Nonclinical safety and pharmacokinetic assessment of SPVN06, an AAV-based gene therapy for the treatment of rod-cone dystrophies.

Abstract

Purpose : SPVN06 is an adeno-associated viral (AAV) vector encoding the short and long forms of rod-derived viability factor (RdCVF/L) cDNAs under the control of an ubiquitous and cone specific promoters, respectively. It is currently being tested in patients with retinitis pigmentosa of various genetic etiologies for its tolerability and its potential to promote cone photoreceptor survival upon subretinal administration, independently of the causative mutation.

Methods : SPVN06 nonclinical safety and biodistribution were evaluated in two 3-month non-human primate studies at dose levels ranging from 6E9 to 3E11 vector genomes (vg)/eye. Biodistribution was determined in various tissues, including the retina, by qPCR and RT-qPCR assays targeting amplicons in the vector genome or in the 2 the transgenes mRNAs, respectively. Immune response was assessed by detection of total antibodies against the AAV capsid and RdCVF/L proteins as well as detection of cytotoxic T-cells by ELISpot.

Results : The highest levels of SPVN06 vector genome and transgenes mRNA were measured in the retina and RPE/choroid, consistent with the subretinal route of administration. Peak and plateau expression was noted at 1-month and high levels persisted up to 3 months following SPVN06 administration, the longest timepoint evaluated. SPVN06 vector genome was sporadically detected in some non-ocular tissues, with no detectable transgene expression. Interestingly, we observed expression of RdCVFL in all tissues tested despite the presence of a cone specific promoter, likely due to the interference with the strong ubiquitous promoter driving RdCVF expression. Immune response was limited to transient elevation of anti-capsid antibodies.

Conclusions : A ‘no observed adverse effect level’ (NOAEL) dose of 6E10 vg/eye (highest dose tested) could be determined in the pivotal 3-month GLP toxicology and biodistribution study. A clinical starting dose of 6E9 vg/eye was selected considering appropriate safety margins and a pharmacologically active dose level of 1E8 vg/eye established in the rd10 mouse model of the disease.

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