AAV Gene Therapy

Experience developing 9 gene therapy programs from 2014 to 2023. Responsible for the nonclinical development program and IND-enabling GLP toxicity studies for a monogenic eye disease of the retina, the GUCY2D-associated Leber Congenital Amaurosis (LCA1) gene therapy program. The U.S. Food and Drug Administration (FDA) granted the Regenerative Medicine Advanced Therapy (RMAT) designation to this program based on positive 6-month efficacy data from the Phase I/II clinical trial. Responsible for the nonclinical development program and IND-enabling GLP toxicity study for the Angelman Syndrome gene therapy program and subsequent joint regulatory meeting discussing the advancement of the program to a FIH clinical trial. Responsible for the nonclinical aspects of the EU approved AAV2-hAADC (Eladocagene Exuparvovec) gene therapy program. Responsible for additional GLP and non-GLP toxicity studies requested by authorities for AAV2-hAADC, as well as updates to the BLA for these new data plus an overall revision of all nonclinical components of the BLA for submissions/approvals of non-European Union countries.

Project Team Toxicologist responsible for nonclinical development program:

  • AADC deficiency AAV gene therapy (eladocagene exuparvovec approved in EU July 2022) - 2020 – 2023
  • Angelman Syndrome AAV gene therapy - 2020 - 2023
  • SAR443312 - January 2019 – 2020 (Lentivirus LV - FVIII - XTEN (hemophilia A))
  • SAR443375 - January 2019 – 2020 (Lentivirus FIX (hemophilia B))
  • SAR439483 - January 2014 – 2020 (AAV GUCY2D gene therapy)
  • LC80820 - January 2014 - 2016, 2019 – 2020 (AAV RNAi gene therapy)
  • LC81092 - January 2014 - December 2015 (Hemophilia gene therapy)

Peer Review Manuscripts & Note on Significance:

  • Compton, D.R., DeMarco, S.J., Yalamanchili, P. (2023) AAV2 -hAADC (Eladocagene Exuparvovec) Biodistribution and Expression: Superiority of Intraputaminal Versus Intracerebroventricular and Intrathecal (Lumbar) Routes of Administration. International Journal of Toxicology 42(2) 135-145.

    Publication describing the first gene therapy approved (2022 in Europe) for direct, intraparenchymal brain administration and establishing superiority of intraputaminal route of administration over others, further substantiating the clinical approach treating patients. Not in Scopus

  • Boye, S.L., O'Riordan, C., ; Morris, J., Lukason, M., Compton, D., Baek, R., Elmore, D.M., Peterson, J.J., Fajardo, D., McCullough, K.T., Scaria, A., McVie -Wylie, A., and Boye, S.E. (2023) Preclinical Studies in Support of Phase I/II clinical trials to treat GUCY2D - associated Leber Congenital Amaurosis (LCA1). Molecular Therapy: Methods & Clinical Development 28: 129 -145.

    First publication describing the nonclinical pharmacodynamic and safety data supporting clinical trials (for which efficacy data have been published) and establishing subretinal administration as a viable approach for monogenic inherited retinal diseases of rods and cones, which is distinct from the only gene therapy approved by US FDA to date (2023) treating retinal pigment epithelia (not rod/cone cells per se). Not in Scopus

  • Hwu, P.W., Kiening, K., Anselm, I., Compton, D.R., Nakajima, .T, Opladen, T., Pearl, P.L., Roubertie, A., Roujeau, T., Muramatsu, S.I. (2021) Gene therapy in the putamen for curing AADC deficiency and Parkinson's disease. EMBO Mol Med. Sep 7;13(9):e14712. doi: 10.15252/emmm.202114712. Epub 2021 Aug 23. PMID: 34423905; PMCID: PMC8422070.

    First manuscript summarizing detailed clinical and nonclinical data with probable mechanism(s) of action for the efficacy in patients while contrasting the disease from the more well -known condition of Parkinson.

  • Bolt MW, Whiteley LO, Lynch J, Lauritzen B, de Henestrosa ARF, MacLachlan T, Ulrich P, Philip B, Mahalingaiah PK, Fuller CL, Compton DR (2020) Nonclinical Studies that Support Viral Vector -Delivered Gene Therapies: An EFPIA Gene Therapy Working Group Perspective, Molecular Therapy: Methods & Clinical Development, 19: 89 -98. doi: https://doi.org/10.1016/j.omtm.2020.08.017

    First survey of the variety of approaches taken by industry at a time when there was great uncertainty advancing gene therapies given Guidances as the time.

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