoid differentiation for any subsets of RCCs with specific alterations associated with mesenchymal dedifferentiation. From the standpoint of systemic therapy, more than a decade of using VEGF and mTOR inhibitors showed that they generally had limited efficacy in non–clear cell RCCs compared with clear cell RCCs. MET inhibitors are actively being developed for papillary RCC with a specific focus on MET-driven tumors. Other strategies under investigation include CDK4/6 inhibitors in tumors with cell cycle alterations and EZH2 inhibitors in RCCs with INI1 loss. The emergence of immune checkpoint inhibitors and combination strategies enlarges the spectrum of investigational treatments. Better understanding of driver and passenger alterations and better patient stratification along with dedicated clinical networks will be key to improving the management of these rare tumors.
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SAHEL, JA. "Gene therapy in rare diseases." Acta Ophthalmologica 90 (August 6, 2012): 0. http://dx.doi.org/10.1111/j.1755-3768.2012.3222.x.
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Phillips, M. Ian, and Andrew B. Burns. "The emergence of gene therapy for rare diseases." Expert Opinion on Orphan Drugs 2, no. 11 (October 28, 2014): 1197–209. http://dx.doi.org/10.1517/21678707.2014.978284.
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Wang, Wenqing, Avni Awani, Lauren Reich, Yusuke Nakauchi, Daniel Thomas, Daniel P. Dever, Matthew Porteus, and Katja G. Weinacht. "An Engineered Cell-Traceable Model of Reticular Dysgenesis in Human Hematopoietic Stem Cells Linking Metabolism and Differentiation." Blood 132, Supplement 1 (November 29, 2018): 2558. http://dx.doi.org/10.1182/blood-2018-99-117926.
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Abstract Hematopoietic stem cell (HSC) differentiation is accompanied by a metabolic shift from glycolysis to oxidative phosphorylation (OXPHOS) to meet the increasing energy demand during proliferation and differentiation. However, the role of mitochondrial metabolism in HSC differentiation goes beyond ATP production. Metabolites generated during mitochondrial metabolism may impact in HSC fate decisions through stable epigenetic modifications. Despite some progress in understanding mitochondrial communication during HSC development, their role in human hematopoiesis remains largely elusive, where the lack of appropriate model systems poses a major obstacle. Reticular Dysgenesis (RD), a rare and particularly severe form of severe combined immunodeficiency (SCID), offers an attractive model for studying the role of mitochondrial metabolism in hematopoiesis. RD is an autosomal recessive disease caused by biallelic mutations of the mitochondrial enzyme Adenylate Kinase 2 (AK2). AK2 catalyzes the reversible phosphorylation of adenosine monophosphate (AMP) to adenosine diphosphate (ADP), which serves as the substrate for the ATP synthase. In addition to defective lymphocyte development typical of classic SCID, RD patients also suffer from impaired myeloid development, suggestive of a global defect in hematopoiesis. In a human induced pluripotent stem cell (iPSC) model for RD, hematopoietic stem and progenitor cells (HSPCs) recapitulate a profound maturation arrest of the myeloid lineage, increased oxidative stress and an energy-depleted metabolite and transcriptional profile. We hypothesize that AK2 defects drive hematopoietic cell fate decisions through changes in metabolites that regulate the activities of DNA/histone modifying enzymes and result in stable epigenetic modifications. Methods: Since iPSCs are not suitable to model the epigenetic characteristics of definitive hematopoiesis, we developed a novel model system in which we deleted AK2 in primary human HSCs using CRISPR/Cas9 gene editing technique. We found a highly effective single-guide RNA (sgRNA) targeting the catalytic LID domain of the AK2 gene to introduce directed DNA double stranded breaks (DSBs), and use a homologous recombination (HR)-mediated dual reporter system to track and isolate cells with biallelic AK2 disruption. Results: Our single-color GFP reporter system consistently produces a >60% GFP+ population of AK2-targeted CD34+ umbilical cord blood (UCB) cells. With dual GFP/BFP reporters, we were able to achieve 6% GFP/BFP double positive cells with confirmed biallelic AK2 knock-out. Since HR events on one allele are biologically linked to CRISPR/Cas9 mediated DSBs on the other, we assessed insertion and/or deletion (INDEL) frequency and protein expression in a single reporter (GFP+) population of AK2-targeted UCBs. We detected an INDEL frequency of over 90% on the non-HR alleles along with nearly absent AK2 protein expression by Western Blot. These results indicated that the highly efficient single-color reporter system with >60% targeting efficiency is sufficient to achieve an AK2 biallelic knock-out population in primary HSCs. in vitro myeloid differentiation of these AK2-targeted HSCs recapitulates the RD phenotype with impaired neutrophil but preserved monocyte development. Conclusion: This novel disease model for RD will now allow us to examine the cellular and molecular impact of perturbations in metabolism on human HSC development. We will investigate the effect on differentiation potential, metabolite profile, transcriptome and epigenome in vitro as well as in a xenograft mouse model. Elucidating how metabolism governs differentiation and self-renewal of human HSCs will not only advance our basic understanding of many blood and immune diseases, but has important translational implications for improving the use of HSCs in hematopoietic stem cell transplantation, gene and cell therapy. Disclosures Porteus: CRISPR Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees.
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Girach, Aniz. "The Future of Gene Therapy for Rare Eye Diseases." Cell and Gene Therapy Insights 4, no. 7 (October 15, 2018): 725–31. http://dx.doi.org/10.18609/cgti.2018.073.
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Faria, Rúben, Prisca Boisguérin, Ângela Sousa, and Diana Costa. "Delivery Systems for Mitochondrial Gene Therapy: A Review." Pharmaceutics 15, no. 2 (February 8, 2023): 572. http://dx.doi.org/10.3390/pharmaceutics15020572.
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Mitochondria are membrane-bound cellular organelles of high relevance responsible for the chemical energy production used in most of the biochemical reactions of cells. Mitochondria have their own genome, the mitochondrial DNA (mtDNA). Inherited solely from the mother, this genome is quite susceptible to mutations, mainly due to the absence of an effective repair system. Mutations in mtDNA are associated with endocrine, metabolic, neurodegenerative diseases, and even cancer. Currently, therapeutic approaches are based on the administration of a set of drugs to alleviate the symptoms of patients suffering from mitochondrial pathologies. Mitochondrial gene therapy emerges as a promising strategy as it deeply focuses on the cause of mitochondrial disorder. The development of suitable mtDNA-based delivery systems to target and transfect mammalian mitochondria represents an exciting field of research, leading to progress in the challenging task of restoring mitochondria’s normal function. This review gathers relevant knowledge on the composition, targeting performance, or release profile of such nanosystems, offering researchers valuable conceptual approaches to follow in their quest for the most suitable vectors to turn mitochondrial gene therapy clinically feasible. Future studies should consider the optimization of mitochondrial genes’ encapsulation, targeting ability, and transfection to mitochondria. Expectedly, this effort will bring bright results, contributing to important hallmarks in mitochondrial gene therapy.
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Seibel, Peter, Jörg Trappe, Gaetano Villani, Thomas Klopstock, Sergio Papa, and Heinz Reichmann. "Transfection of mitochondria: strategy towards a gene therapy of mitochondrial DNA diseases." Nucleic Acids Research 23, no. 1 (1995): 10–17. http://dx.doi.org/10.1093/nar/23.1.10.
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Kilix, Sven. "Trends in cell and gene therapy clinical development for rare and ultra-rare diseases." Cell and Gene Therapy Insights 6, no. 3 (April 29, 2020): 543–47. http://dx.doi.org/10.18609/cgti.2020.063.
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Ylä-Herttuala, Seppo. "Bumps in the Road for Commercial Gene Therapy for Rare Diseases." Molecular Therapy 25, no. 10 (October 2017): 2225. http://dx.doi.org/10.1016/j.ymthe.2017.09.012.
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Prasad, Suyash. "Advancing the Development of AAV-Based Gene Therapy for Rare Diseases." Cell and Gene Therapy Insights 4, no. 7 (October 15, 2018): 671–78. http://dx.doi.org/10.18609/cgti.2018.065.
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Kent, Alastair, and Cor Oosterwijk. "A patient and family perspective on gene therapy for rare diseases." Journal of Gene Medicine 9, no. 10 (2007): 922–23. http://dx.doi.org/10.1002/jgm.1097.
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Kingwell, Katie. "‘Bespoke Gene Therapy Consortium’ sets out to enable gene therapies for ultra-rare diseases." Nature Reviews Drug Discovery 20, no. 12 (November 12, 2021): 886–87. http://dx.doi.org/10.1038/d41573-021-00193-6.
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MacKay, Geoff. "Developing gene therapies for rare diseases: an interview with Geoff MacKay." Regenerative Medicine 16, no. 10 (October 2021): 905–8. http://dx.doi.org/10.2217/rme-2021-0126.
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Geoff MacKay is a pioneer in cell and gene therapy with a track record of successful leadership at innovative biotechs. He is currently the president and CEO of AVROBIO, a clinical-stage lentiviral gene therapy company that treats lysosomal disorders, and a board member of Talaris Therapeutics and Satellos Bioscience. He is also the founding CEO of eGenesis, a biotech that applies CRISPR-Cas9 gene editing to xenotransplantation and the former president and CEO of Organogenesis, a world-leading cell therapy company. Earlier in his career, MacKay spent 11 years at Novartis in senior leadership positions within the global transplantation and immunology franchise.
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Bañuls, Lucía, Daniel Pellicer, Silvia Castillo, María Mercedes Navarro-García, María Magallón, Cruz González, and Francisco Dasí. "Gene Therapy in Rare Respiratory Diseases: What Have We Learned So Far?" Journal of Clinical Medicine 9, no. 8 (August 8, 2020): 2577. http://dx.doi.org/10.3390/jcm9082577.
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Gene therapy is an alternative therapy in many respiratory diseases with genetic origin and currently without curative treatment. After five decades of progress, many different vectors and gene editing tools for genetic engineering are now available. However, we are still a long way from achieving a safe and efficient approach to gene therapy application in clinical practice. Here, we review three of the most common rare respiratory conditions—cystic fibrosis (CF), alpha-1 antitrypsin deficiency (AATD), and primary ciliary dyskinesia (PCD)—alongside attempts to develop genetic treatment for these diseases. Since the 1990s, gene augmentation therapy has been applied in multiple clinical trials targeting CF and AATD, especially using adeno-associated viral vectors, resulting in a good safety profile but with low efficacy in protein expression. Other strategies, such as non-viral vectors and more recently gene editing tools, have also been used to address these diseases in pre-clinical studies. The first gene therapy approach in PCD was in 2009 when a lentiviral transduction was performed to restore gene expression in vitro; since then, transcription activator-like effector nucleases (TALEN) technology has also been applied in primary cell culture. Gene therapy is an encouraging alternative treatment for these respiratory diseases; however, more research is needed to ensure treatment safety and efficacy.
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Shaimardanova, Alisa A., Valeriya V. Solovyeva, Shaza S. Issa, and Albert A. Rizvanov. "Gene Therapy of Sphingolipid Metabolic Disorders." International Journal of Molecular Sciences 24, no. 4 (February 11, 2023): 3627. http://dx.doi.org/10.3390/ijms24043627.
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Sphingolipidoses are defined as a group of rare hereditary diseases resulting from mutations in the genes encoding lysosomal enzymes. This group of lysosomal storage diseases includes more than 10 genetic disorders, including GM1-gangliosidosis, Tay–Sachs disease, Sandhoff disease, the AB variant of GM2-gangliosidosis, Fabry disease, Gaucher disease, metachromatic leukodystrophy, Krabbe disease, Niemann–Pick disease, Farber disease, etc. Enzyme deficiency results in accumulation of sphingolipids in various cell types, and the nervous system is also usually affected. There are currently no known effective methods for the treatment of sphingolipidoses; however, gene therapy seems to be a promising therapeutic variant for this group of diseases. In this review, we discuss gene therapy approaches for sphingolipidoses that are currently being investigated in clinical trials, among which adeno-associated viral vector-based approaches and transplantation of hematopoietic stem cells genetically modified with lentiviral vectors seem to be the most effective.
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Dabbous, M., C. Francois, L. Chachoua, E. Hanna, and M. Toumi. "PND5 OVERCOMING MARKET ACCESS AND COMMERCIALIZATION CHALLENGES IN GENE THERAPIES FOR RARE CNS DISEASES: GENE THERAPY CLINICAL TRIALS FOR RARE CNS DISEASES LANDSCAPE." Value in Health 22 (November 2019): S737—S738. http://dx.doi.org/10.1016/j.jval.2019.09.2756.
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Jeena, M. T., Sangpil Kim, Seongeon Jin, and Ja-Hyoung Ryu. "Recent Progress in Mitochondria-Targeted Drug and Drug-Free Agents for Cancer Therapy." Cancers 12, no. 1 (December 18, 2019): 4. http://dx.doi.org/10.3390/cancers12010004.
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The mitochondrion is a dynamic eukaryotic organelle that controls lethal and vital functions of the cell. Being a critical center of metabolic activities and involved in many diseases, mitochondria have been attracting attention as a potential target for therapeutics, especially for cancer treatment. Structural and functional differences between healthy and cancerous mitochondria, such as membrane potential, respiratory rate, energy production pathway, and gene mutations, could be employed for the design of selective targeting systems for cancer mitochondria. A number of mitochondria-targeting compounds, including mitochondria-directed conventional drugs, mitochondrial proteins/metabolism-inhibiting agents, and mitochondria-targeted photosensitizers, have been discussed. Recently, certain drug-free approaches have been introduced as an alternative to induce selective cancer mitochondria dysfunction, such as intramitochondrial aggregation, self-assembly, and biomineralization. In this review, we discuss the recent progress in mitochondria-targeted cancer therapy from the conventional approach of drug/cytotoxic agent conjugates to advanced drug-free approaches.
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Boehnke, A., C. Minartz, S. Radeck, and A. Neubauer. "POSC206 How Gene Therapy for Rare Diseases Differs from Chronic Therapy: The Case of AADC-Deficiency." Value in Health 25, no. 1 (January 2022): S148. http://dx.doi.org/10.1016/j.jval.2021.11.721.
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Faria, Rúben, Milan Paul, Swati Biswas, Eric Vivès, Prisca Boisguérin, Ângela Sousa, and Diana Costa. "Peptides vs. Polymers: Searching for the Most Efficient Delivery System for Mitochondrial Gene Therapy." Pharmaceutics 14, no. 4 (March 31, 2022): 757. http://dx.doi.org/10.3390/pharmaceutics14040757.
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Together with the nucleus, the mitochondrion has its own genome. Mutations in mitochondrial DNA are responsible for a variety of disorders, including neurodegenerative diseases and cancer. Current therapeutic approaches are not effective. In this sense, mitochondrial gene therapy emerges as a valuable and promising therapeutic tool. To accomplish this goal, the design/development of a mitochondrial-specific gene delivery system is imperative. In this work, we explored the ability of novel polymer- and peptide-based systems for mitochondrial targeting, gene delivery, and protein expression, performing a comparison between them to reveal the most adequate system for mitochondrial gene therapy. Therefore, we synthesized a novel mitochondria-targeting polymer (polyethylenimine–dequalinium) to load and complex a mitochondrial-gene-based plasmid. The polymeric complexes exhibited physicochemical properties and cytotoxic profiles dependent on the nitrogen-to-phosphate-group ratio (N/P). A fluorescence confocal microscopy study revealed the mitochondrial targeting specificity of polymeric complexes. Moreover, transfection mediated by polymer and peptide delivery systems led to gene expression in mitochondria. Additionally, the mitochondrial protein was produced. A comparative study between polymeric and peptide/plasmid DNA complexes showed the great capacity of peptides to complex pDNA at lower N/P ratios, forming smaller particles bearing a positive charge, with repercussions on their capacity for cellular transfection, mitochondria targeting and, ultimately, gene delivery and protein expression. This report is a significant contribution to the implementation of mitochondrial gene therapy, instigating further research on the development of peptide-based delivery systems towards clinical translation.
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Camponeschi, Francesca, Simone Ciofi-Baffoni, Vito Calderone, and Lucia Banci. "Molecular Basis of Rare Diseases Associated to the Maturation of Mitochondrial [4Fe-4S]-Containing Proteins." Biomolecules 12, no. 7 (July 21, 2022): 1009. http://dx.doi.org/10.3390/biom12071009.
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The importance of mitochondria in mammalian cells is widely known. Several biochemical reactions and pathways take place within mitochondria: among them, there are those involving the biogenesis of the iron–sulfur (Fe-S) clusters. The latter are evolutionarily conserved, ubiquitous inorganic cofactors, performing a variety of functions, such as electron transport, enzymatic catalysis, DNA maintenance, and gene expression regulation. The synthesis and distribution of Fe-S clusters are strictly controlled cellular processes that involve several mitochondrial proteins that specifically interact each other to form a complex machinery (Iron Sulfur Cluster assembly machinery, ISC machinery hereafter). This machinery ensures the correct assembly of both [2Fe-2S] and [4Fe-4S] clusters and their insertion in the mitochondrial target proteins. The present review provides a structural and molecular overview of the rare diseases associated with the genes encoding for the accessory proteins of the ISC machinery (i.e., GLRX5, ISCA1, ISCA2, IBA57, FDX2, BOLA3, IND1 and NFU1) involved in the assembly and insertion of [4Fe-4S] clusters in mitochondrial proteins. The disease-related missense mutations were mapped on the 3D structures of these accessory proteins or of their protein complexes, and the possible impact that these mutations have on their specific activity/function in the frame of the mitochondrial [4Fe-4S] protein biogenesis is described.
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Nair, Ayushi, Alosh Greeny, Rajalakshmi Rajendran, Mohamed A. Abdelgawad, Mohammed M. Ghoneim, Roshni Pushpa Raghavan, Sachithra Thazhathuveedu Sudevan, Bijo Mathew, and Hoon Kim. "KIF1A-Associated Neurological Disorder: An Overview of a Rare Mutational Disease." Pharmaceuticals 16, no. 2 (January 19, 2023): 147. http://dx.doi.org/10.3390/ph16020147.
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KIF1A-associated neurological diseases (KANDs) are a group of inherited conditions caused by changes in the microtubule (MT) motor protein KIF1A as a result of KIF1A gene mutations. Anterograde transport of membrane organelles is facilitated by the kinesin family protein encoded by the MT-based motor gene KIF1A. Variations in the KIF1A gene, which primarily affect the motor domain, disrupt its ability to transport synaptic vesicles containing synaptophysin and synaptotagmin leading to various neurological pathologies such as hereditary sensory neuropathy, autosomal dominant and recessive forms of spastic paraplegia, and different neurological conditions. These mutations are frequently misdiagnosed because they result from spontaneous, non-inherited genomic alterations. Whole-exome sequencing (WES), a cutting-edge method, assists neurologists in diagnosing the illness and in planning and choosing the best course of action. These conditions are simple to be identified in pediatric and have a life expectancy of 5–7 years. There is presently no permanent treatment for these illnesses, and researchers have not yet discovered a medicine to treat them. Scientists have more hope in gene therapy since it can be used to cure diseases brought on by mutations. In this review article, we discussed some of the experimental gene therapy methods, including gene replacement, gene knockdown, symptomatic gene therapy, and cell suicide gene therapy. It also covered its clinical symptoms, pathogenesis, current diagnostics, therapy, and research advances currently occurring in the field of KAND-related disorders. This review also explained the impact that gene therapy can be designed in this direction and afford the remarkable benefits to the patients and society.
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Gazizova, I. R. "Modern possibilities for correction of disturbances of cellular energetics in ophthalmology." Kazan medical journal 93, no. 4 (August 15, 2012): 668–71. http://dx.doi.org/10.17816/kmj1568.
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Disturbances in the mitochondrial functions that are responsible for energy metabolism of the cell, plays an important role in the development of many diseases of the eye. Among diseases of the vision organ the one with sufficient evidence of mitochondrial pathology is Leber’s release, which is associated with mutations of the mitochondrial deoxyribonucleic acid. This article provides an overview of the published literature on the research investigations of modern methods and means of correction of mitochondrial dysfunction during inflammatory and neurodegenerative diseases of the eye. Describe were the potential methods of replacement therapy and protection of mitochondria from the aggressive effects of free radicals. With the help of gene technology an increase in the number of antioxidant enzymes in the cells of the retina can be achieved. Recent authors have focused on the possibility of using mitochondria-targeted antioxidants. The possibility of controlling the main links of the apoptotic cascade and reducing the loss of retinal ganglion cells using gene therapy has been investigated in an experiment. Restoration of the balance of calcium and mitochondrial membrane potential in the phenomenon of excitotoxicity has been shown by using calcium channel blockers. We believe that gene therapy of mitochondrial dysfunction is the most promising trend for the correction of cellular energetic disturbances in ophthalmology.
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Кононец, В. И., Г. М. Жармаханова, Л. М. Сырлыбаева, Э. Б. Нурбаулина, Ж. Т. Жусупова, С. К. Саханова, А. К. Таутанова, and С. К. Балмагамбетова. "INHERITED DISORDERS OF THE UREA CYCLE: LITERATURE REVIEW." Farmaciâ Kazahstana, no. 5 (November 28, 2022): 27–42. http://dx.doi.org/10.53511/pharmkaz.2022.52.45.004.
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Цикл мочевины представляет собой метаболический путь избавления от избыточного азота, который образуется в основном в виде аммиака. Избыток аммиака приводит к опасным для жизни состояниям. Нарушения цикла мочевины (НЦМ) включают заболевания, проявляющиеся гипераммониемией, которые возникают либо в неонатальном периоде, либо позже. Причиной наследственных нарушений цикла мочевины являются врожденные дефекты ферментов или транспортеров цикла мочевины. В орнитиновом цикле используются пять ферментов, два из которых, карбамоилфосфатсинтетаза 1 и орнитинтранскарбамилаза, находятся в митохондриальном матриксе, тогда как другие (аргининосукцинатсинтетаза, аргининосукцинатлиаза и аргиназа 1 - в цитоплазме. Кроме того, для функционирования цикла мочевины необходимы N-ацетилглутаматсинтаза и, по крайней мере, два белка-транспортера. Тяжесть и возраст начала заболевания определяются нарушением функции фермента или транспортера и связаны с соответствующими генными мутациями. У пациентов развивается гипераммониемия либо вскоре после рождения (около 50%), либо позже в любом возрасте, что приводит к смерти или тяжелой неврологической инвалидности у многих выживших. Несмотря на возможность использования эффективной консервативной терапии и трансплантации печени, результаты остаются неудовлетворительными. Это может быть связано с нераспознаванием и запоздалой диагностикой из-за неспецифической клинической картины и недостаточной осведомленностью медицинских работников из-за редкости заболевания. Стратегия терапии наследственных нарушений цикла мочевины заключается в предотвращении необратимой токсичности воздействия высокого содержания аммиака на мозг. Патогенез и естественное течение заболеваний этой группы плохо изучены из-за их редкой встречаемости. В обзоре рассмотрены современные представления об эпидемиологии, патогенезе, клинических проявлениях, диагностике, включая генетический анализ и лечении наследственных нарушений цикла мочевины. The urea cycle is a metabolic pathway to get rid of excess nitrogen, which is formed mainly in the form of ammonia. Excess ammonia leads to life-threatening conditions. Urea cycle disorders (UCDs) include diseases manifesting as hyperammonemia that occur either in the neonatal period or later. The cause of hereditary disorders of the urea cycle are congenital defects in the enzymes or transporters of the urea cycle. The ornithine cycle uses five enzymes, two of which, carbamoyl phosphate synthetase 1 and ornithine transcarbamylase, are located in the mitochondrial matrix, while others (argininosuccinate synthetase, argininosuccinate lyase, and arginase 1) are located in the cytoplasm. In addition, N-acetylglutamate synthase and at least two transporter proteins are required for the functioning of the urea cycle. The severity and age of onset of the disease are determined by the dysfunction of the enzyme or transporter and are associated with the corresponding gene mutations. Patients develop hyperammonemia either shortly after birth (about 50%) or later at any age, resulting in death or severe neurological disability in many survivors. Despite the existence of effective therapy by alternative routes and liver transplantation, the results remain unsatisfactory. This may be due to misrecognition and delayed diagnosis due to the non-specific clinical presentation and lack of awareness among healthcare professionals due to the rarity of the disease. The treatment strategy for hereditary disorders of the urea cycle is to prevent the irreversible toxicity of high ammonia exposure to the brain. The pathogenesis and natural course of diseases in this group are poorly understood due to their rare occurrence. The review considers modern concepts of epidemiology, pathogenesis, clinical manifestations, diagnosis, including genetic analysis, and treatment of hereditary disorders of the urea cycle.
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Vemana, Hari Priya, Aishwarya Saraswat, Shraddha Bhutkar, Ketan Patel, and Vikas V. Dukhande. "A novel gene therapy for neurodegenerative Lafora disease via EPM2A-loaded DLinDMA lipoplexes." Nanomedicine 16, no. 13 (June 2021): 1081–95. http://dx.doi.org/10.2217/nnm-2020-0477.
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Aim: To develop novel cationic liposomes as a nonviral gene delivery vector for the treatment of rare diseases, such as Lafora disease – a neurodegenerative epilepsy. Materials & methods: DLinDMA and DOTAP liposomes were formulated and characterized for the delivery of gene encoding laforin and expression of functional protein in HEK293 and neuroblastoma cells. Results: Liposomes with cationic lipids DLinDMA and DOTAP showed good physicochemical characteristics. Nanosized DLinDMA liposomes demonstrated desired transfection efficiency, negligible hemolysis and minimal cytotoxicity. Western blotting confirmed successful expression and glucan phosphatase assay demonstrated the biological activity of laforin. Conclusion: Our study is a novel preclinical effort in formulating cationic lipoplexes containing plasmid DNA for the therapy of rare genetic diseases such as Lafora disease.
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Quiviger, Mickael, Aristeidis Giannakopoulos, Sebastien Verhenne, Corinne Marie, Eleana F. Stavrou, Karen Vanhoorelbeke, Zsuzsanna Izsvák, Simon F. De Meyer, Aglaia Athanassiadou, and Daniel Scherman. "Improved molecular platform for the gene therapy of rare diseases by liver protein secretion." European Journal of Medical Genetics 61, no. 11 (November 2018): 723–28. http://dx.doi.org/10.1016/j.ejmg.2018.04.010.
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Nakhle, Jean, Anne-Marie Rodriguez, and Marie-Luce Vignais. "Multifaceted Roles of Mitochondrial Components and Metabolites in Metabolic Diseases and Cancer." International Journal of Molecular Sciences 21, no. 12 (June 20, 2020): 4405. http://dx.doi.org/10.3390/ijms21124405.
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Mitochondria are essential cellular components that ensure physiological metabolic functions. They provide energy in the form of adenosine triphosphate (ATP) through the electron transport chain (ETC). They also constitute a metabolic hub in which metabolites are used and processed, notably through the tricarboxylic acid (TCA) cycle. These newly generated metabolites have the capacity to feed other cellular metabolic pathways; modify cellular functions; and, ultimately, generate specific phenotypes. Mitochondria also provide intracellular signaling cues through reactive oxygen species (ROS) production. As expected with such a central cellular role, mitochondrial dysfunctions have been linked to many different diseases. The origins of some of these diseases could be pinpointed to specific mutations in both mitochondrial- and nuclear-encoded genes. In addition to their impressive intracellular tasks, mitochondria also provide intercellular signaling as they can be exchanged between cells, with resulting effects ranging from repair of damaged cells to strengthened progression and chemo-resistance of cancer cells. Several therapeutic options can now be envisioned to rescue mitochondria-defective cells. They include gene therapy for both mitochondrial and nuclear defective genes. Transferring exogenous mitochondria to target cells is also a whole new area of investigation. Finally, supplementing targeted metabolites, possibly through microbiota transplantation, appears as another therapeutic approach full of promises.
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Karahan, Ekin Begum, and Guvenc Kockaya. "Gene and Cell Therapies Overview Under the Light of Health Economics." Health Economics and Management Review 3, no. 4 (2022): 15–22. http://dx.doi.org/10.21272/hem.2022.4-02.
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With the increase in drug development studies for rare diseases, gene therapies have recently come to the fore more frequently. In addition to orphan drugs used in the treatment of rare diseases, advanced therapy medicinal products have been developed. Advanced therapy medicinal products are a fast-growing field. Although it is not a treatment method used only in the field of rare diseases, it is also used in the fields of oncology and cardiovascular diseases, musculoskeletal diseases. Regenerative medicine can be promising in cases where advanced therapy medicinal products are difficult and clinically uncertain. There are various cell therapies related to regenerative medicine and cell-based therapies are one of them. Gene therapies, cell-based therapies, advanced therapy medicinal products and regenerative medicine products have high producer price and high production cost. Because all these treatments have limited clinical evidence and high costs, they are difficult to evaluate in terms of health technology assessment (HTA), and special considerations are needed for evaluation. As a solution, costs should be limited and clinical developments should be provided in cooperation with the society. SAVE (equivalent to young life saved) is recommended to evaluate the lifetime health profiles of curative treatments such as gene therapies. In order to reduce the budgetary burden of gene therapies, outcome-directed entry agreements with income-based payments are recommended. Compulsory use of gene therapies and non-reimbursement of these drugs can lead to catastrophic health expenditures. Various payment methods are offered to avoid catastrophic health expenditures. Income-based payment and outcome-based payment are some of these methods. It is also advocated that high prices should be accepted by the society, since gene therapies to be applied in the treatment of rare diseases will be applied to a small population. Both the support of the society to accept the high price of gene therapies, the support of the producer and the support of the payer are important in the development of gene therapies and their supply to the market.
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Levina, A. S., I. V. Babachenko, N. V. Skripchenko, T. A. Chebotareva, and O. I. Demina. "Therapy of chronic herpesvirus infection in frequently ill children. Possible causes of inefficiency." Russian Journal of Woman and Child Health 5, no. 4 (2022): 332–39. http://dx.doi.org/10.32364/2618-8430-2022-5-4-332-339.
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Background: therapy for frequently ill children (FIC) with chronic herpesvirus infection includes antivirals and immunomodulators as these patients are considered immunocompromised. According to our data based on the prevalence of diseases and the viral replication activity, therapy may fail in 22% of cases. Aim: to identify a spectrum of rare genetic variants associated with primary immunodeficiency (PID) detected in FIC with stable, active persistence of herpesvirus infections that were resistant to repeat courses of antiviral and immunotropic therapy Patients and Methods: DNA samples of 33 frequently ill children with chronic herpesvirus infection who did not respond to therapy were analyzed using targeted high-throughput multigene sequencing to identify mutations in PID-associated genes. Results: pathogenic variants matching the potential diagnosis of PID were identified in two (6.1%) children. Rare genetic variants associated with the development of autoinflammatory diseases were found in 54.5% of cases. The p.Gln705Lys NLRP3 gene variant was the most common finding — it was detected in 5 (15.2%) children. Rare variants of the MEFV gene (MEFV p.Thr767Ile and MEFV p.Lys695Arg) were found in three (9.2%) children. In seven (21.2%) children rare variants of the NOD2 gene were identified, in four of them (12.2%) it was NOD2 p.Leu1007fs. Conclusions: the inefficiency of therapy in frequently ill children with chronic herpesvirus infection could be associated with characteristics of the innate immune system. Such children should be referred to immunology consultant and undergo molecular genetic testing. The detection of rare genetic variants associated with autoinflammatory diseases in more than half of the patients indicates that frequent (occurring every month) diseases with fever may mimic hidden or sometimes typical autoinflammatory diseases, despite the detection of the markers of viral and bacterial agents in a child KEYWORDS: frequently ill children, chronic herpesvirus infection, rare genetic variants, primary immunodeficiency. FOR CITATION: Levina A.S., Babachenko I.V., Skripchenko N.V. et al. Therapy of chronic herpesvirus infection in frequently ill children. Possible causes of inefficiency. Russian Journal of Woman and Child Health. 2022;5(4):332–339 (in Russ.). DOI: 10.32364/2618-8430- 2022-5-4-332-339.
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Liedtke, Maik, Christin Völkner, Andreas Hermann, and Moritz J. Frech. "Impact of Organelle Transport Deficits on Mitophagy and Autophagy in Niemann–Pick Disease Type C." Cells 11, no. 3 (February 1, 2022): 507. http://dx.doi.org/10.3390/cells11030507.
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Defective mitochondria are pathophysiological features of a number of neurodegenerative diseases. Here, we investigated mitochondrial dysfunction in the context of the rare lysosomal storage diseases Niemann–Pick disease type C1 and type C2 (NP-C1 and NP-C2). Mutations in either the NPC1 or NPC2 gene lead to cholesterol accumulation in late endosomes and lysosomes, resulting in impaired cholesterol homeostasis. The extent to which this may lead to mitochondrial dysfunction has been poorly studied so far. Therefore, we investigated the morphology, function, and transport of mitochondria, as well as their degradation via mitophagy, in a disease-associated human neural cell model of NP-C. By performing live cell imaging, we observed markedly reduced mitochondrial transport, although morphology and function were not appreciably altered. However, we observed a defective mitophagy induction shown by a reduced capability to elevate parkin expression and engulf mitochondria in autophagosomes after treatment with carbonyl cyanide 3-chlorophenylhydrazone (CCCP). This was accompanied by defects in autophagy induction, exhibited by a hampered p62 expression and progression, shown by increased LC3BII levels and a defective fusion of autophagosomes and lysosomes. The latter might have been additionally influenced by the observed reduced lysosomal transport. Hence, we hypothesized that a reduced recycling of mitochondria contributes to the pathophysiology of NP-C.
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Côté, Hélène CF. "Possible Ways Nucleoside Analogues Can Affect Mitochondrial Dna Content and Gene Expression during HIV Therapy." Antiviral Therapy 10, no. 2_suppl (February 2005): 3–11. http://dx.doi.org/10.1177/135965350501002s02.
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In recent years, research into nucleoside reverse transcriptase inhibitor (NRTI)-related mitochondrial (mt) toxicity in HIV therapy has led to conflicting results and many unanswered questions regarding the molecular mechanisms that lead to such toxicity. From the early hypothesis that inhibition of the human mt polymerase γ by NRTIs was responsible for the drugs’ mt toxicity, an increasingly complex picture is emerging that probably involves multiple mt pathways. Results have been presented suggesting that NRTIs affect not only mtDNA but also mtRNA, nucleotide phosphorylation and the mt respiratory chain. Based on the current level of knowledge, this overview addresses some of the potential mechanisms through which NRTIs could affect mitochondria and ultimately cause the toxicity symptoms observed in HIV patients receiving NRTI-containing antiretroviral therapy.
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Bacon, Siobhan, and Rachel Crowley. "Developments in rare bone diseases and mineral disorders." Therapeutic Advances in Chronic Disease 9, no. 1 (November 24, 2017): 51–60. http://dx.doi.org/10.1177/2040622317739538.
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In the last decade, there have been a number of significant advances made in the field of rare bone diseases. In this review, we discuss the expansion of the classification system for osteogenesis imperfecta (OI) and the resultant increase in therapeutic options available for management of OI. Bisphosphonates remain the most widely used intervention for OI, although the effect on fracture rate reduction is equivocal. We review the other therapies showing promising results, including denosumab, teriparatide, sclerostin, transforming growth factor β inhibition and gene targeted approaches. X-linked hypophosphataemia (XLH) is the most common heritable form of osteomalacia and rickets caused by a mutation in the phosphate regulating endopeptidase gene resulting in elevated serum fibroblast growth factor 23 (FGF23) and decreased renal phosphate reabsorption. The traditional treatment is phosphate replacement. We discuss the development of a human anti-FGF23 antibody (KRN23) as a promising development in the treatment of XLH. The current management of primary hypoparathyroidism is replacement with calcium and active vitamin D. This can be associated with under or over replacement and its inherent complications. We review the use of recombinant parathyroid hormone (1–84), which can significantly reduce the requirements for calcium and vitamin D resulting in greater safety and quality of life for individuals with hypoparathyroidism. The use of receptor activator of nuclear factor κB ligand infusions in the treatment of a particular form of osteopetrosis and enzyme replacement therapy for hypophosphatasia are also discussed.
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Santiago, Felicidade, and Antonio Torrelo. "Pustular Eruptions in Children as Manifestations of Autoinflammatory Diseases." Journal of the Portuguese Society of Dermatology and Venereology 77, no. 2 (July 12, 2019): 145–52. http://dx.doi.org/10.29021/spdv.77.2.1066.
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Nowadays, in clinical practice, when attending a child with a pustular eruption and systemic inflammation, it is mandatory to think of an autoinflammatory disease, once infectious causes have been ruled out. Although rare, autoinflammatory disease must be recognized as early as possible, accurately diagnosed (including gene testing), and treated with targeted therapy if available.
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Girach, Aniz, Isabelle Audo, David G. Birch, Rachel M. Huckfeldt, Byron L. Lam, Bart P. Leroy, Michel Michaelides, et al. "RNA-based therapies in inherited retinal diseases." Therapeutic Advances in Ophthalmology 14 (January 2022): 251584142211346. http://dx.doi.org/10.1177/25158414221134602.
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Inherited retinal diseases (IRDs) are a genetically and phenotypically heterogeneous group of genetic eye disorders. There are more than 300 disease entities, and together this group of disorders affects millions of people globally and is a frequent cause of blindness or low-vision certification. However, each type is rare or ultra-rare. Characteristically, the impaired vision in IRDs is due to retinal photoreceptor dysfunction and loss resulting from mutation in a gene that codes for a retinal protein. Historically, IRDs have been considered incurable and individuals living with these blinding conditions could be offered only supportive care. However, the treatment landscape for IRDs is beginning to evolve. Progress is being made, driven by improvements in understanding of genotype–phenotype relationships, through advances in molecular genetic testing and retinal imaging. Alongside this expanding knowledge of IRDs, the current era of precision medicine is fueling a growth in targeted therapies. This has resulted in the first treatment for an IRD being approved. Several other therapies are currently in development in the IRD space, including RNA-based therapies, gene-based therapies (such as augmentation therapy and gene editing), cell therapy, visual prosthetics, and optogenetics. RNA-based therapies are a novel approach within precision medicine that have demonstrated success, particularly in rare diseases. Three antisense oligonucleotides (AONs) are currently in development for the treatment of specific IRD subtypes. These RNA-based therapies bring several key advantages in the setting of IRDs, and the potential to bring meaningful vision benefit to individuals living with inherited blinding disorders. This review will examine the increasing breadth and relevance of RNA-based therapies in clinical medicine, explore the key features that make AONs suitable for treating genetic eye diseases, and provide an overview of the three-leading investigational AONs in clinical trials.
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Gorbunova, Victoria N. "Congenital metabolic diseases. Lysosomal storage diseases." Pediatrician (St. Petersburg) 12, no. 2 (August 11, 2021): 73–83. http://dx.doi.org/10.17816/ped12273-83.
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The classification and epidemiology of hereditary metabolic disorders are presented. That is a large group consisting from more them 800 monogenic diseases, each of which caused by inherited deficiency of certain metabolic fate. Many of these disorders are extremely rare, but their total incidence in the population is close to 1:10005000. Lysosomal storage diseases (LSD) resulting from inherited deficiency in lysosomal functions occupy a special place among hereditary metabolic disorders. The defects of catabolism cause the accumulation of undigested or partially digested macromolecules in lysosomes (that is, storage), which can result in cellular damage. About 60 diseases take part in this group with total incidence of about 1:70008000. LSDs typically present in infancy and childhood, although adult-onset forms also occur. Most of them have a progressive neurodegenerative clinical course, although symptoms in other organ systems are frequent. The etiology and pathogenetic aspects of their main clinical entities: mucopolysaccharidosis, glycolipidosis, mucolipidosis, glycoproteinosis, etc, are presented. Mucopolysaccharidoses caused by malfunctioning of lysosomal enzymes needed to break down glycosaminoglycans are more frequent among LSD. Sphingolipidoses caused by defects of lipid catabolism are second for frequency group of LSD. The state-of-art in field of newborn screening. clinical, biochemical and molecular diagnostics of these grave diseases are discussed. The main directions of modern lysosomal storage diseases therapy are characterized: transplantation of hematopoietic stem cells; enzyme replacement therapy; therapy with limitation of substrate synthesis (substrate-reducing therapy); pharmacological chaperone therapy. Perspective directions for LSD therapy are gene therapy and genome editing which are at advanced preclinical stages.
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O'Reilly, Marina, Donald B. Kohn, Jeffrey Bartlett, Janet Benson, Philip J. Brooks, Barry J. Byrne, Carlos Camozzi, et al. "Gene Therapy for Rare Diseases: Summary of a National Institutes of Health Workshop, September 13, 2012." Human Gene Therapy 24, no. 4 (April 2013): 355–62. http://dx.doi.org/10.1089/hum.2013.064.
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Massaro, Giulia, Amy F. Geard, Wenfei Liu, Oliver Coombe-Tennant, Simon N. Waddington, Julien Baruteau, Paul Gissen, and Ahad A. Rahim. "Gene Therapy for Lysosomal Storage Disorders: Ongoing Studies and Clinical Development." Biomolecules 11, no. 4 (April 20, 2021): 611. http://dx.doi.org/10.3390/biom11040611.
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Rare monogenic disorders such as lysosomal diseases have been at the forefront in the development of novel treatments where therapeutic options are either limited or unavailable. The increasing number of successful pre-clinical and clinical studies in the last decade demonstrates that gene therapy represents a feasible option to address the unmet medical need of these patients. This article provides a comprehensive overview of the current state of the field, reviewing the most used viral gene delivery vectors in the context of lysosomal storage disorders, a selection of relevant pre-clinical studies and ongoing clinical trials within recent years.
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Speer, Rebecca R., Uzoamaka C. Ezeanya, Sarah J. Beaudoin, Kristen M. Glass, and Christiana N. Oji-Mmuo. "Term Neonate Presenting with the Combined Occurrence of Mucolipidosis Type II and Leigh Syndrome." Journal of Pediatric Genetics 09, no. 02 (October 24, 2019): 137–41. http://dx.doi.org/10.1055/s-0039-1700519.
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AbstractMucolipidosis II α/beta (MLII) is an autosomal recessive disease in which a gene mutation leads to improper targeting of lysosomal enzymes with an end result of accumulation of lysosomes in the mitochondria resulting in a dysfunctional mitochondria.1 Leigh syndrome (LS) is a rare progressive neurodegenerative disorder associated with dysfunctional mitochondria and oxidative phosphorylation.4 Both disease processes typically present in infancy.3 7 Herein, we present a case of an infant diagnosed with both mucolipidosis II and Leigh syndrome. Genetic analysis in this case revealed two mutations (NDUFA12 c.178C > T p.Arg60* and GNPTAB c.732_733delAA) on the long arm of chromosome 12 as the etiology of MLII and LS in this neonate, respectively. We are unaware of any previously published cases of the presence of these two diseases occurring in the same patient. The complex clinical presentation of this case led to a delay in the diagnosis, and we believe that the clinical phenotypes of these two conditions were likely worsened. The genetic alterations presented in this case occurred as a result of mutations on chromosome 12. We suggest further investigation into the potential overlap in the pathophysiology, specifically the inheritance pattern, linkage disequilibrium, mitochondrial–lysosomal interaction, or crosstalk contributing to both diseases.
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Castejón-Vega, Beatriz, Maurizio Battino, José L. Quiles, Beatriz Bullon, Mario D. Cordero, and Pedro Bullón. "Potential Role of the Mitochondria for the Dermatological Treatment of Papillon-Lefèvre." Antioxidants 10, no. 1 (January 12, 2021): 95. http://dx.doi.org/10.3390/antiox10010095.
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The Papillon–Lefèvre syndrome (PLS) is a rare autosomal recessive disorder caused by mutations in the Cathepsin C (CTSC) gene, characterized by periodontitis and palmoplantar hyperkeratosis. The main inflammatory deficiencies include oxidative stress and autophagic dysfunction. Mitochondria are the main source of reactive oxygen species; their impaired function is related to skin diseases and periodontitis. The mitochondrial function has been evaluated in PLS and mitochondria have been targeted as a possible treatment for PLS. We show for the first time an important mitochondrial dysfunction associated with increased oxidative damage of mtDNA, reduced CoQ10 and mitochondrial mass and aberrant morphologies of the mitochondria in PLS patients. Mitochondrial dysfunction, determined by oxygen consumption rate (OCR) in PLS fibroblasts, was treated with CoQ10 supplementation, which determined an improvement in OCR and a remission of skin damage in a patient receiving a topical administration of a cream enriched with CoQ10 0.1%. We provide the first evidence of the role of mitochondrial dysfunction and CoQ10 deficiency in the pathophysiology of PLS and a future therapeutic option for PLS.
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YANG, KUN, and NAN YAN. "N-Glycanase 1 Deficiency Triggers Innate Immune Activation Through Dysregulated Mitophagy." Journal of Immunology 200, no. 1_Supplement (May 1, 2018): 41.12. http://dx.doi.org/10.4049/jimmunol.200.supp.41.12.
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Abstract The cytosolic N-glycanase 1 (Ngly1) is an evolutionarily conserved de-glycosylating enzyme, which plays a critical role in the quality control of newly synthesized glycoproteins. Misfolded N-glycoproteins retro-translocated from endoplasmic reticulum lumen to cytosol are deglycosylated by Ngly1 prior to proteasome degradation. Mutations in the human NGLY1 gene are associated with a severe rare congenital disorder characterized by global development delay, neurological abnormalities and liver diseases. The pathogenesis of the NGLY1-associated disease remains largely unknown. In this study, we observed an aberrant innate immune activation in both human and mouse Ngly1−/− cells, as evidenced by elevated expression of interferon-stimulated genes that are collectively known as the ‘type I interferon gene signature’. Using pharmacological inhibitors and RNAi knockdown, we identified the cytosolic DNA sensing pathway as the key innate immune pathway activated in Ngly1−/− cells. We also found that Ngly1−/− cells exhibited fragmented mitochondria and mtDNA leakage into the cytosol, which likely serve as the source for self DNA sensed by the innate immunity. Mitochondria are dynamic organelles, and aged or damaged mitochondria are cleared through mitophagy. We found that mitophagy was impaired in the absence of NGLY1. Together, our data reveal the first evidence of immune dysregulation associated with NGLY1 deficiency, as well as defects in mitophagy that likely lead to accumulation of damaged mitochondria, mtDNA leakage into the cytosol and activation of cytosolic DNA sensing pathway.
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Laure Kpoumie, Carolle. "Gene Therapy : The New Weapon Against Diseases Until There Difficult To Overcome: Some Current Facts Of Gene Therapy And Cases Of Sickle Cell Anaemia." Journal of Clinical Research and Reports 4, no. 3 (June 8, 2020): 01–07. http://dx.doi.org/10.31579/2690-1919/075.
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Sickle cell anaemia is an inherited genetic disease that affects the hemoglobin chains of red blood cell hemoglobin, carrying oxygen less well through the body. It is a rare disease, however, it is the most widespread genetic disease in the world and especially widespread in sub-Saharan Africa. It causes anemia, painful seizures that affect several organs, it is also called sickle cell anemia, this disease results in a deformation of red blood cells in the form of sickle or a crescent moon, which prevents normal circulation in the blood vessels. This will cause blood flow to be blocked. It is a disease that is geographically concentrated in certain areas such as Africa, India, Brazil, the Mediterranean Basin, but it is currently found everywhere because of mass migration and has been considered since 2008 by United Nations as a public health priority. Sickle cell disease affects black people and accounts for 50% of deaths in childhood.
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Ren, Duohao, Sylvain Fisson, Deniz Dalkara, and Divya Ail. "Immune Responses to Gene Editing by Viral and Non-Viral Delivery Vectors Used in Retinal Gene Therapy." Pharmaceutics 14, no. 9 (September 19, 2022): 1973. http://dx.doi.org/10.3390/pharmaceutics14091973.
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Inherited retinal diseases (IRDs) are a leading cause of blindness in industrialized countries, and gene therapy is quickly becoming a viable option to treat this group of diseases. Gene replacement using a viral vector has been successfully applied and advanced to commercial use for a rare group of diseases. This, and the advances in gene editing, are paving the way for the emergence of a new generation of therapies that use CRISPR–Cas9 to edit mutated genes in situ. These CRISPR-based agents can be delivered to the retina as transgenes in a viral vector, unpackaged transgenes or as proteins or messenger RNA using non-viral vectors. Although the eye is considered to be an immune-privileged organ, studies in animals, as well as evidence from clinics, have concluded that ocular gene therapies elicit an immune response that can under certain circumstances result in inflammation. In this review, we evaluate studies that have reported on pre-existing immunity, and discuss both innate and adaptive immune responses with a specific focus on immune responses to gene editing, both with non-viral and viral delivery in the ocular space. Lastly, we discuss approaches to prevent and manage the immune responses to ensure safe and efficient gene editing in the retina.
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Borzenkov, S., N. Svyrydova, and L. Borzenkova. "Rare causes of stroke in young people." East European Journal of Neurology, no. 1(19) (December 20, 2018): 27–30. http://dx.doi.org/10.33444/2411-5797.2018.1(19).27-30.
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One of the reasons that can lead to a stroke in young people is Fabry’s disease. This is one of the rare, genetically determined diseases of the X – linked type of inheritance, belonging to the group of lysosomal diseases of accumulation (synonyms: diffuse universal angiokeratoma, hereditary dystonic lipidosis, deficiency of alpha galactosidase A). The genetics of Fabry disease is due to mutations in the GLA gene characterized by a significant decrease in the activity or absence of the enzyme α-galactosidase A. These deviations result in the accumulation of glycosphingolipids, namely, ceramide accumulated in the cytoplasm or lysosomes of cells of various organs and tissues, disrupting their function, causing ischemia and tissue fibrosis. A specific laboratory diagnosis is the determination of the activity of alpha-galactosidase A. In Fabry’s disease, the activity of alpha-galactosidase A in men in men is always reduced, and in women, the activity of GLA may be near the lower limit of norm, or slightly lower, or normal. In Fabry disease symptomatic therapy and enzyme replacement therapy are used to reduce the severity and prevent the symptoms of Fabry disease. Antiplatelet therapy should be the basis of treatment. With timely access to enzyme replacement therapy, the prognosis is favorable.
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Wang, Yung-Chun, Yuchang Wu, Julie Choi, Garrett Allington, Shujuan Zhao, Mariam Khanfar, Kuangying Yang, et al. "Computational Genomics in the Era of Precision Medicine: Applications to Variant Analysis and Gene Therapy." Journal of Personalized Medicine 12, no. 2 (January 27, 2022): 175. http://dx.doi.org/10.3390/jpm12020175.
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Rapid methodological advances in statistical and computational genomics have enabled researchers to better identify and interpret both rare and common variants responsible for complex human diseases. As we continue to see an expansion of these advances in the field, it is now imperative for researchers to understand the resources and methodologies available for various data types and study designs. In this review, we provide an overview of recent methods for identifying rare and common variants and understanding their roles in disease etiology. Additionally, we discuss the strategy, challenge, and promise of gene therapy. As computational and statistical approaches continue to improve, we will have an opportunity to translate human genetic findings into personalized health care.
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Ratican, Sara E., Andrew Osborne, and Keith R. Martin. "Progress in Gene Therapy to Prevent Retinal Ganglion Cell Loss in Glaucoma and Leber’s Hereditary Optic Neuropathy." Neural Plasticity 2018 (2018): 1–11. http://dx.doi.org/10.1155/2018/7108948.
Full textAbstract:
The eye is at the forefront of the application of gene therapy techniques to medicine. In the United States, a gene therapy treatment for Leber’s congenital amaurosis, a rare inherited retinal disease, recently became the first gene therapy to be approved by the FDA for the treatment of disease caused by mutations in a specific gene. Phase III clinical trials of gene therapy for other single-gene defect diseases of the retina and optic nerve are also currently underway. However, for optic nerve diseases not caused by single-gene defects, gene therapy strategies are likely to focus on slowing or preventing neuronal death through the expression of neuroprotective agents. In addition to these strategies, there has also been recent interest in the potential use of precise genome editing techniques to treat ocular disease. This review focuses on recent developments in gene therapy techniques for the treatment of glaucoma and Leber’s hereditary optic neuropathy (LHON). We discuss recent successes in clinical trials for the treatment of LHON using gene supplementation therapy, promising neuroprotective strategies that have been employed in animal models of glaucoma and the potential use of genome editing techniques in treating optic nerve disease.
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Bower, Jacquelyn J., Liujiang Song, Prabhakar Bastola, and Matthew L. Hirsch. "Harnessing the Natural Biology of Adeno-Associated Virus to Enhance the Efficacy of Cancer Gene Therapy." Viruses 13, no. 7 (June 23, 2021): 1205. http://dx.doi.org/10.3390/v13071205.
Full textAbstract:
Adeno-associated virus (AAV) was first characterized as small “defective” contaminant particles in a simian adenovirus preparation in 1965. Since then, a recombinant platform of AAV (rAAV) has become one of the leading candidates for gene therapy applications resulting in two FDA-approved treatments for rare monogenic diseases and many more currently in various phases of the pharmaceutical development pipeline. Herein, we summarize rAAV approaches for the treatment of diverse types of cancers and highlight the natural anti-oncogenic effects of wild-type AAV (wtAAV), including interactions with the cellular host machinery, that are of relevance to enhance current treatment strategies for cancer.
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Meswani, Parag. "From rare monogenic diseases to Parkinson’s: market access considerations for gene therapy across large and small indications." Cell and Gene Therapy Insights 6, no. 7 (August 18, 2020): 1057–65. http://dx.doi.org/10.18609/cgti.2020.115.
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Lee, Seo-Young, and Sun-Ku Chung. "Integrating Gene Correction in the Reprogramming and Transdifferentiation Processes: A One-Step Strategy to Overcome Stem Cell-Based Gene Therapy Limitations." Stem Cells International 2016 (2016): 1–9. http://dx.doi.org/10.1155/2016/2725670.
Full textAbstract:
The recent advent of induced pluripotent stem cells (iPSCs) and gene therapy tools has raised the possibility of autologous cell therapy for rare genetic diseases. However, cellular reprogramming is inefficient in certain diseases such as ataxia telangiectasia, Fanconi anemia, LIG4 syndrome, and fibrodysplasia ossificans progressiva syndrome, owing to interference of the disease-related genes. To overcome these therapeutic limitations, it is necessary to fundamentally correct the abnormal gene during or prior to the reprogramming process. In addition, as genetic etiology of Parkinson’s disease, it has been well known that induced neural stem cells (iNSCs) were progressively depleted by LRRK2 gene mutation, LRRK2 (G2019S). Thus, to maintain the induced NSCs directly derived from PD patient cells harboring LRRK2 (G2019S), it would be ideal to simultaneously treat the LRRK2 (G2019S) fibroblast during the process of TD. Therefore, simultaneous reprogramming (or TD) and gene therapy would provide the solution for therapeutic limitation caused by vulnerability of reprogramming or TD, in addition to being suitable for general application to the generation of autologous cell-therapy products for patients with genetic defects, thereby obviating the need for the arduous processes currently required.