scholarly journals Long-term restoration of visual function in end-stage retinal degeneration using subretinal human melanopsin gene therapy

2017 ◽  
Vol 114 (42) ◽  
pp. 11211-11216 ◽  
Author(s):  
Samantha R. De Silva ◽  
Alun R. Barnard ◽  
Steven Hughes ◽  
Shu K. E. Tam ◽  
Chris Martin ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Retinal Degeneration ◽  
Viral Vector ◽  
Therapeutic Option ◽  
Ectopic Expression ◽  
Action Potential Firing ◽  
Pupil Light Reflex ◽  
Potential Firing ◽  
End Stage

Optogenetic strategies to restore vision in patients who are blind from end-stage retinal degenerations aim to render remaining retinal cells light sensitive once photoreceptors are lost. Here, we assessed long-term functional outcomes following subretinal delivery of the human melanopsin gene (OPN4) in the rd1 mouse model of retinal degeneration using an adeno-associated viral vector. Ectopic expression of OPN4 using a ubiquitous promoter resulted in cellular depolarization and ganglion cell action potential firing. Restoration of the pupil light reflex, behavioral light avoidance, and the ability to perform a task requiring basic image recognition were restored up to 13 mo following injection. These data suggest that melanopsin gene therapy via a subretinal route may be a viable and stable therapeutic option for the treatment of end-stage retinal degeneration in humans.

Chronic Lung Allograft Dysfunction: Evolving Concepts and Therapies

2018 ◽  
Vol 39 (02) ◽  
pp. 155-171 ◽  
Author(s):  
Ariss DerHovanessian ◽  
W. Wallace ◽  
Joseph Lynch ◽  
John Belperio ◽  
S. Weigt
Keyword(s):  
Lung Transplantation ◽  
Therapeutic Option ◽  
Bronchiolitis Obliterans Syndrome ◽  
Term Survival ◽  
Chronic Lung Allograft Dysfunction ◽  
Allograft Dysfunction ◽  
Restrictive Allograft Syndrome ◽  
Technical Advances ◽  
End Stage

AbstractLung transplantation has become an established therapeutic option for a variety of end-stage lung diseases. Technical advances in graft procurement, implantation, perioperative care, immunosuppression, and posttransplant medical management have led to significant improvements in 1-year survival, but outcomes after the first year have improved minimally over the last two decades. The main limitation to better long-term survival after lung transplantation is chronic lung allograft dysfunction (CLAD). CLAD also impairs quality of life and increases the costs of medical care. Our understanding of CLAD manifestations, risk factors, and mechanisms is rapidly evolving. Recognition of different CLAD phenotypes (e.g., bronchiolitis obliterans syndrome and restrictive allograft syndrome) and the unique pathogenic mechanisms will be important for developing novel therapies. In addition to alloimmune-mediated rejection, we now recognize the importance of alloimmune-independent mechanisms of injury to the allograft. CLAD is the consequence of dysregulated repair of allograft injury. Unfortunately, currently available therapies for CLAD are usually not effective. However, the advances in knowledge, reviewed in this manuscript, should lead to novel strategies for CLAD prevention and treatment, as well as improvement in long-term outcomes after lung transplantation. We provide an overview of the evolving terminology related to CLAD, its varying clinical phenotypes and their diagnosis, natural history, pathogenesis, and potential treatments.

scholarly journals Neuroprotection of Retinal Ganglion Cells with AAV2-BDNF Pretreatment Restoring Normal TrkB Receptor Protein Levels in Glaucoma

2020 ◽  
Vol 21 (17) ◽  
pp. 6262
Author(s):  
Anna Wójcik-Gryciuk ◽  
Olga Gajewska-Woźniak ◽  
Katarzyna Kordecka ◽  
Paweł M. Boguszewski ◽  
Wioletta Waleszczyk ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Viral Vector ◽  
Ganglion Cells ◽  
Receptor Protein ◽  
Retinal Ganglion ◽  
Trkb Receptor ◽  
Protein Levels ◽  
Bdnf Signaling ◽  
Selection Of

Intravitreal delivery of brain-derived neurotrophic factor (BDNF) by injection of recombinant protein or by gene therapy can alleviate retinal ganglion cell (RGC) loss after optic nerve injury (ONI) or laser-induced ocular hypertension (OHT). In models of glaucoma, BDNF therapy can delay or halt RGCs loss, but this protection is time-limited. The decreased efficacy of BDNF supplementation has been in part attributed to BDNF TrkB receptor downregulation. However, whether BDNF overexpression causes TrkB downregulation, impairing long-term BDNF signaling in the retina, has not been conclusively proven. After ONI or OHT, when increased retinal BDNF was detected, a concomitant increase, no change or a decrease in TrkB was reported. We examined quantitatively the retinal concentrations of the TrkB protein in relation to BDNF, in a course of adeno-associated viral vector gene therapy (AAV2-BDNF), using a microbead trabecular occlusion model of glaucoma. We show that unilateral glaucoma, with intraocular pressure ( IOP) increased for five weeks, leads to a bilateral decrease of BDNF in the retina at six weeks, accompanied by up to four-fold TrkB upregulation, while a moderate BDNF overexpression in a glaucomatous eye triggers changes that restore normal TrkB concentrations, driving signaling towards long-term RGCs neuroprotection. We conclude that for glaucoma therapy, the careful selection of the appropriate BDNF concentration is the main factor securing the long-term responsiveness of RGCs and the maintenance of normal TrkB levels.

Presynaptic Efficacy Directs Normalization of Synaptic Strength in Layer 2/3 Rat Neocortex After Paired Activity

2007 ◽  
Vol 97 (4) ◽  
pp. 2965-2975 ◽  
Author(s):  
Neil R. Hardingham ◽  
Giles E. Hardingham ◽  
Kevin D. Fox ◽  
Julian J. B. Jack
Keyword(s):  
Long Term Potentiation ◽  
Synaptic Strength ◽  
Action Potential Firing ◽  
Initial Strength ◽  
Adult Rat ◽  
Term Potentiation ◽  
Layer 2 ◽  
Potential Firing ◽  
Rat Neocortex

Paired neuronal activity is known to induce changes in synaptic strength that result in the synapse in question having different properties to unmodified synapses. Here we show that in layer 2/3 excitatory connections in young adult rat cortex paired activity acts to normalize the strength and quantal parameters of connections. Paired action potential firing produces long-term potentiation in only a third of connections, whereas a third remain with their amplitude unchanged and a third exhibit long-term depression. Furthermore, the direction of plasticity can be predicted by the initial strength of the connection: weak connections potentiate and strong connections depress. A quantal analysis reveals that changes in synaptic efficacy were predominantly presynaptic in locus and that the key determinant of the direction and magnitude of synaptic modification was the initial release probability ( Pr) of the synapse, which correlated inversely with change in Pr after pairing. Furthermore, distal synapses also exhibited larger potentiations including postsynaptic increases in efficacy, whereas more proximal inputs did not. This may represent a means by which distal synapses preferentially increase their efficacy to achieve equal weighting at the soma. Paired activity thus acts to normalize synaptic strength, by both pre- and postsynaptic mechanisms.

scholarly journals Gene Therapy Applications of Non-Human Lentiviral Vectors

Viruses ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 1106
Author(s):  
Altar M. Munis
Keyword(s):  
Gene Therapy ◽  
Gene Transfer ◽  
Transgene Expression ◽  
Viral Vector ◽  
Lentiviral Vector ◽  
Cell Therapies ◽  
Dividing Cells ◽  
Cell Genome ◽  
Hiv 1

Recent commercialization of lentiviral vector (LV)-based cell therapies and successful reports of clinical studies have demonstrated the untapped potential of LVs to treat diseases and benefit patients. LVs hold notable and inherent advantages over other gene transfer agents based on their ability to transduce non-dividing cells, permanently transform target cell genome, and allow stable, long-term transgene expression. LV systems based on non-human lentiviruses are attractive alternatives to conventional HIV-1-based LVs due to their lack of pathogenicity in humans. This article reviews non-human lentiviruses and highlights their unique characteristics regarding virology and molecular biology. The LV systems developed based on these lentiviruses, as well as their successes and shortcomings, are also discussed. As the field of gene therapy is advancing rapidly, the use of LVs uncovers further challenges and possibilities. Advances in virology and an improved understanding of lentiviral biology will aid in the creation of recombinant viral vector variants suitable for translational applications from a variety of lentiviruses.

Retinoschisin Gene Therapy and Natural History in theRs1h-KO Mouse: Long-term Rescue from Retinal Degeneration

2007 ◽  
Vol 48 (8) ◽  
pp. 3837 ◽  
Author(s):  
Sten Kjellstrom ◽  
Ronald A. Bush ◽  
Yong Zeng ◽  
Yuichiro Takada ◽  
Paul A. Sieving
Keyword(s):  
Gene Therapy ◽  
Natural History ◽  
Retinal Degeneration

scholarly journals 711. Intravenous Neonatal Gene Therapy Corrects GM2 Gangliosidosis in Sandhoff Mice for Long-Term, By Using AAV Viral Vector Expressing a New Hexosaminidase Variant

2015 ◽  
Vol 23 ◽  
pp. S283-S284
Author(s):  
Karlaina J.L. Osmon ◽  
Evan Woodley ◽  
Patrick Thompson ◽  
Katalina Ong ◽  
Subha Karumuthil-Melethil ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Viral Vector ◽  
Gm2 Gangliosidosis

Abstract 5423: rAAV-Mediated Gene Therapy with Inducible Nitric Oxide Synthase (iNOS) Affords Permanent Cardioprotection (1 Year) without Adverse Functional Consequences

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Qianhong Li ◽  
Yiru Guo ◽  
Wen-Jian Wu ◽  
Qinghui Ou ◽  
Santosh K Sanganalmath ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Gene Transfer ◽  
Viral Vector ◽  
Long Term Effects ◽  
Inos Gene ◽  
Inos Protein Expression ◽  
Functional Consequences ◽  
And Function ◽  
Oxide Synthase

The ultimate goal of prophylactic gene therapy is to confer permanent protection against ischemia. Although gene therapy with iNOS is known to protect against myocardial infarction at 3 days and up to 2 months, the long-term effects of iNOS gene therapy on myocardial ischemic injury and function are unknown. To address this issue, we created a recombinant adeno-associated viral vector carrying the iNOS gene (rAAV/iNOS) which enables long-lasting transgene expression. Mice received injections in anterior LV wall of rAAV/LacZ or rAAV/iNOS; 1 year later, they underwent a 30-min coronary occlusion (O) and 4 h of reperfusion (R). iNOS gene transfer resulted in elevated iNOS protein expression (+ 2.9-fold vs. LacZ group, n=6, P<0.05; Fig ) and iNOS activity (+ 3.3-fold vs. LacZ group, n=4, P<0.05) 1 year later. Infarct size (% of risk region) was dramatically reduced at 1 year after iNOS gene transfer (13.5+/−2.2%, n=12, vs. 42.9+/−2.6%, n=12, in LacZ group; Fig ). The infarct-sparing effects of iNOS gene therapy at 1 year were as powerful as those observed 24 h after ischemic PC (six 4-min O/4-min R cycles) (16.3+/−2.3%, n=8; Fig ). Importantly, compared with the LacZ group (n=11), iNOS gene transfer (n=10) had no effect on LV dimensions or function for up to 1 year (at 1 year: LVEDD 4.4+/−0.1 vs. 4.2+/−0.2 mm; LVESD 2.9+/−0.1 vs. 2.9+/−0.2 mm; FS 34+/−1.8 vs. 32+/−2.6%; EF 56+/−2.3 vs. 60+/−2.9%) (echocardiography). These data demonstrate, for the first time, that rAAV-mediated iNOS gene transfer affords long-term, probably permanent (1 year) cardioprotection without adverse functional consequences, providing a strong rationale for further preclinical testing of prophylactic gene therapy.

A Reappraisal of the Role of Chlorambucil in Patients with End Stage Ovarian Cancer Who Have Previously been Treated with Platinum Regimens

2000 ◽  
Vol 45 (2) ◽  
pp. 51-53 ◽  
Author(s):  
K.S. McCully ◽  
G.V. Narayansingh ◽  
G.P. Cumming ◽  
T.K. Sarkar ◽  
D.E. Parkin
Keyword(s):  
Ovarian Cancer ◽  
Side Effects ◽  
Epithelial Ovarian Cancer ◽  
Therapeutic Option ◽  
Median Number ◽  
Younger Women ◽  
Platinum Based Chemotherapy ◽  
End Stage

The role of chlorambucil in end stage platinum resistant epithelial ovarian cancer was evaluated in women with end stage ovarian cancer. They had received platinum based chemotherapy and all other intravenous chemotherapeutic options had been exhausted. Over a 15 year period, 30 patients were identified. The median age was 64.5 years (range 45–81). The median number of chlorambucil pulses was 4 (range 1–16). The median survival following the introduction of chlorambucil was 5.5 months (range 0.72 – 38.8). The 22 patients who survived for longer than three months were significantly younger than those who did not (p= 0.03). Apart from two patients who developed transient myelosupression there were no toxic side effects. Chlorambucil should be considered as a therapeutic option in end stage ovarian cancer. It is has minimal toxicity, and can be prescribed safely for long term use. In younger women, an increase in benefit may be anticipated.

scholarly journals Limited time window for retinal gene therapy in a preclinical model of ciliopathy

2020 ◽  
Vol 29 (14) ◽  
pp. 2337-2352
Author(s):  
Poppy Datta ◽  
Avri Ruffcorn ◽  
Seongjin Seo
Keyword(s):  
Gene Therapy ◽  
Mouse Model ◽  
Retinal Degeneration ◽  
Time Window ◽  
Therapeutic Effects ◽  
Limited Time ◽  
Term Efficacy ◽  
Disease Stages ◽  
Retinal Gene Therapy

Abstract Retinal degeneration is a common clinical feature of ciliopathies, a group of genetic diseases linked to ciliary dysfunction, and gene therapy is an attractive treatment option to prevent vision loss. Although the efficacy of retinal gene therapy is well established by multiple proof-of-concept preclinical studies, its long-term effect, particularly when treatments are given at advanced disease stages, is controversial. Incomplete treatment and intrinsic variability of gene delivery methods may contribute to the variable outcomes. Here, we used a genetic rescue approach to ‘optimally’ treat retinal degeneration at various disease stages and examined the long-term efficacy of gene therapy in a mouse model of ciliopathy. We used a Bardet–Biedl syndrome type 17 (BBS17) mouse model, in which the gene-trap that suppresses Bbs17 (also known as Lztfl1) expression can be removed by tamoxifen administration, restoring normal gene expression systemically. Our data indicate that therapeutic effects of retinal gene therapy decrease gradually as treatments are given at later stages. These results suggest the presence of limited time window for successful gene therapy in certain retinal degenerations. Our study also implies that the long-term efficacy of retinal gene therapy may depend on not only the timing of treatment but also other factors such as the function of mutated genes and residual activities of mutant alleles.

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