Gene Therapy Strategies for Usher Syndrome Type 1B

Williams, David S.; Lopes, Vanda S.

doi:10.1007/978-1-4614-0631-0_31

Cited by 4 publications

(4 citation statements)

References 43 publications

(40 reference statements)

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“…The first demonstration of a functional rescue by way of gene therapy in shaker1 mice, utilized an HIV-based lentiviral vector expressing human MYO7A (HIV-MYO7A) that rescued two other shaker1 phenotypes when introduced via a subretinal injection [28] , [39] . The HIV-MYO7A vector corrected the abnormal phagocytosis and melanosome motility that caused an apical localization of the melanosomes in treated shaker1 mice [40] .…”

Section: Discussionmentioning

confidence: 99%

EIAV-Based Retinal Gene Therapy in the shaker1 Mouse Model for Usher Syndrome Type 1B: Development of UshStat

et al. 2014

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Usher syndrome type 1B is a combined deaf-blindness condition caused by mutations in the MYO7A gene. Loss of functional myosin VIIa in the retinal pigment epithelia (RPE) and/or photoreceptors leads to blindness. We evaluated the impact of subretinally delivered UshStat, a recombinant EIAV-based lentiviral vector expressing human MYO7A, on photoreceptor function in the shaker1 mouse model for Usher type 1B that lacks a functional Myo7A gene. Subretinal injections of EIAV-CMV-GFP, EIAV-RK-GFP (photoreceptor specific), EIAV-CMV-MYO7A (UshStat) or EIAV-CMV-Null (control) vectors were performed in shaker1 mice. GFP and myosin VIIa expression was evaluated histologically. Photoreceptor function in EIAV-CMV-MYO7A treated eyes was determined by evaluating α-transducin translocation in photoreceptors in response to low light intensity levels, and protection from light induced photoreceptor degeneration was measured. The safety and tolerability of subretinally delivered UshStat was evaluated in macaques. Expression of GFP and myosin VIIa was confirmed in the RPE and photoreceptors in shaker1 mice following subretinal delivery of the EIAV-CMV-GFP/MYO7A vectors. The EIAV-CMV-MYO7A vector protected the shaker1 mouse photoreceptors from acute and chronic intensity light damage, indicated by a significant reduction in photoreceptor cell loss, and restoration of the α-transducin translocation threshold in the photoreceptors. Safety studies in the macaques demonstrated that subretinal delivery of UshStat is safe and well-tolerated. Subretinal delivery of EIAV-CMV-MYO7A (UshStat) rescues photoreceptor phenotypes in the shaker1 mouse. In addition, subretinally delivered UshStat is safe and well-tolerated in macaque safety studies These data support the clinical development of UshStat to treat Usher type 1B syndrome.

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Section: Discussionmentioning

confidence: 99%

EIAV-Based Retinal Gene Therapy in the shaker1 Mouse Model for Usher Syndrome Type 1B: Development of UshStat

et al. 2014

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“…The ability to deliver LV-MYO7A to the RPE and photoreceptors was tested by Hashimoto et al [12], by performing subretinal injections into Myo7a-null mice (see [13] for the discussion on the use of Myo7a-null mice as a murine Usher1B model). The MYO7A was driven by a chimeric promoter, composed of elements from CMV and a minimal region of the native MYO7A promoter [14].…”

Section: Hiv-derived Vectorsmentioning

confidence: 99%

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

Lopes¹,

Diemer

Williams

2014

Retinal Degenerative Diseases

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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.

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“…Oxford Biomedica are leading a clinical trial to evaluate the safety of subretinally-delivered lentiviral vectors containing the gene encoding myosin VIIa (http:// clinicaltrials.gov/show/NCT01505062). This was initiated after a demonstration that melanosome apical localisation in RPE cells and opsin transport in photoreceptor cells could be restored in myosin VIIa-defective mice following a subretinal injection of an equine lentivirus carrying the fulllength myosin VIIa cDNA [122]. However, lentiviral transfection of photoreceptor cells is not very efficient, and since photoreceptors are the primary target cells of the USH1 retinopathy, alternative strategies are likely to be needed.…”

Section: Multiple Therapeutic Approaches For the Treatment Of Ush Vis...mentioning

confidence: 99%

“…New vectors targeting visual and auditory sensory cells, and allowing the successful transfer of cDNAs of different sizes is needed, especially since some of the USH proteins are very large. The targeting of photoreceptor cells using adeno-associated viruses (AAV)(either oversized viruses, or a combination of two AAVs containing parts of the USHc DNA, for reconstitution of the full protein in vivo), has been recently undertaken for myosin VIIa and also other USH proteins [122][123][124][125][126]. Some potential therapeutic approaches have recently been developed in some USH mouse models.…”

Section: Multiple Therapeutic Approaches For the Treatment Of Ush Vis...mentioning

confidence: 99%

The retinal phenotype of Usher syndrome: Pathophysiological insights from animal models

El-Amraoui

Petit

2014

Comptes Rendus. Biologies

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Gene Therapy Strategies for Usher Syndrome Type 1B

Cited by 4 publications

References 43 publications

EIAV-Based Retinal Gene Therapy in the shaker1 Mouse Model for Usher Syndrome Type 1B: Development of UshStat

EIAV-Based Retinal Gene Therapy in the shaker1 Mouse Model for Usher Syndrome Type 1B: Development of UshStat

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

The retinal phenotype of Usher syndrome: Pathophysiological insights from animal models

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