Primary Cilia, Ciliogenesis and the Actin Cytoskeleton: A Little Less Resorption, A Little More Actin Please DOI Creative Commons
Claire E. L. Smith,

Alice V. R. Lake,

Colin A. Johnson

et al.

Frontiers in Cell and Developmental Biology, Journal Year: 2020, Volume and Issue: 8

Published: Dec. 17, 2020

Primary cilia are microtubule-based organelles that extend from the apical surface of most mammalian cells, forming when basal body (derived mother centriole) docks at cell membrane. They act as universal cellular "antennae" in vertebrates receive and integrate mechanical chemical signals extracellular environment, serving diverse roles chemo-, mechano- photo-sensation control developmental signaling, polarity proliferation. Mutations ciliary genes cause a major group inherited disorders called ciliopathies. There very few preventative treatments or new therapeutic interventions modify disease progression long-term outlook patients with these conditions. Recent work has identified least four distinct but interrelated processes regulate formation maintenance, comprising cycle, proteostasis, signaling pathways structural influences actin cytoskeleton. The cytoskeleton is composed microfilaments formed filamentous (F) polymers globular G-actin subunits. Actin filaments organized into bundles networks, attached to membrane, by cross-linking proteins. During migration, filament form either radially leading edge axial stress fibers. Early studies demonstrated loss-of-function mutations ciliopathy increased fiber impaired ciliogenesis whereas pharmacological inhibition polymerization promoted ciliogenesis. These suggest cytoskeleton, F-actin branching fibers all inhibit primary cilium formation, depolymerization depletion enhance Here, we review mechanistic basis for effects on ciliogenesis, which comprise several acting concert different timescales. both physical barrier cilia-targeted vesicle transport membrane remodeling required In contrast, may loss localizing disassembly factors base, itself activate YAP/TAZ pathway promote disassembly. fundamental role present potential targets disease-modifying approaches treating

Language: Английский

The approved gene therapy drugs worldwide: from 1998 to 2019 DOI

Cuicui Ma,

Zhen-Ling Wang,

Ting Xu

et al.

Biotechnology Advances, Journal Year: 2019, Volume and Issue: 40, P. 107502 - 107502

Published: Dec. 27, 2019

Language: Английский

Citations

287
Development and Clinical Translation of Approved Gene Therapy Products for Genetic Disorders DOI Creative Commons

Alireza Shahryari,

Marie Saghaeian Jazi, Saeed Mohammadi

et al.

Frontiers in Genetics, Journal Year: 2019, Volume and Issue: 10

Published: Sept. 25, 2019

The field of gene therapy is striving more than ever to define a path the clinic and market. Twenty products have already been approved over two thousand human clinical trials reported world-wide. These advances raise great hope treat devastating rare inherited diseases as well intractable illnesses. Gene presently starting become commercially profitable number cell-based entered market clinic. Understanding precise pathomechanisms emerging efficient specific targeting delivery tools are revolutionizing global Currently, cancers monogenic disorders indications one. elevated prevalence genetic cancers, clear manipulation guidelines, increasing financial support for in major trends. This article addresses history development twenty that up-to-now markets mainly North America, Europe Asia.

Language: Английский

Citations

233
Folding and Misfolding of Human Membrane Proteins in Health and Disease: From Single Molecules to Cellular Proteostasis DOI Creative Commons
Justin T. Marinko, Hui Huang, Wesley D. Penn

et al.

Chemical Reviews, Journal Year: 2019, Volume and Issue: 119(9), P. 5537 - 5606

Published: Jan. 4, 2019

Advances over the past 25 years have revealed much about how structural properties of membranes and associated proteins are linked to thermodynamics kinetics membrane protein (MP) folding. At same time biochemical progress has outlined cellular proteostasis networks mediate MP folding manage misfolding in cell. When combined with results from genomic sequencing, these studies established paradigms for molecular etiologies a variety diseases. This emerging framework paved way development new class small molecule “pharmacological chaperones” that bind stabilize misfolded variants, some which now clinical use. In this review, we comprehensively outline current perspectives on integral MPs as well mechanisms quality control. Based perspectives, highlight opportunities innovations bridge our understanding energetics nuanced complexity biological systems. Given many linkages between human disease, also examine exciting leverage advances address challenges therapeutics precision medicine.

Language: Английский

Citations

227
Retinal stem cell transplantation: Balancing safety and potential DOI Creative Commons
Mandeep S. Singh, Susanna S. Park, Thomas A. Albini

et al.

Progress in Retinal and Eye Research, Journal Year: 2019, Volume and Issue: 75, P. 100779 - 100779

Published: Sept. 5, 2019

Stem cell transplantation holds great promise as a potential treatment for currently incurable retinal degenerative diseases that cause poor vision and blindness. Recently, safety data have emerged from several Phase I/II clinical trials of stem transplantation. These trials, usually run in partnership with academic institutions, are based on sound preclinical studies focused patient safety. However, reports serious adverse events arising therapy other poorly regulated centers now the lay scientific press. While progress research blindness has been greeted enthusiasm by patients, scientists, doctors industry alike, these raised concerns about whether patients truly protected undue harm. The aim this review is to summarize appraise human context its be developed into an effective diseases.

Language: Английский

Citations

200
Managing Bardet–Biedl Syndrome—Now and in the Future DOI Creative Commons
Elizabeth Forsythe, Joanna Kenny,

Chiara Bacchelli

et al.

Frontiers in Pediatrics, Journal Year: 2018, Volume and Issue: 6

Published: Feb. 13, 2018

Bardet-Biedl syndrome is a rare autosomal recessive multisystem disorder caused by defects in genes encoding for proteins that localise to the primary cilium. Twenty one disease-causing have been identified date. It of most well studied conditions family diseases defective cilia collectively known as ciliopathies. In this review we provide an update on diagnostic developments, clinical features and progress management syndrome. Advances technologies including exome whole genome sequencing are expanding spectrum patients who diagnosed with increasing number cases uncertainty. As result developments small only or two being diagnosed. Our understanding syndrome-associated renal disease has evolved reviewed here. Novel interventions developing at rapid pace explored genetic therapeutics such gene therapy, exon skipping nonsense suppression therapy editing. Other non-genetic therapies repurposing, targeted non-pharmacological also discussed.

Language: Английский

Citations

183
Mechanisms of Photoreceptor Death in Retinitis Pigmentosa DOI Open Access
Fay Newton, Roly Megaw

Genes, Journal Year: 2020, Volume and Issue: 11(10), P. 1120 - 1120

Published: Sept. 24, 2020

Retinitis pigmentosa (RP) is the most common cause of inherited blindness and characterised by progressive loss retinal photoreceptors. However, RP a highly heterogeneous disease and, while much progress has been made in developing gene replacement editing treatments for RP, it also necessary to develop that are applicable all causative mutations. Further understanding mechanisms leading photoreceptor death essential development these treatments. Recent work therefore focused on role apoptotic non-apoptotic cell pathways various trigger degenerating In particular, several recent studies have begun elucidate microglia innate immune response progression RP. Here, we discuss some rod cone summarise clinical trials targeting pathways.

Language: Английский

Citations

161
Polymer- and lipid-based nanocarriers for ocular drug delivery: Current status and future perspectives DOI Creative Commons

Haijie Han,

Su Li, Mingyu Xu

et al.

Advanced Drug Delivery Reviews, Journal Year: 2023, Volume and Issue: 196, P. 114770 - 114770

Published: March 7, 2023

Ocular diseases seriously affect patients' vision and life quality, with a global morbidity of over 43 million blindness. However, efficient drug delivery to treat ocular diseases, particularly intraocular disorders, remains huge challenge due multiple barriers that significantly the ultimate therapeutic efficacy drugs. Recent advances in nanocarrier technology offer promising opportunity overcome these by providing enhanced penetration, increased retention, improved solubility, reduced toxicity, prolonged release, targeted loaded eyes. This review primarily provides an overview progress contemporary applications nanocarriers, mainly polymer- lipid-based treating various eye highlighting their value achieving delivery. Additionally, covers administration routes, as well prospective future developments challenges field nanocarriers for diseases.

Language: Английский

Citations

154
Inherited retinal diseases: Linking genes, disease-causing variants, and relevant therapeutic modalities DOI
Nina Schneider, Yogapriya Sundaresan, Prakadeeswari Gopalakrishnan

et al.

Progress in Retinal and Eye Research, Journal Year: 2021, Volume and Issue: 89, P. 101029 - 101029

Published: Nov. 25, 2021

Language: Английский

Citations

129
Retinitis Pigmentosa: Progress in Molecular Pathology and Biotherapeutical Strategies DOI Open Access
Wanqin Liu, Shanshan Liu, Ping Li

et al.

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(9), P. 4883 - 4883

Published: April 28, 2022

Retinitis pigmentosa (RP) is genetically heterogeneous retinopathy caused by photoreceptor cell death and retinal pigment epithelial atrophy that eventually results in blindness bilateral eyes. Various types pathological phenotypic changes have been disclosed RP demand in-depth research of its pathogenic mechanism may account for inter-patient responses to mainstream drug treatment. As the primary method studying genetic characteristics RP, molecular biology has widely used disease diagnosis clinical trials. Current technology iterations, such as gene therapy, stem optogenetics, are advancing towards precise applications. Specifically, technologies, effective delivery vectors, CRISPR/Cas9 technology, iPSC-based transplantation, hasten pace personalized precision medicine RP. The combination conventional therapy state-of-the-art medication promising revolutionizing treatment strategies. This article provides an overview latest on pathogenesis, diagnosis, retinitis pigmentosa, aiming a convenient reference what achieved so far.

Language: Английский

Citations

92
Retinitis Pigmentosa: Current Clinical Management and Emerging Therapies DOI Open Access
Xuan‐Thanh‐An Nguyen,

Lude Moekotte,

Astrid S. Plomp

et al.

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(8), P. 7481 - 7481

Published: April 19, 2023

Retinitis pigmentosa (RP) comprises a group of inherited retinal dystrophies characterized by the degeneration rod photoreceptors, followed cone photoreceptors. As result photoreceptor degeneration, affected individuals experience gradual loss visual function, with primary symptoms progressive nyctalopia, constricted fields and, ultimately, central vision loss. The onset, severity and clinical course RP shows great variability unpredictability, most patients already experiencing some degree disability in childhood. While is currently untreatable for majority patients, significant efforts have been made development genetic therapies, which offer new hope treatment dystrophies. In this exciting era emerging gene it remains imperative to continue supporting using all available options manage their condition. Patients wide variety physical, mental social-emotional difficulties during lifetime, require timely intervention. This review aims familiarize readers management that are RP.

Language: Английский

Citations

60