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Ľ Ďuďáková, B Kousal, H Kolářová, L Hlavatá, P Lišková
The aim of this review is to provide a comprehensive summary of current gene therapy clinical trials for monogenic and optic nerve disorders.The number of genes for which gene-based therapies are being developed is growing. At the time of writing this review gene-based clinical trials have been registered for Leber congenital amaurosis 2 (LCA2), retinitis pigmentosa 38, Usher syndrome 1B, Stargardt disease, choroideremia, achromatopsia, Leber hereditary optic neuropathy (LHON) and X-linked retinoschisis. Apart from RPE65 gene therapy for LCA2 and MT-ND4 for LHON which has reached phase III, all other trials are in investigation phase I and II, i...
2016: Ceská a Slovenská Oftalmologie
Bo Chang
Leber's congenital amaurosis (LCA) is an inherited retinal degenerative disease characterized by severe loss of vision in the first year of life. In addition to early vision loss, a variety of other eye-related abnormalities including roving eye movements, deep-set eyes, and sensitivity to bright light also occur with this disease. Many animal models of LCA are available and the study them has led to a better understanding of the pathology of the disease, and has led to the development of therapeutic strategies aimed at curing or slowing down LCA...
2016: Methods in Molecular Biology
Joshua Schimmer, Steven Breazzano
Spark Therapeutics recently reported positive phase III results for SPK-RPE65 targeting the treatment of visual impairment caused by RPE65 gene mutations (often referred to as Leber congenital amaurosis type 2, or LCA2, but may include other retinal disorders), marking an important inflection point for the field of gene therapy. The results highlight the ability to successfully design and execute a randomized trial of a gene therapy and also reinforce the potentially predictive nature of early preclinical and clinical data...
December 2015: Human Gene Therapy. Clinical Development
Joshua Schimmer, Steven Breazzano
Investor interest in gene therapy has increased substantially over the past few years, and the next major catalyst for the field is likely to be Spark Therapeutics's phase III trial for the treatment of visual impairment caused by RPE65 gene mutations (often referred to as Leber congenital amaurosis type 2, or LCA2, but may include other retinal disorders). Analysis of the approach from the basic genetics, underlying visual mechanisms, clinical data, and commercialization considerations helps frame investor expectations and the potential implications for the broader field...
September 2015: Human Gene Therapy. Clinical Development
Masahiro Kono
Cones are photoreceptor cells used for bright light and color vision. Retinoids are vitamin A derivatives, one of which is the 11-cis aldehyde form that serves as the chromophore for both cone and rod visual pigments. In the visual disease, Type 2 Leber congenital amaurosis (LCA2), 11-cis-retinal generation is inhibited or abolished. Work by others has shown that patients with LCA2 have symptoms consistent with degenerating cones. In mouse models for LCA2, early cone degeneration is readily apparent: cone opsins and other proteins associated with the outer segment are delocalized and cell numbers decline rapidly within the first month...
2015: Progress in Molecular Biology and Translational Science
Caterina Ripamonti, G Bruce Henning, Robin R Ali, James W Bainbridge, Scott J Robbie, Venki Sundaram, Vy A Luong, L Ingeborgh van den Born, Ingele Casteels, Thomy J L de Ravel, Anthony T Moore, Andrew Stockman
PURPOSE: To characterize visual losses associated with genetic mutations in the RPE65 gene that cause defects in the RPE-specific isomerase, RPE65. RPE65 is an important component of the retinoid cycle that restores 11-cis-retinal after its photoisomerization to its all-trans form. The defects investigated here cause Leber's congenital amaurosis (LCA2), an autosomal, recessively-inherited, severe, congenital-onset rod-cone dystrophy. METHODS: Vision was assessed in nine patients and 10 normal controls by measuring: (1) long-wavelength sensitive (L-) cone temporal acuity (critical flicker fusion frequency or cff) as a function of target illuminance, and (2) L-cone temporal contrast sensitivity as a function of temporal frequency at a fixed-target illuminance...
September 25, 2014: Investigative Ophthalmology & Visual Science
Vanda S Lopes, Tanja Diemer, David S Williams
Usher syndrome type 1B, which is characterized by congenital deafness and progressive retinal degeneration, is caused by the loss of the function of MYO7A. Prevention of the retinal degeneration should be possible by delivering functional MYO7A to retinal cells. Although this approach has been used successfully in clinical trials for Leber congenital amaurosis (LCA2), it remains a challenge for Usher 1B because of the large size of the MYO7A cDNA. Different viral vectors have been tested for use in MYO7A gene therapy...
2014: Advances in Experimental Medicine and Biology
Fahad I Al-Saikhan
The advances in gene therapy hold significant promise for the treatment of ophthalmic conditions. Several studies using animal models have been published. Animal models on retinitis pigmentosa, Leber's Congenital Amaurosis (LCA), and Stargardt disease have involved the use of adeno-associated virus (AAV) to deliver functional genes into mice and canines. Mice models have been used to show that a mutation in cGMP phosphodiesterase that results in retinitis pigmentosa can be corrected using rAAV vectors. Additionally, rAAV vectors have been successfully used to deliver ribozyme into mice with a subsequent improvement in autosomal dominant retinitis pigmentosa...
April 2013: Saudi Journal of Ophthalmology: Official Journal of the Saudi Ophthalmological Society
Francesco Testa, Albert M Maguire, Settimio Rossi, Eric A Pierce, Paolo Melillo, Kathleen Marshall, Sandro Banfi, Enrico M Surace, Junwei Sun, Carmela Acerra, J Fraser Wright, Jennifer Wellman, Katherine A High, Alberto Auricchio, Jean Bennett, Francesca Simonelli
OBJECTIVE: The aim of this study was to show the clinical data of long-term (3-year) follow-up of 5 patients affected by Leber congenital amaurosis type 2 (LCA2) treated with a single unilateral injection of adeno-associated virus AAV2-hRPE65v2. DESIGN: Clinical trial. PARTICIPANTS: Five LCA2 patients with RPE65 gene mutations. METHODS: After informed consent and confirmation of trial eligibility criteria, the eye with worse visual function was selected for subretinal delivery of adeno-associated virus (AAV2-hRPE65v2)...
June 2013: Ophthalmology
Qinxiang Zheng, Yueping Ren, Radouil Tzekov, Yuanping Zhang, Bo Chen, Jiangping Hou, Chunhui Zhao, Jiali Zhu, Ying Zhang, Xufeng Dai, Shan Ma, Jia Li, Jijing Pang, Jia Qu, Wensheng Li
Leber congenital amaurosis (LCA) is one of the most severe forms of inherited retinal degeneration and can be caused by mutations in at least 15 different genes. To clarify the proteomic differences in LCA eyes, a cohort of retinal degeneration 12 (rd12) mice, an LCA2 model caused by a mutation in the RPE65 gene, were injected subretinally with an AAV vector (scAAV5-smCBA-hRPE65) in one eye, while the contralateral eye served as a control. Proteomics were compared between untreated rd12 and normal control retinas on P14 and P21, and among treated and untreated rd12 retinas and control retinas on P42...
2012: PloS One
J-J Pang, L Lei, X Dai, W Shi, X Liu, A Dinculescu, J H McDowell
In recent years, more and more mutant genes that cause retinal diseases have been detected. At the same time, many naturally occurring mouse models of retinal degeneration have also been found, which show similar changes to human retinal diseases. These, together with improved viral vector quality allow more and more traditionally incurable inherited retinal disorders to become potential candidates for gene therapy. Currently, the most common vehicle to deliver the therapeutic gene into target retinal cells is the adenoassociated viral vector (AAV)...
March 2012: Current Molecular Medicine
Peter H Tang, Mona C Buhusi, Jian-Xing Ma, Rosalie K Crouch
RPE65 is an abundantly expressed protein within the retinal pigment epithelium (RPE) of the eye that is required for retinoid metabolism to support vision. Its genetic mutations are linked to the congenital disease Leber congenital amaurosis Type 2 (LCA2) characterized by the early onset of central vision loss. Current gene therapy trials have targeted restoration of functional RPE65 within the RPE of these patients with some success. Recent data show that RPE65 is also present within mouse cones to promote function...
December 14, 2011: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Manzar Ashtari, Laura L Cyckowski, Justin F Monroe, Kathleen A Marshall, Daniel C Chung, Alberto Auricchio, Francesca Simonelli, Bart P Leroy, Albert M Maguire, Kenneth S Shindler, Jean Bennett
Leber congenital amaurosis (LCA) is a rare degenerative eye disease, linked to mutations in at least 14 genes. A recent gene therapy trial in patients with LCA2, who have mutations in RPE65, demonstrated that subretinal injection of an adeno-associated virus (AAV) carrying the normal cDNA of that gene (AAV2-hRPE65v2) could markedly improve vision. However, it remains unclear how the visual cortex responds to recovery of retinal function after prolonged sensory deprivation. Here, 3 of the gene therapy trial subjects, treated at ages 8, 9, and 35 years, underwent functional MRI within 2 years of unilateral injection of AAV2-hRPE65v2...
June 2011: Journal of Clinical Investigation
Xia Li, Wensheng Li, Xufeng Dai, Fansheng Kong, Qinxiang Zheng, Xiangtian Zhou, Fan Lü, Bo Chang, Bärbel Rohrer, William W Hauswirth, Jia Qu, Ji-jing Pang
PURPOSE: RPE65 function is necessary in the retinal pigment epithelium (RPE) to generate chromophore for all opsins. Its absence results in vision loss and rapid cone degeneration. Recent Leber congenital amaurosis type 2 (LCA with RPE65 mutations) phase I clinical trials demonstrated restoration of vision on RPE65 gene transfer into RPE cells overlying cones. In the rd12 mouse, a naturally occurring model of RPE65-LCA early cone degeneration was observed; however, some peripheral M-cones remained...
January 2011: Investigative Ophthalmology & Visual Science
Francesca Simonelli, Albert M Maguire, Francesco Testa, Eric A Pierce, Federico Mingozzi, Jeannette L Bennicelli, Settimio Rossi, Kathleen Marshall, Sandro Banfi, Enrico M Surace, Junwei Sun, T Michael Redmond, Xiaosong Zhu, Kenneth S Shindler, Gui-Shuang Ying, Carmela Ziviello, Carmela Acerra, J Fraser Wright, Jennifer Wellman McDonnell, Katherine A High, Jean Bennett, Alberto Auricchio
The safety and efficacy of gene therapy for inherited retinal diseases is being tested in humans affected with Leber's congenital amaurosis (LCA), an autosomal recessive blinding disease. Three independent studies have provided evidence that the subretinal administration of adeno-associated viral (AAV) vectors encoding RPE65 in patients affected with LCA2 due to mutations in the RPE65 gene, is safe and, in some cases, results in efficacy. We evaluated the long-term safety and efficacy (global effects on retinal/visual function) resulting from subretinal administration of AAV2-hRPE65v2...
March 2010: Molecular Therapy: the Journal of the American Society of Gene Therapy
Albert M Maguire, Francesca Simonelli, Eric A Pierce, Edward N Pugh, Federico Mingozzi, Jeannette Bennicelli, Sandro Banfi, Kathleen A Marshall, Francesco Testa, Enrico M Surace, Settimio Rossi, Arkady Lyubarsky, Valder R Arruda, Barbara Konkle, Edwin Stone, Junwei Sun, Jonathan Jacobs, Lou Dell'Osso, Richard Hertle, Jian-xing Ma, T Michael Redmond, Xiaosong Zhu, Bernd Hauck, Olga Zelenaia, Kenneth S Shindler, Maureen G Maguire, J Fraser Wright, Nicholas J Volpe, Jennifer Wellman McDonnell, Alberto Auricchio, Katherine A High, Jean Bennett
Leber's congenital amaurosis (LCA) is a group of inherited blinding diseases with onset during childhood. One form of the disease, LCA2, is caused by mutations in the retinal pigment epithelium-specific 65-kDa protein gene (RPE65). We investigated the safety of subretinal delivery of a recombinant adeno-associated virus (AAV) carrying RPE65 complementary DNA (cDNA) ( number, NCT00516477 []). Three patients with LCA2 had an acceptable local and systemic adverse-event profile after delivery of AAV2...
May 22, 2008: New England Journal of Medicine
Jun Xu, Xinghui Qiu, Jiayin Dai, Hong Cao, Min Yang, Jing Zhang, Muqi Xu
To date, no pure bacterial cultures that could degrade acetochlor have been described. In this study, one strain of microorganism capable of degrading acetochlor, designated as LCa2, was isolated from acetochlor-contaminated soil. The strain LCa2 is Pseudomonas oleovorans according to the criteria of Bergey's manual of determinative bacteriology and sequence analysis of the partial 16S rRNA gene. Optimum growth temperature and pH were 35 degrees C and 8.0, respectively. The strain could degrade 98.03% of acetochlor treated at a concentration of 7...
June 2006: Biodegradation
Fernanda B O Porto, Isabelle Perrault, David Hicks, Jean-Michel Rozet, Noëlle Hanoteau, Sylvain Hanein, Josseline Kaplan, José Alain Sahel
BACKGROUND: Leber's congenital amaurosis (LCA) encompasses the most precocious and severe forms of inherited retinal dystrophy, displaying very significant visual handicap at or soon after birth. Among the currently identified mutations, alterations in the gene coding for retinal pigment epithelium 65-kDa protein (RPE65) lead to LCA2. Existing animal models for LCA2 (RPE65(-/-) null mice and naturally occurring RPE65(-/-) Briard dogs) exhibit near normal retinal histology at birth, although no recordable photofunction can be detected...
July 2002: Journal of Gene Medicine
Shing-Hwa Liu, Shoei-Yn Lin-Shiau
In this study, mercuric chloride was applied to the primary cultures of mouse pancreatic islet cells for studying its effects on resting membrane potential and the intracellular free calcium ion concentration ([Ca 2+), using the techniques of electrophysiology and fluorometry. It was observed that mercuric chloride (1-100 microM) caused a rapid and sustained depolarization, and induced a rapid first phase and a large sustained second phase of elevation in fura-2 fluorescence ratio in islet cells. The depolarization and increased lCa2+]i induced by mercuric chloride could be inhibited by dithiothreitol (a sulfhydryl-containing reducing agent)...
February 2002: Journal of Toxicology and Environmental Health. Part A
M Sakakibara, H Ikeno, S Usui, C Collin, D L Alkon
Two-microelectrode voltage-clamp measurements were made to determine the kinetics and voltage dependence of ionic currents across the soma membrane of the Hermissenda type B photoreceptor. The voltage-dependent outward potassium currents, IA and ICa(2+)-K+, the inward voltage-dependent calcium current, ICa2+ and the light-induced current, IIgt, were then described with Hodgkin-Huxley-type equations. The fast-activating and inactivating potassium current, IA, was described by the equation; IA(t) = gA(max)(ma infinity[1-exp(-t/tau ma)])3 x (ha infinity [1-exp(-t/tau ha)] + exp(-t/tau ha)) (Vm-EK), where the parameters ma infinity, ha infinity, tau ma, and tau ha are functions of membrane potential, Vm, and ma infinity and ha infinity are steady-state activation and inactivation parameters...
July 1993: Biophysical Journal
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