<i>CHM/REP1</i> cDNA delivery by lentiviral vectors provides functional expression of the transgene in the retinal pigment epithelium of choroideremia mice

Tolmachova, Tanya; Tolmachov, Oleg; Wavre‐Shapton, Silène T.; Tracey‐White, Dhani; Futter, Clare E.; Seabra, Miguel C.

doi:10.1002/jgm.1652

Cited by 41 publications

(37 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…component (12)(13)(14)(15). These experimental conditions fail to recapitulate the cellular and molecular environment of diseased photoreceptors in patients who have a complex spatial distribution of stages of disease across the retina (Fig.…”

Section: Significancementioning

confidence: 99%

Successful arrest of photoreceptor and vision loss expands the therapeutic window of retinal gene therapy to later stages of disease

Beltran

Cideciyan

Iwabe

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Inherited retinal degenerations cause progressive loss of photoreceptor neurons with eventual blindness. Corrective or neuroprotective gene therapies under development could be delivered at a predegeneration stage to prevent the onset of disease, as well as at intermediate-degeneration stages to slow the rate of progression. Most preclinical gene therapy successes to date have been as predegeneration interventions. In many animal models, as well as in human studies, to date, retinal gene therapy administered well after the onset of degeneration was not able to modify the rate of progression even when successfully reversing dysfunction. We evaluated consequences of gene therapy delivered at intermediate stages of disease in a canine model of X-linked retinitis pigmentosa (XLRP) caused by a mutation in the Retinitis Pigmentosa GTPase Regulator (RPGR) gene. Spatiotemporal natural history of disease was defined and therapeutic dose selected based on predegeneration results. Then interventions were timed at earlier and later phases of intermediate-stage disease, and photoreceptor degeneration monitored with noninvasive imaging, electrophysiological function, and visual behavior for more than 2 y. All parameters showed substantial and significant arrest of the progressive time course of disease with treatment, which resulted in long-term improved retinal function and visual behavior compared with control eyes. Histology confirmed that the human RPGR transgene was stably expressed in photoreceptors and associated with improved structural preservation of rods, cones, and ON bipolar cells together with correction of opsin mislocalization. These findings in a clinically relevant large animal model demonstrate the long-term efficacy of RPGR gene augmentation and substantially broaden the therapeutic window for intervention in patients with RPGR-XLRP.

show abstract

Section: Significancementioning

confidence: 99%

Successful arrest of photoreceptor and vision loss expands the therapeutic window of retinal gene therapy to later stages of disease

Beltran

Cideciyan

Iwabe

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Despite these favorable factors, the main challenge in developing gene therapy for choroideremia at present remains the lack of an animal model that accurately reflects the human condition. Recently, it has been reported that subretinal injections of a lentiviral CHM/REP1 cDNA transgene resulted in efficient transduction of the RPE, longterm expression for at least 6 mo and a rescued prenylation defect in the CHM mouse (Tolmachova et al 2012). An open-label, dose-escalation phase 1 clinical trial is being undertaken in Oxford University to assess the safety and tolerability of the AAV2.REP1 vector administered at two different doses to the retina in 12 choroideremia patients (see http://ClinicalTrials.gov .identifier: NCT01461213, PI: Rob McLaren).…”

Section: Gene Therapymentioning

confidence: 99%

Clinical Characteristics and Current Therapies for Inherited Retinal Degenerations

Sahel

Marazova

Audo

2014

Cold Spring Harbor Perspectives in Medicine

188

155

View full text Add to dashboard Cite

“…Correction of mutant phenotypes was nevertheless observed in both the photoreceptor and RPE cells, near the injection site. Expression was detected up to 3 weeks after injection ( [12] and unpublished observations), and it is expected that it would be retained longer [15].…”

Section: Hiv-derived Vectorsmentioning

confidence: 90%

Assessment of Different Virus-Mediated Approaches for Retinal Gene Therapy of Usher 1B

Lopes¹,

Diemer

Williams

2014

Retinal Degenerative Diseases

View full text Add to dashboard Cite

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. Here, we review approaches with lentiviruses, which can accommodate larger genes, as well as attempts to use adeno-associated virus (AAV), which has a smaller packaging capacity. In conclusion, both types of viral vector appear to be effective. Despite concerns about the ability of lentiviruses to access the photoreceptor cells, a phenotype of the photoreceptors of Myo7a-mutant mice can be corrected. And although MYO7A cDNA is significantly larger than the nominal carrying capacity of AAV, AAV-MYO7A in single vectors also corrected Myo7a-mutant phenotypes in photoreceptor and RPE cells. Interestingly, however, a dual AAV vector approach was found to be much less effective.

show abstract

CHM/REP1 cDNA delivery by lentiviral vectors provides functional expression of the transgene in the retinal pigment epithelium of choroideremia mice

Abstract: Lentiviral CHM/REP1 cDNA transgene rescues the prenylation defect in CHM mouse RPE and thus could be used to restore REP1 activity in the RPE of CHM patients.

Cited by 41 publications

References 27 publications

Successful arrest of photoreceptor and vision loss expands the therapeutic window of retinal gene therapy to later stages of disease

Successful arrest of photoreceptor and vision loss expands the therapeutic window of retinal gene therapy to later stages of disease

Clinical Characteristics and Current Therapies for Inherited Retinal Degenerations

Assessment of Different Virus-Mediated Approaches for Retinal Gene Therapy of Usher 1B

Contact Info

Product

Resources

About