Maguire, AM, High, KA, Auricchio, A, Wright, JF, Pierce, EA, Testa, F et al.. Age-dependent effects of RPE65 gene therapy for Leber's congenital amaurosis: a phase 1 dose-escalation trial. Lancet 374: 1597-1605

F M Kirby Center for Molecular Ophthalmology, Scheie Eye Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
The Lancet (Impact Factor: 45.22). 11/2009; 374(9701):1597-605. DOI: 10.1016/S0140-6736(09)61836-5
Source: PubMed


Gene therapy has the potential to reverse disease or prevent further deterioration of vision in patients with incurable inherited retinal degeneration. We therefore did a phase 1 trial to assess the effect of gene therapy on retinal and visual function in children and adults with Leber's congenital amaurosis.
We assessed the retinal and visual function in 12 patients (aged 8-44 years) with RPE65-associated Leber's congenital amaurosis given one subretinal injection of adeno-associated virus (AAV) containing a gene encoding a protein needed for the isomerohydrolase activity of the retinal pigment epithelium (AAV2-hRPE65v2) in the worst eye at low (1.5 x 10(10) vector genomes), medium (4.8 x 10(10) vector genomes), or high dose (1.5 x 10(11) vector genomes) for up to 2 years.
AAV2-hRPE65v2 was well tolerated and all patients showed sustained improvement in subjective and objective measurements of vision (ie, dark adaptometry, pupillometry, electroretinography, nystagmus, and ambulatory behaviour). Patients had at least a 2 log unit increase in pupillary light responses, and an 8-year-old child had nearly the same level of light sensitivity as that in age-matched normal-sighted individuals. The greatest improvement was noted in children, all of whom gained ambulatory vision. The study is registered with, number NCT00516477.
The safety, extent, and stability of improvement in vision in all patients support the use of AAV-mediated gene therapy for treatment of inherited retinal diseases, with early intervention resulting in the best potential gain.
Center for Cellular and Molecular Therapeutics at the Children's Hospital of Philadelphia, Foundation Fighting Blindness, Telethon, Research to Prevent Blindness, F M Kirby Foundation, Mackall Foundation Trust, Regione Campania Convenzione, European Union, Associazione Italiana Amaurosi Congenita di Leber, Fund for Scientific Research, Fund for Research in Ophthalmology, and National Center for Research Resources.


Available from: Thomas Michael Redmond, Jul 08, 2014
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    • "The great advances in ocular gene therapy in the past decade can be attributed to the use of AAV vectors. As such AAV vectors have been prominently used in the most recent gene therapy clinical trials, especially in retinal disease, that have shown overwhelming safety and in some trials, efficacy [3] [4] [6]. The main limitation of this virus considering ocular applications is its limited packaging capacity (less than "
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    • "However it remains debated whether these studies have been able to show an age-dependent effect of the treatment since the two studies with larger patient cohorts including younger aged patients have reached contradictory conclusions. In the first study Maguire et al. (2009) concludes that treatment at a younger age does have an overall effect on improved visual function although a later study conducted by Jacobson et al. (2012) shows no correlation between age and treatment effect. The younger patients in the first study (Maguire et al., 2009) do indeed show a more consistent improvement in visual sensitivity when compared to the older group of patients where the results were more variable but this could easily be explained by the heterogeneity of disease severity caused by RPE65 deficiency, generating a complex and individualist relationship between disease progression and age. "
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    • "To date, these inherent properties have been exploited for the development and delivery of gene-and drug-based therapeutics. For example, gene therapy has been used in clinical trials to treat one form of Leber congenital amaurosis (Jacobson et al., 2012; Maguire et al., 2009), while pharmacological agents have been introduced via intraocular injection or encapsulated cell technology in an attempt to mitigate diseases such as wet AMD and RP (Birch et al., 2013; Haller, 2013; Kauper et al., 2012). However, for these types of treatments to succeed, retinal cell types (e.g., photoreceptors and RPE) and structural connections must still exist in vivo. "
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