scholarly journals Deletion of M-opsin prevents “M cone” degeneration in a mouse model of Leber congenital amaurosis

2019 ◽  
Author(s):  
Hui Xu ◽  
Nduka Enemchukwu ◽  
Xiaoyue Zhong ◽  
Olivia Zhang ◽  
Yingbin Fu
Keyword(s):  
Gene Therapy ◽  
Mouse Model ◽  
General Mechanism ◽  
Mouse Line ◽  
Photoreceptor Degeneration ◽  
Multiple Forms ◽  
Leber Congenital Amaurosis ◽  
Reporter Mouse ◽  
Therapy Strategy ◽  
Gene Therapy Strategy

AbstractMutations in RPE65 or lecithin-retinol acyltransferase (LRAT) disrupt 11-cis-retinal synthesis and cause Leber congenital amaurosis (LCA). In Lrat−/− mouse model, mislocalized medium (M)-wavelength sensitive opsin was degraded whereas mislocalized short (S)-wavelength sensitive opsin accumulated before the onset of cone degeneration. The mechanism for the foveal medium (M)/long (L)-wavelength-sensitive cone degeneration in LCA is unknown. By crossing Lrat−/− mice with a proteasome reporter mouse line, we showed that M-opsin enriched dorsal cones in Lrat−/− mice exhibit proteasome stress due to the degradation of large amounts of M-opsin. Deletion of M-opsin relieves the proteasome stress and completely prevents “M cone” degeneration in Lrat−/−Opn1sw−/− mice (a pure “M cone” LCA model, Opn1sw−/− encoding S-opsin) for at least 12 months. Our results suggest that M-opsin degradation associated proteasome stress plays a major role in “M cone” degeneration in Lrat−/− model. This finding may represent a general mechanism for “M cone” degeneration for multiple forms of cone degeneration due to M-opsin mislocalization and degradation. Our results have important implications for the current gene therapy strategy for LCA that emphasizes the need for a combinatorial therapy to both improve vision and slow photoreceptor degeneration.

scholarly journals Gene Therapy Using a miniCEP290 Fragment Delays Photoreceptor Degeneration in a Mouse Model of Leber Congenital Amaurosis

2018 ◽  
Vol 29 (1) ◽  
pp. 42-50 ◽  
Author(s):  
Wei Zhang ◽  
Linjing Li ◽  
Qin Su ◽  
Guangping Gao ◽  
Hemant Khanna
Keyword(s):  
Gene Therapy ◽  
Mouse Model ◽  
Photoreceptor Degeneration ◽  
Leber Congenital Amaurosis

p12CDK2-AP1 Gene Therapy Strategy Inhibits Tumor Growth in an In vivo Mouse Model of Head and Neck Cancer

2005 ◽  
Vol 11 (10) ◽  
pp. 3939-3948 ◽  
Author(s):  
Marxa L. Figueiredo ◽  
Yong Kim ◽  
Maie A.R. St. John ◽  
David T.W. Wong
Keyword(s):  
Gene Therapy ◽  
Head And Neck Cancer ◽  
Mouse Model ◽  
Tumor Growth ◽  
Head And Neck ◽  
Neck Cancer ◽  
Therapy Strategy ◽  
Gene Therapy Strategy

scholarly journals Insulin receptor activation by proinsulin preserves synapses and vision in retinitis pigmentosa

2020 ◽  
Author(s):  
Alonso Sánchez-Cruz ◽  
Alberto Hernández-Pinto ◽  
Concepción Lillo ◽  
Carolina Isiegas ◽  
Miguel Marchena ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Mouse Model ◽  
Retinitis Pigmentosa ◽  
Insulin Receptor ◽  
Visual Function ◽  
Synaptic Connectivity ◽  
Receptor Signaling ◽  
Therapy Strategy ◽  
Insulin Receptor Signaling ◽  
Gene Therapy Strategy

Abstract Background Synaptic loss, neuronal cell death, and circuit remodeling are common features of central nervous system neurodegenerative disorders. Retinitis pigmentosa, the leading cause of inherited blindness, is a group of retinal dystrophies characterized by photoreceptor cell dysfunction and death. The insulin receptor, a key controller of metabolism, also regulates neuronal survival and synaptic formation, maintenance, and activity. Indeed, deficient insulin receptor signaling has been implicated in several brain neurodegenerative pathologies. Methods We employed a gene therapy strategy to enhance insulin receptor signaling in the Pde6b rd10/rd10 mouse model of RP by using recombinant AAV serotype 2/1 viral vectors bearing cDNA from the human proinsulin gene. Insulin receptor expression and signaling were analyzed by PCR and immunostaining. Synaptic connectivity was evaluated by electron microscopy and immunostaining. Proinsulin levels were measured by ELISA. Photoreceptor preservation was assayed by histological analysis and visual function was assessed by electroretinography and optomotor test. Results We present evidence linking impaired insulin receptor signaling with retinitis pigmentosa. We found a selective decrease in the levels of the insulin receptor and its downstream effector phospho-S6 in retinal horizontal cell axons in the rd10 mouse model of retinitis pigmentosa, as well as aberrant synapses between rod photoreceptors and the postsynaptic terminals of horizontal and bipolar cells. A gene therapy strategy to induce sustained proinsulin production restored retinal insulin receptor signaling, by increasing S6 phosphorylation, without peripheral metabolic consequences. Moreover, proinsulin preserved photoreceptor synaptic connectivity and prolonged visual function as determined by electroretinography and optomotor tests. Conclusion These findings point to a disease-modifying role of insulin receptor and support the therapeutic potential of proinsulin in retinitis pigmentosa.

scholarly journals GLT1 gene delivery based on bone marrow-derived cells ameliorates motor function and survival in a mouse model of ALS

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Natsuko Ohashi ◽  
Tomoya Terashima ◽  
Miwako Katagi ◽  
Yuki Nakae ◽  
Junko Okano ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Gene Therapy ◽  
Bone Marrow ◽  
Mouse Model ◽  
Lentiviral Vector ◽  
White Blood Cells ◽  
Glutamate Toxicity ◽  
Pathological Lesion ◽  
Arginase 1 ◽  
Therapy Strategy

AbstractAmyotrophic lateral sclerosis (ALS) is an intractable neurodegenerative disease. CD68-positive bone marrow (BM)-derived cells (BMDCs) accumulate in the pathological lesion in the SOD1(G93A) ALS mouse model after BM transplantation (BMT). Therefore, we investigated whether BMDCs can be applied as gene carriers for cell-based gene therapy by employing the accumulation of BMDCs. In ALS mice, YFP reporter signals were observed in 12–14% of white blood cells (WBCs) and in the spinal cord via transplantation of BM after lentiviral vector (LV) infection. After confirmation of gene transduction by LV with the CD68 promoter in 4–7% of WBCs and in the spinal cord of ALS mice, BM cells were infected with LVs expressing glutamate transporter (GLT) 1 that protects neurons from glutamate toxicity, driven by the CD68 promoter, which were transplanted into ALS mice. The treated mice showed improvement of motor behaviors and prolonged survival. Additionally, interleukin (IL)-1β was significantly suppressed, and IL-4, arginase 1, and FIZZ were significantly increased in the mice. These results suggested that GLT1 expression by BMDCs improved the spinal cord environment. Therefore, our gene therapy strategy may be applied to treat neurodegenerative diseases such as ALS in which BMDCs accumulate in the pathological lesion by BMT.

scholarly journals Gene therapy strategy of glomerulosclerosis.

Ensho ◽  
1998 ◽  
Vol 18 (4) ◽  
pp. 265-269
Author(s):  
Yasufumi Kaneda ◽  
Yoshitaka Isaka ◽  
Enyu Imai
Keyword(s):  
Gene Therapy ◽  
Therapy Strategy ◽  
Gene Therapy Strategy

scholarly journals Peritoneal Dialysis in the 21st Century: The Potential of Gene Therapy

2002 ◽  
Vol 13 (suppl 1) ◽  
pp. S117-S124
Author(s):  
Catherine M. Hoff ◽  
Ty R. Shockley
Keyword(s):  
Gene Therapy ◽  
Peritoneal Dialysis ◽  
Genetic Engineering ◽  
Genetic Manipulation ◽  
Membrane Damage ◽  
Peritoneal Membrane ◽  
Functional Changes ◽  
Therapy Strategy ◽  
Transfer Strategies ◽  
Gene Therapy Strategy

ABSTRACT. One of the greatest biotechnologic advances of the last 25 yr is genetic engineering—the ability to identify and isolate individual genes and transfer genetic elements between cells. Genetic engineering forms the basis of a unique biotechnology platform called gene therapy: an approach to treating disease through genetic manipulation. It is becoming clear that during peritoneal dialysis, the peritoneal membrane undergoes various structural and functional changes that compromise the dialyzing efficiency of the membrane and eventually lead to membrane failure. A gene therapy strategy based on genetic modification of the peritoneal membrane could improve the practice of peritoneal dialysis through the production of proteins that would be of therapeutic value in preventing membrane damage and preserving its dialyzing capacity. The peritoneal membrane can be genetically modified by either ex vivo or in vivo gene transfer strategies with a variety of potentially therapeutic genes, including those for anti-inflammatory cytokines, fibrinolytic factors, and antifibrotic molecules. These genes could be administered either on an acute basis, such as in response to peritonitis, or on an intermittent basis to maintain physiologic homeostasis and perhaps to prevent the adverse changes in the membrane that occur over time. The anticipated effect of a gene therapy strategy could be measured in maintenance of desired transport characteristics and in patients being able to remain on the therapy for longer periods of time without the negative outcomes. In summary, the use of a gene therapy strategy to enhance peritoneal dialysis is an innovative and exciting concept with the potential to provide new treatment platforms for patients with end-stage renal disease.

scholarly journals Replacement Gene Therapy with a HumanRPGRIP1Sequence Slows Photoreceptor Degeneration in a Murine Model of Leber Congenital Amaurosis

2010 ◽  
Vol 21 (8) ◽  
pp. 993-1004 ◽  
Author(s):  
Basil S. Pawlyk ◽  
Oleg V. Bulgakov ◽  
Xiaoqing Liu ◽  
Xiaoyun Xu ◽  
Michael Adamian ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Murine Model ◽  
Photoreceptor Degeneration ◽  
Leber Congenital Amaurosis
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