LCA5-LCA

Summary

Leber congenital amaurosis (LCA) refers to a group of inherited retinal diseases with congenital or early-onset vision loss. There are more than two dozen genes that cause LCA, one of those genes being LCA5. The LCA5 gene encodes a protein called Lebercilin which localizes the photoreceptor cells and plays a crucial role in the structure and function of photoreceptors.

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LCA5-associated LCA is a severe form of retinal ciliopathy. Initially, we evaluated two unrelated patients with the same homozygous LCA5 mutation using dark-adapted psychophysics and pupillometry to assess visual function. Our results showed major early rod cell loss and relative retention of cone cells highlighting the importance of targeting gene therapy towards cone cells (103). In a multicenter study, we compared visual acuity of different genetic forms of LCA including LCA5 (Walia et al., 2010). In a case study, we documented retinal locations targetable for gene therapy using cross-sectional OCT imaging and autofluorescence imaging (O’Connor et al., 2022).

Recently, we provided a preliminary report of our phase Ib/IIa gene therapy clinical trial using AAV8 LCA5-LCA (OPGx-001) in LCA5 patients (272). The trial observed no serious AEs related to the treatment and exhibited improvements in cone-mediated vision and VR orientation and mobility tests. Efficacy was detectable in severely affected patients at around one-month post treatment that persisted for at least 12 months.

Human clinical trial was preceded by pre-clinical studies. Using the LCA5 null mouse, we analyzed the effects of using a recombinant AAV vector (AAV7m8) both intravitreally and subretinally (Song et al., 2018). This in vivo gene transfer displayed partial rescue of retinal structure and visual function. Additionally, the study showed restoration of the Lebercilin protein and cilia quantity in LCA5 patient-derived iPSC-RPEs. In another collaborative study, severe and rapid photoreceptor degeneration was comparable between LCA5 human patients with biallelic mutations and LCA5^gt/gt mice (Uyhazi et al., 2020). Using a different AAV vector (AAV8-hLCA5) in LCA5^gt/gt mice, we evaluated the therapeutic window for gene therapy if the residual outer nuclear layer (ONL) was found to be greater than 30% of normal. This study suggested that LCA5-LCA patients could potentially benefit from gene augmentation therapies despite the severe early-onset retinal degeneration phenotype.

In summary, we have conducted and performed various experiments and trials to better understand the nature of the LCA5 retinal disease in hopes of developing an effective therapeutic treatment for patients.

6 Publications on LCA5 (Lebercilin)

272. ALEMAN TS, Uyhazi KE, Roman AJ, Weber ML, O'Neil EC, Swider M, Sumaroka A, Maguire KH, Aleman EM, Santos AJ, Kim RJ, Parchinski KM, Billek A, Fradin M, Chung W, Margaritis P, Sun J, Scoles DH, Wu V, Garafalo AV, Jayagopal A, Yerxa B, Tuller S, Maguire AM, Bennett J, CIDECIYAN AV. Recovery of cone-mediated vision in Lebercilin associated retinal ciliopathy after gene therapy: One-year results of a phase I/II trial. Molecular Therapy 33:4784-4798, 2025. [PubMed] [DOI]

O'Connor K, O'Neil EC, ALEMAN TS. Relative preservation of the extramacular retina in LCA5-associated Leber congenital amaurosis. American Journal of Ophthalmology Case Reports 25:101260, 2022. [PubMed] [DOI]

Uyhazi KE, Aravand P, Bell BA, Wei Z, Leo L, Serrano LW, Pearson DJ, Shpylchak I, Pham J, Vasireddy V, Bennett J, ALEMAN TS. Treatment potential for LCA5-associated Leber congenital amaurosis. Investigative Ophthalmology & Visual Science 61:30, 2020. [PubMed] [DOI]

Song JY, Aravand P, Nikonov S, Leo L, Lyubarsky A, Bennicelli JL, Pan J, Wei Z, Shpylchak I, Herrera P, Bennett DJ, Commins N, Maguire AM, Pham J, den Hollander AI, Cremers FPM, Koenekoop RK, Roepman R, Nishina P, Zhou S, Pan W, Ying GS, ALEMAN TS, de Melo J, McNamara I, Sun J, Mills J, Bennett J. Amelioration of neurosensory structure and function in animal and cellular models of a congenital blindness. Molecular Therapy 26:1581-1593, 2018. [PubMed] [DOI]

Walia S, Fishman GA, JACOBSON SG, ALEMAN TS, Koenekoop RK, Traboulsi EI, Weleber RG, Pennesi ME, Heon E, Drack A, Lam BL, Allikmets R, Stone EM. Visual acuity in patients with Leber’s congenital amaurosis and early childhood-onset retinitis pigmentosa. Ophthalmology 117:1190-8, 2010. [PubMed] [DOI]

103. JACOBSON SG, ALEMAN TS, CIDECIYAN AV, Sumaroka A, Schwartz SB, Windsor EAM, Swider M, Herrera W, Stone EM. Leber congenital amaurosis caused by Lebercilin (LCA5) mutation: Retained photoreceptors adjacent to retinal disorganization. Molecular Vision, 15:1098-1106, 2009. [PubMed] [PDF]

Last updated June 18th, 2026