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A4 - AAV Vectors - Preclinical and Proof-of-Concept In-Vivo Studies (Excluding Non-Human Primates)

20: Curable Hyperactive Behaviors and Serum Biomarkers upon Gene Replacement Therapy in Succinic Semialdehyde Dehydrogenase Deficiency in Mice

Type: Oral Abstract Session

Presentation Details
Session Title: AAV Vectors - Preclinical and Proof-of-Concept: Therapy Focus

Introduction: Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare metabolic neurodevelopmental disorder due to loss of function mutations of ALDH5A1 gene. SSADH is essential for degradation of the inhibitory neurotransmitter γ-aminobutyric acid (GABA). In SSADHD, pathologic accumulation of GABA and its metabolite γ-hydroxybutyrate (GHB) results in early life encephalopathy with autism, refractory epilepsy, and high mortality rate from seizures. Targeted drug treatments for SSADHD are ineffective. Gene replacement therapy is a potential cure for SSADHD but is unavailable. As a step toward clinical translation of SSADH gene replacement, we developed and tested the therapeutic efficacy of a novel vector encompassing a human ALDH5A1 full length native promoter (FLnP) tethered with a human ALDH5A1 coding sequence, namely AAV-FLnP-hALDH5A1, and tested its efficacy using SSADH deficient mice. Methods: We packaged AAV-FLnP-hALDH5A1 into PHP.eB capsid and injected into homozygous (HOM) SSADH deficient mice and wild-type (WT) littermates via intraperitoneal (IP) injection at high dose (~6-8x1013 gc/kg) at P14 symptomatic stage. Survival was recorded and tracked until P100. Automated native exploratory behavioral tracking was performed using a high resolution ventral view camera at P100. Whole blood, brain tissues, and internal organs were collected at P100 for serum metabolites and protein analyses. Results: AAV-FLnP-hALDH5A1 administration resulted in significant increase in survival at P100 (55%) compared to 0% (p=0.0002, Fisher Exact Test) in untreated HOM mice (1A). Western blot data revealed that SSADH was restored to 70-95% WT levels in the brain of treated mutants, and up to 50% in other vital organs (1B). Importantly, the level of restored SSADH in brain and myocardium correlated with HOM mice survival. At a behavioral level, we found hyperactive behavior (distance travelled) before treatment (WT=495±46m, HOM=848±16m, p=0.0043, Mann-Whitney test) is reversible upon AAV-FLnP-hALDH5A1 treatment (WT+AAV=517±64m, HOM+AAV=557±38m, p=0.4278, Mann-Whitney test) (2A). These behavioral results corroborate serum biomarkers GHB and GABA demonstrating phenotypic reversibility upon AAV-FLnP-hALDH5A1 treatment: GHB (in µM) - WT=8.99±0.80, untreated HOM=672.17±108.99, AAV-treated HOM=18.60±1.32 (p=0.00001, One-way ANOVA) (2B); GABA (in µM) - WT=5.07±0.17, untreated HOM=10.31±0.47, AAV-treated HOM=6.43±1.10 (p=0.0003, One-way ANOVA) (2C). Conclusions: We demonstrated hyperactive behaviors and disease-associated serum biomarkers in SSADH deficient mice are reversible upon treatment of AAV-FLnP-hALDH5A1 at symptomatic stage. AAV-FLnP-hALDH5A1 therapeutic effects directly correlate with the amount of restored SSADH in brain and myocardium, providing insights into tissue targeting, delivery route, AAV serotype selection, and relevant biomarker for eventual clinical translation of our findings into a first-in-class therapy for SSADHD.

Plain Language Summary
Succinic semialdehyde dehydrogenase deficiency (SSADHD) is a rare metabolic neurodevelopmental disorder (<500 cases) due to loss-of-function mutations of the ALDH5A1 gene. Patients with SSADHD display autistic behaviors, exhibit drug-resistant epilepsy, and face high mortality risks due to uncontrolled seizures. Currently, there is no effective treatment for SSADHD. Gene replacement therapy is a potential cure for SSADHD but is unavailable. Here, we report preclinical findings of an adeno-associated virus (AAV)-based gene replacement strategy in SSADH knock-out mice. We incorporated a full-length native promoter in the AAV vector, driving the functional expression of the human ALDH5A1 gene resembling that of neurotypical brain. We found that our approach increases survival, allows symptom reversal, alleviates hyperactive behaviors, and renormalizes disease-relevant serum metabolites in mice. Our results provide insights into the clinical translation of this first-in-class therapy in SSADHD. Similar approaches incorporating a native promoter in AAV might be broadly applicable for other neurodevelopmental disorders.

Henry Lee1, Gabrielle McGinty1, Amanda Liebhardt1, Bjoern Welzel1, Alex Zhang1, Clifford Woolf1, Guangping Gao2, Alexander Rotenberg1

1Neurology, Boston Children's Hospital, Boston, MA,2UMass Chan Medical School, Worcester, MA"

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