Abstract Details

B - Gene Targeting and Gene Correction -> B1 – Gene Targeting and Gene Correction – In Vivo Studies (Basic development of novel technologies for genome editing, with or without site-specific endonuclease.

1365: A Human-Ready Regulated AAV9/miniMECP2-miRARE Gene Therapy (TSHA-102) Improves Survival, Weight, and Behavior after Intracerebroventricular (ICV) Dosing in the Neonatal Knockout Rett (RTT) Mouse Model

Type: Poster Session

Poster Board Number: 1365

Presentation Details

Session Title: Friday Poster Session
Location:
Start Time: 5/19/2023 12:00
End Time: 5/19/2023 14:00

Background: Methyl-CpG binding protein 2 (MeCP2) is an X-linked transcription regulator whose loss-of-function and duplication respectively mediate equally severe neurodevelopmental disorders: Rett syndrome (RTT) and MECP2 duplication syndrome. To create an effective gene therapy for RTT while mitigating the risk of overexpression-related side effects, researchers developed a miR-Responsive Autoregulatory Element (miRARE). Insertion of miRARE into the 3’UTR of a miniMECP2-myc viral genome was previously shown to improve the therapeutic profile of miniMECP2-myc gene therapy. More recently, researchers published an abstract describing the efficacy of TSHA-102, a clinical-candidate version of the AAV9/miniMECP2-miRARE vector (lacking the myc epitope tag), after intrathecal administration at postnatal day 7 (P7), P14, and P28. To illustrate the full therapeutic potential of TSHA-102, we also evaluated efficacy after neonatal administration. Methods: TSHA-102 was assessed in a pharmacology study in neonatal Mecp2^-/Y KO mice. This study evaluated the efficacy of TSHA-102 dosing via intracerebroventricular (ICV) route at Postnatal Day 2 (PD2). Efficacy parameters evaluated included body weight (BW), survival, and phenotypic scores (Bird score). Results: ICV administration of TSHA-102 in P2 KO mice at a dose of 8.8 x 10¹⁰ vg/mouse [Human Equivalent Dose, (HED) 2.86 x 10¹⁴ vg/participant (Emami et al 2018)] significantly improved survival, BW, and behavior. The median survival for vehicle-treated KO mice was 8.1 weeks. While the longest-lived vehicle‐treated KO mouse survived to only 13.3 weeks, ~50% of the treated KO mice survived to 36 weeks of age, the age at which monitoring was ended. TSHA‐102 significantly improved BW in KO mice compared to vehicle treated KO mice. Bird score, a composite measure of six different phenotypes, was significantly improved in TSHA‐102‐treated KO mice. TSHA‐102 significantly delayed the average age of onset for severe clasping from approximately 7 to 21 weeks and severely abnormal gait from approximately 8 to 20 weeks. Conclusions: TSHA‐102 treatment at 8.8 x 10¹⁰ vg/mouse extended survival significantly in neonatal Mecp2^‐/Y males, improved weight, improved their overall phenotypic score, and delayed the age of onset for severely abnormal limb clasping and gait.

Kome Okposo¹, Emdadul Haque¹, Chanchal Sadhu², Suyash Prasad², Mary Newman², Michael W. Lawlor³, Steven J. Gray⁴, Sarah E. Sinnett<sup>4

1</sup>Department of Research and Development, Taysha Gene Therapies, Dallas, TX,²Formerly of Department of Research and Development, Taysha Gene Therapies, Dallas, TX,³Diverge Translational Science Laboratory, Milwaukee, WI,⁴Department of Pediatric, University of Texas Southwestern Medical Center, Dallas, TX
  S.E. Sinnett: 1; Commercial Interest i.e. Company X; Taysha Gene Therapies. 1; What was received? i.e. Honorarium; Royalties, lab income, and personal income. 1; For what role? i.e. Speaker; Co-Inventor, Academic Primary Investigator. 2; Commercial Interest i.e. Company X; Abeona Therapeutics. 2; What was received? i.e. Honorarium; Royalties. 2; For what role? i.e. Speaker; Co-Inventor.