No adverse effects on weight, general activity, or survival in knockout mice and wild type littermates were observed throughout the study.
Data from a preclinical study presented at the 24th Annual Meeting of the American Society of Gene & Cell Therapy (ASGCT), May 12-15, showed that scAAV9 gene therapy could provide a meaningful benefit to patients with SLC13A5 deficiency.
SLC13A5 deficiency, an autosomal recessive disorder, is due to mutations in the SLC13A5 gene, which codes for a plasma membrane sodium-dependent citrate transporter. There are currently no treatments available that target the underlying cause of this disease.
Lead author Rachel Bailey, PhD, assistant professor, University of Texas Southwestern Medical Center, and colleagues compared the efficacy and safety of scAAV9/SLC13A5, a self-complementary vector encoding a codon-optimized human SLC13A5 gene, delivered intrathecally via lumbar puncture (IT) or intra-cisterna magna (ICM) in SLC13A5 knockout (KO) mice and wild type (WT) littermates.
Both KO mice and WT littermates were treated with the gene therapy through IT or ICM delivery at 10 to 12 weeks of age and were monitored for weight and survival. At 1-month post-treatment and beyond, KO mice treated with the gene therapy had significantly decreased plasma citrate levels compared to KO mice treated with vehicle which showed sustained, high citrate levels.
In addition to blood collected at baseline and 5 months after first treatment, the mice received telemetry implants to record electroencephalogram (EEG) and electromyography (EMG) activity over 2 60-hour recording sessions. KO mice treated with vehicle had increased spike train activity and seizure frequency compared to WT littermates and, notably, that the vector treatment reduced this epileptic activity with greater rescue achieved with ICM delivery than IT delivery.
Following the 60-hour recording sessions, mice were tested for susceptibility to seizure induction by pentylenetetrazol (PTZ). KO mice had increased PTZ-induced seizure susceptibility, which was rescued to WT levels with ICM delivery of scAAV9/SLC13A5 and to a lesser extent with IT delivery.
The safety profile of scAAV9/SLC13A5 was robust, with no adverse events on weight, general activity, or survival in KO or WT mice with either IT or ICM delivery.
Bailey and colleagues noted that they used KO mice due to their similarities to patients in that they have increased citrate and abnormalities in TCA intermediates despite not having an overt phenotype. They also noted that these mice have low, but increased epileptic activity compared with WT mice.