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Robert E. MacLaren, Markus Groppe, Alun R. Barnard, Tanya Tolmachova, Matthew J. During, Susan M. Downes, Andrew J. Lotery, Graeme C. Black, Andrew R. Webster, Miguel C. Seabra; Gene Therapy For Choroideremia - Initial Report On A New Clinical Trial. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5577. doi: https://doi.org/.
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To report the initial findings from a new clinical trial using gene therapy with an adeno-associated viral (AAV) vector encoding Rab escort protein-1 (REP1) to treat patients suffering from choroideremia (NCT01461213).
An AAV2 vector encoding human REP1 driven by a CBA promoter with a woodchuck hepatitis virus post-translational regulatory element (WPRE) was made to Good Medical Practice (GMP) standards and approved for clinical use by the UK Medicines and Healthcare products Regulatory Authority (MHRA). The final vector solution was 1 x 10e12 genome particles (gp) per ml, in 0.001% PF68 surfactant. Two cohorts each of six patients will receive a total dose of 1 x 10e10 gp or 1 x 10e11 gp delivered by subretinal injection. Disease status is measured at baseline using microperimetry, electroretinography, autofluorescence and spectral domain optical coherence tomography (OCT). The primary end point is delivery of vector without complications and the secondary endpoint is measurement of choroidal shrinkage compared to the control eye.
Preclinical testing revealed that surfactant was essential to prevent loss of AAV particles in the plastic injection system. In the first patient to be treated, the retina overlying a residual central island of choroid was detached in a controlled two step procedure, which created a space into which 0.1 ml of the AAV vector suspension was injected through a 41 gauge teflon needle on a 23 gauge cannula. Subretinal fluid was evident at post-operative day one, but had reabsorbed by one week. By one month best corrected visual acuity had returned to at least baseline levels.
In choroideremia the retina can be detached for subretinal injection of an AAV vector expressing REP1 with no immediately obvious detrimental effects on structure or function. The global deficiency of the RPE and choroid does not appear to inhibit reabsorption of subretinal fluid. Choroideremia appears to be a good candidate disease for gene replacement therapy. High resolution clinical imaging tests will require several months to determine whether or not sight loss can be prevented.
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