Gene therapy for Aryl-hydrocarbon-interacting protein-like 1 (AIPL1) associated Leber Congenital Amaurosis

Abstract

Purpose : Aryl-hydrocarbon-interacting protein-like 1 (AIPL1) associated Leber Congenital Amaurosis type 4 (LCA4) is characterized by severe sight impairment and rapidly progressive retinal degeneration in infancy. This study investigated the safety of a gene therapy using an adeno-associated viral vector expressing AIPL1 (rAAV2/8.hRKp.AIPL1) in four children with LCA4.

Methods : Four children with biallelic disease-causing sequence variants in AIPL1 were identified; two were homozygous for c.834G>A p.(Trp278Ter), one was homozygous for c.465+1G>C, and one compound heterozygous for c.618_619dupCT p.(Cys207Serfs*3) and c.265T>C p.(Cys89Arg). Their visual acuities were perception of light (n=3) and recognition of high-contrast shapes (n=1) bilaterally. Optical coherence tomography demonstrated relative preservation of central macular outer retinal structure. Following informed consent, the children underwent a 23G pars plana vitrectomy and subretinal injection of rAAV2/8.hRKp.AIPL1 through a 41G canula in their better eye. The Hospital Institutional Review Board approved the administration as an unlicensed medicinal product on compassionate grounds. rAAV2/8.hRKp.AIPL1 was manufactured to good manufacturing practice standards under a Medicines and Healthcare products Regulatory Agency 'Specials' license.

Results : The children were aged 1.0, 2.1, 2.6 and 2.8 years at time of surgery. Between 0.1 and 0.4ml of rAAV2/8.hRKp.AIPL1 was injected through a single retinotomy generating a bleb that involved the macula in each instance. Patients have been followed for a mean of 2.5 years (range 2.1-3.4 years) after surgery. Both the surgery and steroid prophylaxis were well tolerated in all children. One patient required intra-operative cryopexy for two suspicious peripheral retinal areas and one patient had a post-operative subconjunctival hemorrhage. No retinal breaks or detachments were observed. There were no cases of intraocular inflammation, increased intraocular pressure, cataract or systemic adverse events attributable to the treatment. Assessment of functional and anatomical efficacy is on-going, with promising signs observed.

Conclusions : Subretinal injection of rAAV2/8.hRKp.AIPL1 has been well tolerated in all four children, with no safety concerns to date. Additional follow-up and investigation in more infants will be required to better characterise the safety and efficacy of rAAV2/8.hRKp.AIPL1.

This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.