<p>Voretigene Neparvovec and Gene Therapy for Leber’s Congenital Amaurosis: Review of Evidence to Date</p>

Abstract

Gene therapy has now evolved as the upcoming modality for management of many disorders, both inheritable and non-inheritable. Knowledge of genetics pertaining to a disease has therefore become paramount for physicians across most specialities. Inheritable retinal dystrophies (IRDs) are notorious for progressive and relentless vision loss, frequently culminating in complete blindness in both eyes. Leber's congenital amaurosis (LCA) is a typical example of an IRD that manifests very early in childhood. Research in gene therapy has led to the development and approval of voretigene neparvovec (VN) for use in patients of LCA with a deficient biallelic RPE65 gene. The procedure involves delivery of a recombinant virus vector that carries the RPE65 gene in the subretinal space. This comprehensive review reports the evidence thus far in support of gene therapy for LCA. We explore and compare the various gene targets including but not limited to RPE65, and discuss the choice of vector and method for ocular delivery. The review details the evolution of gene therapy with VN in a phased manner, concluding with the challenges that lie ahead for its translation for use in communities that differ much both genetically and economically.

Subretinal Injection Techniques for Retinal Disease: A Review

“…It does not require retrobulbar anesthesia or PPV, it avoids complications and it provides more surface area coverage for the eye’s posterior segment. However, the SCS is not structurally a privileged immune environment and the existence of the choriocapillaris layer allows the medication to be cleared quickly, limiting the retina’s ability to be effectively stimulated by it [ 83 ].…”

“…As noted above, many complications have been described with subretinal injections. These include maculopathy, macular holes, retinal and/or RPE tears, choroidal neovascularization, raised intraocular pressure, irreversible loss of vision, subretinal deposits, cataract, self-resolving subconjunctival and/or retinal hemorrhage, endophthalmitis, outer nuclear layer thinning, vector suspension reflux into the vitreous chamber with subsequent reduction of subretinal drug volumes, and possible immune responses targeting the viral capsids causing vitritis [ 65 , 66 , 83 , 84 , 85 ]. Further, incorrect depth evaluation can lead to undesired events such as choroidal rupture, iatrogenic intrusion of Bruch’s membrane, unintended injection of drug into the vitreous chamber or SCS, and retinal detachment [ 74 ].…”

CRISPR/Cas systems usher in a new era of disease treatment and diagnosis

“…LCA10 is the most prevalent subtype of LCA, a severe retinal degeneration caused by mutations in the CEP290 gene. Gene therapy clinical trials for treating LCA2 by subretinal injection of AAV encoding the full RPE65 gene have shown great success in terms of both safety and efficiency [172,173]. However, the large size of the CEP290 gene limits the loading capacity of the full length gene, and the CRISPR/Cas9 system has been developed to optimize the strategy [174].…”

Szemészeti javallat alapján végzett génterápiás kezelés RPE65 biallelikus génmutáció okozta öröklődő ideghártya-dystrophiában.

“…A voretigén neparvovec az első szemészeti génterápia, melyet a biallelikus RPE65 által közvetített öröklött retina-dystrophiák kezelésére fejlesztettek. A voretigén neparvovec beadása pars plana vitrectomia során subretinalisan történik, így a gyógyszer közvetlenül a fotoreceptorok és a retinalis epithelsejtek sejtmembránjához kerül, azokhoz a retinalis területekhez, amelyek az RPE65-gén mutációja következtében elsősorban károsodnak [20]. Klinikai vizsgálatok alapján a voretigén neparvovec kezelés szignifikáns mértékben javította az RPE65-gén mutációjában szenvedő betegek látásélességét és funkcionális látását [21,22].…”

“…A szemtükör feltalálását követően pár évvel Donders ismertette a kórképre jellemző szemfenéki eltéréseket, és ő használta első alkalommal a retinitis pigmentosa elnevezést [3]. A Leber-féle congenitalis amaurosis a progresszív öröklődő retinabetegségek egyik legsúlyosabb típusa, kialakulásában legalább 28 különböző géndefektusnak lehet szerepe [4,5]. A betegség az első leírójáról, Theodor Leberről kapta az elnevezést [6].…”