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Choroideremia Gene Therapy

2021; Lippincott Williams & Wilkins; Volume: 61; Issue: 4 Linguagem: Inglês

10.1097/iio.0000000000000385

1536-9617

Byron L. Lam, Janet L. Davis, Ninel Z. Gregori,

Retinopathy of Prematurity Studies

Introduction Choroideremia is a rare X-linked recessive retinal degeneration of photoreceptors, retinal pigment epithelium (RPE), and choroid that progresses in a centripetal manner.1 Choroideremia results from pathologic genetic variants of the CHM gene on the X chromosome with nearly all being loss-of-function null mutations.1 The CHM gene product, Rab escort protein 1 (REP-1), is expressed in all human cells and plays an important role in intracellular protein trafficking.2 REP has 2 isoforms, REP-1 and REP-2, where the autosomal inherited REP-2 can compensate for REP-1 deficiency in most tissues except in the RPE, photoreceptors, and choroid.3 All males harboring disease-causing CHM mutations are affected with progressive retinal degeneration from early childhood. A family history of X-linked retinal degeneration may or may not be present. In contrast, the vast majority of female carriers of CHM mutations are asymptomatic although female carriers may show patchy fundus pigmentation due to mosaicism, where 1 X chromosome is randomly inactivated in each cell in fetal development.4 Depending on the proportion of retinal cells that contain the active mutant gene, female carriers may rarely exhibit severe retinal degeneration. The estimated prevalence of males with choroideremia ranges from 1 in 100,000 to 200,000 persons, and choroideremia may be underdiagnosed because of overlapping symptoms with retinitis pigmentosa (RP) and other retinal dystrophies.1,5 Clinical Assessment On initial presentation in choroideremia, peripheral visual field loss with corresponding areas of degeneration of the choroid and retina along with a normal-appearing fovea are typically found. The areas of chorioretinal degeneration are typically demarcated. A few islands of hyperpigmentation representing RPE hyperplasia may be present. Choroideremia is often misdiagnosed as RP given similar symptoms of night visual impairment and early peripheral visual loss. However, choroideremia has relatively demarcated areas of chorioretinal atrophy with mild retinal vascular attenuation while RP typically has diffuse peripheral retinal degeneration with severe vascular attenuation. Choroideremia may have rare islands of hyperpigmentation, and in contrast a hallmark of RP is the formation of pigmentary clumping (“bone spicules” appearance) likely in part related to RPE migration along retinal vessels toward the inner retina reflecting capillary network at the time of formation. Mild optic disc pallor may develop in advance stage of choroideremia whereas severe diffuse optic disc pallor is common in advanced RP.6 Genetic testing to include detection of CHM (REP-1) gene mutations is essential to confirm the diagnosis of choroideremia. Chorioretinal degeneration mimicking choroideremia may occur in a variety of other IRD genotypes including gyrate atrophy and C2orf71-associated inherited retinal disease as well as other IRDs.7 A combination of optical coherence tomography (OCT) and fundus autofluorescence (FAF) identifies areas of intact RPE and photoreceptor layers and are helpful to determine choroideremia severity and disease progression. Microperimetry, preferably performed after partial dark adaptation, measures retinal sensitivities at specific loci and determines visual function of the viable retina as well as the retinal fixation point. In areas of end-stage degeneration, OCT reveals complete loss of RPE and choroid with residual retinal tissue. In areas of active degeneration, OCT shows areas of thinning of the retinal layer with loss of ellipsoid zone (EZ) layer, outer retinal tubulations, decreased RPE reflectance, and choroidal thinning. Some patients may develop cystoid macular edema and rarely schisis of the retina or choroidal neovacular membrane. The FAF visualizes the remaining viable retina where areas of intact RPE layer are hyperfluorescent. The remaining islands with preserved RPE appear as areas with normal or increased autofluorescence intensity due to lipofuscin accumulation while areas with RPE atrophy are characterized by hypoautofluorescence. Thus FAF intensity is a good indicator for lipofuscin content and RPE integrity. Natural History Males with choroideremia typically experiences subtle nyctalopia starting in childhood with progressive peripheral areas of visual field loss from degeneration of the choroid and retina that gradually coalesce and progress toward the macula. Given these early symptoms are insidious, children and young adolescent males with choroideremia are mostly asymptomatic. Most patients are diagnosed in their late teens or 20s when the central island of vision becomes constricted to <30 degrees with progressively fewer islands of peripheral vision, resulting in difficulties with activities of daily living. Central visual acuity is typically unaffected or mildly affected until advanced stages of the disease when chorioretinal atrophy encroaches into the fovea. Variability of disease severity occurs among affected persons; however, in general, severe visual acuity loss is present by middle age and complete loss of vision can occur in some patients in later life. Prospective longitudinal natural history studies of choroideremia are scarce. The 2-year, prospective, multicenter, observational study (NIGHT study: NSR-CHM-OS1, NCT03359551) is the largest and examines over 300 adult males with genetically confirmed choroideremia and active disease visible within the macula with measurable best-corrected visual acuity (BCVA) in at least one eye using the Early Treatment of Diabetic Retinopathy Study (ETDRS) letter chart.8,9 Preserved area of EZ, preserved area of autofluorescence (PAF), microperimetry, contrast sensitivity, color vision, and reading-speed tests were assessed every 4 months over a period of 20 months. Participants slowly lost BCVA at ~0.5 letters annually. However, older patients with more advanced disease may experience greater decline (Lam et al,10 IOVS 2021;62;ARVO E-Abstract 3545798). PAF area, preserved EZ area, and mean retinal sensitivity on microperimetry consistently decreased at each visit and were generally symmetric. In contrast, bilateral asymmetry for BCVA is evident with a mean inter-eye difference of nearly 20 ETDRS letters with only 26% of individuals showed 15 ETDRS letters with maintenance of the BCVA gain up to 12 months (Nightstar Topline Results). There was no difference detected in the rate of decline of preserved FAF area in treated and control eyes over the study period of 24 months although subfoveal choroidal thickness which is associated with better BCVA declined at a lower rate in the treated versus control eyes from baseline (−5% vs. −24%, respectively).20 Clinical trials using the same AAV2-REP1 vector [Nightstar/Biogen timrepigene emparvovec (BIIB111/AAV2-REP1)] include the GEMINI open-label phase 2 trial to assess safety of bilateral, sequential administration (NCT03507686) and the STAR phase 3 trial to assess efficacy and safety with unilateral randomization to low dose, high dose, and control treatment groups (NCT03496012). The phase 3 STAR trial did not meet its primary endpoint of proportion of participants with a ≥15 ETDRS letter improvement from baseline in BCVA at month 12 in the interventional group in comparison to the noninterventional control group and did not demonstrate efficacy on key secondary endpoints (Biogen topline results June 14, 2021, http://media.biogen.com/news-releases/news-release-details/biogen-announces-topline-results-phase-3-gene-therapy-study), Safety results from the phase 3 STAR study were consistent with previous studies. Of interest, Spark Therapeutics (Philadelphia, PA) initiated a phase 1/2 study of unilateral subretinal administration of AAV2-hCHM vector in subjects with choroideremia and BCVA of better than 20/200 in the study eye (NCT02341807). In addition, 4D molecular therapeutics has initiated a dose escalating phase 1 trial of unilateral intravitreal administration of AAV capsid variant (4D-100) carrying a transgene encoding a codon-optimized human CHM gene in subjects with choroideremia and BCVA of better than 20/200 in the study eye (NCT04483440). Initial clinical safety data at both of the 2 dose levels in the 4D molecular therapeutics trial indicate that 4D-110 was well-tolerated and did not result in any dose-limiting toxicity (n=6; all patients followed between 1 and 9 mo) (4D Molecular Therapeutics topline results June 24, 2021, https://ir.4dmoleculartherapeutics.com/news-releases/news-release-details/4d-molecular-therapeutics-announces-rare-disease-ophthalmology). Gene Therapy Future Given the gene therapy results as well as the progressive nature of the chorioretinal atrophy in choroideremia and the significant unmet need, slowing down the disease progression may be more of an attainable treatment goal than improvement in visual function. Macular-targeted subretinal gene therapy for choroideremia improves BCVA in some treated eyes and the improvement may continue at least up to a few years. However, the phase 3 STAR trial did not meet its primary endpoint of proportion of participants with a ≥15 ETDRS letter improvement from baseline in BCVA at month 12 in the interventional group in comparison to the noninterventional control group and did not demonstrate efficacy on key secondary endpoints. Whether and to what extent macular subretinal gene therapy for choroideremia may slow down disease progression in the macular region requires further study. Intravitreal gene therapy for choroideremia is in early clinical trial testing and its safety and efficacy remain to be determined.