Choroideremia Gene Therapy Phase 2 Clinical Trial: 24-Month Results

Lam, Byron L.; Davis, Janet L.; Gregori, Ninel Z.; MacLaren, Robert E.; Girach, Aniz; Verriotto, Jennifer; Rodriguez, Belen; Rosa, Potyra R.; Zhang, Xiaojun; Feuer, William J.

doi:10.1016/j.ajo.2018.09.012

Cited by 128 publications

(105 citation statements)

References 19 publications

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“…Retinal gene therapy is a complex biological process that depends on multiple factors of which successful vector delivery plays a critical role in determining the safety and efficacy of clinical trials. The two modes of vector delivery in current clinical trials are subretinal 1,[43][44][45][46] and intravitreal [47][48][49][50] administration of adeno-associated viral (AAV) vectors, although suprachoroidal 51 and sub-inner limiting membrane (ILM) 52 approaches are also in preclinical studies. Intravitreal delivery is less technically challenging and has the potential for more widespread retinal gene expression, extending beyond the bleb created by a subretinal injection, as shown in preclinical studies.…”

Section: Delivery Of Vectors and Surgical Challengesmentioning

confidence: 99%

“…46 Improvements in surgical technique since the first patients were injected have improved the safety of subretinal vector administration in current clinical trials. 1,[43][44][45][46] Specifically, to overcome surgical challenges, a two-step technique for subretinal gene therapy has been proposed. 41 This helps to initiate the subretinal bleb with a balanced salt solution during the first step and thus avoid potential vector reflux in cases of difficult detachment.…”

Section: Delivery Of Vectors and Surgical Challengesmentioning

confidence: 99%

“…Gene augmentation for CHM is being explored in multicenter clinical trials using a treatment scenario that departs significantly from the earlier experience in LCA. [43][44][45][46][62][63][64] In mid-to end-stage CHM, there is no alternative but to treat small, fragile central islands of relatively preserved retina that sustain visual acuity that is often way above the legal limit of blindness, a scenario that is quite different from RPE65 and other forms of LCA where severely dysfunctional but less structurally fragile retinas are targets for treatment. The resulting shift in the benefit-to-risk ratio is to be expected for the larger group of non-LCA IRDs at the disease stages that are typically considered for initial clinical trials.…”

Section: Treating Residual Relatively Preserved Functional Retinamentioning

confidence: 99%

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Perspectives on Gene Therapy: Choroideremia Represents a Challenging Model for the Treatment of Other Inherited Retinal Degenerations

MacDonald

Moen²,

Duncan

et al. 2020

Trans. Vis. Sci. Tech.

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Section: Delivery Of Vectors and Surgical Challengesmentioning

confidence: 99%

Section: Delivery Of Vectors and Surgical Challengesmentioning

confidence: 99%

Section: Treating Residual Relatively Preserved Functional Retinamentioning

confidence: 99%

See 1 more Smart Citation

Perspectives on Gene Therapy: Choroideremia Represents a Challenging Model for the Treatment of Other Inherited Retinal Degenerations

MacDonald

Moen²,

Duncan

et al. 2020

Trans. Vis. Sci. Tech.

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“…Initial degeneration due to RP occurs in the photoreceptors, and inner retinal thickness is gradually decreased in advanced-stage RP [10][11][12] . Choroideremia is a rare inherited retinal dystrophy that clinically manifests with gradual vision loss and progressive retinal degeneration with degeneration of retinal pigment epithelium (RPE) cell and photoreceptor, and choroidal atrophy 13 . Because choroideremia is caused by a single mutation or deletion of the CHM gene, gene therapy is an attractive treatment in choroideremia, and both phase II and phase III clinical trials have been actively conducted recently 13,14 .…”

mentioning

confidence: 99%

“…Choroideremia is a rare inherited retinal dystrophy that clinically manifests with gradual vision loss and progressive retinal degeneration with degeneration of retinal pigment epithelium (RPE) cell and photoreceptor, and choroidal atrophy 13 . Because choroideremia is caused by a single mutation or deletion of the CHM gene, gene therapy is an attractive treatment in choroideremia, and both phase II and phase III clinical trials have been actively conducted recently 13,14 . These two diseases result in a common histologic change, which is the loss of the selective photoreceptor layer, leaving a relatively preserved inner retinal layer 11,15,16 .…”

mentioning

confidence: 99%

Morphologic and electrophysiologic findings of retinal degeneration after intravitreal sodium iodate injection following vitrectomy in canines

Ahn

Cha

et al. 2020

Sci Rep

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We developed and characterized a canine model of outer retinal degeneration induced by sodium iodate (SI) intravitreal injection after vitrectomy. In the preliminary study, we repeatedly injected SI intravitreally into the eyes of three canines to develop outer retinal degeneration two weeks after vitrectomy. Based on the preliminary study, a single dose of either 1.2 mg or 1.0 mg SI/0.05 mL was also injected (1.2 mg in n = 5 canines, 1.0 mg in n = 2 canines). Spectral domain-optical coherence tomography (OCT), electroretinography (ERG), and histological examinations were performed at baseline and following intravitreal injection. In the preliminary study, after a 0.5-mg SI injection and a 1.0-mg SI injection and after two 0.8-mg SI injections, retinal degeneration with retinal thinning was observed on OCT imaging. In the second study, after a single 1.0-or 1.2-mg SI injection, outer retinal degeneration was induced. All eyes showed diffuse outer retinal degeneration on OCT and a loss of both cone and rod responses in ERG. Histological examination also showed the loss of outer retinal layer. Intravitreally injected SI (1.0-1.2 mg) in a vitrectomized canine model induced outer retinal degeneration effectively, and could be evaluated through in vivo ophthalmic examination.

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Efficacy and Safety of Retinal Gene Therapy Using Adeno-Associated Virus Vector for Patients With Choroideremia

et al. 2019

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IMPORTANCE Choroideremia (CHM) is a rare, degenerative, genetic retinal disorder resulting from mutation of the CHM gene, leading to an absence of functional ras-associated binding escort protein 1 (REP1). There is currently no approved treatment for CHM.OBJECTIVE To assess the safety and efficacy of retinal gene therapy with an adeno-associated virus vector (AAV2) designed to deliver a functional version of the CHM gene (AAV2-REP1) for treatment of patients with choroideremia. DESIGN, SETTING, AND PARTICIPANTS Tübingen Choroideremia Gene Therapy (THOR) was a single-center, phase 2, open-label randomized clinical trial. Data were collected from January 11, 2016, to February 26, 2018. Twenty-four-month data are reported for 6 men with a molecularly confirmed diagnosis of CHM. Intention-to-treat analysis was used.INTERVENTIONS Patients received AAV2-REP1 by a single, 0.1-mL subretinal injection of 10 11 genome particles during vitrectomy into 1 eye randomly assigned to receive treatment. MAIN OUTCOMES AND MEASURESPrimary end point was change in best-corrected visual acuity (BCVA) on the Early Treatment Diabetic Retinopathy Study chart from baseline to month 24 in the treated eye vs the control eye. Secondary end points included microperimetry variables, change in fundus autofluorescence, and spectral-domain optical coherence tomographic evaluations from baseline to month 24 in the treated eye vs the control eye. RESULTSOn enrollment, the mean (SD) age of the 6 men included in the study was 54.9 (4.1) years. The mean (SD) BCVA score was 60.3 (13.4) (approximately 20/63 Snellen equivalent) in the study eyes and 69.3 (20.6) (approximately 20/40 Snellen equivalent) in the control eyes. At 24 months, the BCVA change was 3.7 (7.5) in the treated eyes and 0.0 (5.1) in the control eyes (difference, 3.7; 95% CI, −7.2 to 14.5; P = .43). Mean change in retinal sensitivity was 10.3 (5.5) dB in the treated eyes and 9.7 (4.9) dB in the control eyes (difference, 0.6; 95% CI, −10.2 to 11.4; P = .74). A total of 28 adverse events were reported; all were consistent with the surgical procedure (eg, conjunctival hyperemia, foreign body sensation), and none were regarded as severe.CONCLUSIONS AND RELEVANCE Among 6 participants, gene therapy with AAV2-REP1 was associated with maintenance or improvement of visual acuity, although no significant difference was found from control eyes. All safety issues were associated with the surgical procedure and none were judged severe. Continued investigations could more precisely define the efficacy and safety of gene therapy with AAV2-REP1 in CHM.

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Choroideremia Gene Therapy Phase 2 Clinical Trial: 24-Month Results

Cited by 128 publications

References 19 publications

Perspectives on Gene Therapy: Choroideremia Represents a Challenging Model for the Treatment of Other Inherited Retinal Degenerations

Perspectives on Gene Therapy: Choroideremia Represents a Challenging Model for the Treatment of Other Inherited Retinal Degenerations

Morphologic and electrophysiologic findings of retinal degeneration after intravitreal sodium iodate injection following vitrectomy in canines

Efficacy and Safety of Retinal Gene Therapy Using Adeno-Associated Virus Vector for Patients With Choroideremia

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