IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-60000-3.html
   My bibliography  Save this article

Optimized AAV capsids for basal ganglia diseases show robust potency and distribution

Author

Listed:
  • D. E. Leib

    (The Children’s Hospital of Philadelphia
    Latus Bio)

  • Y. H. Chen

    (The Children’s Hospital of Philadelphia)

  • L. Tecedor

    (The Children’s Hospital of Philadelphia)

  • P. T. Ranum

    (The Children’s Hospital of Philadelphia
    Latus Bio)

  • M. S. Keiser

    (The Ohio State University)

  • B. C. Lewandowski

    (The Children’s Hospital of Philadelphia)

  • E. M. Carrell

    (The Children’s Hospital of Philadelphia)

  • S. Arora

    (The Children’s Hospital of Philadelphia)

  • I. Huerta-Ocampo

    (The Children’s Hospital of Philadelphia)

  • D. Lai

    (The Children’s Hospital of Philadelphia)

  • C. M. Fluta

    (Latus Bio)

  • C. Cheng

    (The Children’s Hospital of Philadelphia)

  • X. Liu

    (The Children’s Hospital of Philadelphia)

  • B. L. Davidson

    (The Children’s Hospital of Philadelphia
    University of Pennsylvania)

Abstract

Huntington’s disease and other disorders of the basal ganglia create challenges for biomolecule-based medicines given the poor accessibility of these deep brain structures following intracerebral or intravascular delivery. Here, we found that low dose, low volume delivery of unbiased AAV libraries into the globus pallidus allowed recovery of novel capsids capable of broad access to key deep brain and cortical structures relevant for human therapies. One such capsid, AAV-DB-3, provided transduction of up to 45% of medium spiny neurons in the adult NHP striatum, along with substantial transduction of relevant deep layer neurons in the cortex. Notably, AAV-DB-3 behaved similarly in mice as in NHPs and potently transduced human neurons derived from induced pluripotent stem cells. Thus, AAV-DB-3 provides a unique AAV for network level brain gene therapies that translates up and down the evolutionary scale for preclinical studies and eventual clinical use.

Suggested Citation

  • D. E. Leib & Y. H. Chen & L. Tecedor & P. T. Ranum & M. S. Keiser & B. C. Lewandowski & E. M. Carrell & S. Arora & I. Huerta-Ocampo & D. Lai & C. M. Fluta & C. Cheng & X. Liu & B. L. Davidson, 2025. "Optimized AAV capsids for basal ganglia diseases show robust potency and distribution," Nature Communications, Nature, vol. 16(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60000-3
    DOI: 10.1038/s41467-025-60000-3
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-60000-3
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-60000-3?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Trevor J. Gonzalez & Katherine E. Simon & Leo O. Blondel & Marco M. Fanous & Angela L. Roger & Maribel Santiago Maysonet & Garth W. Devlin & Timothy J. Smith & Daniel K. Oh & L. Patrick Havlik & Ruth , 2022. "Cross-species evolution of a highly potent AAV variant for therapeutic gene transfer and genome editing," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Timothy F. Shay & Seongmin Jang & Tyler J. Brittain & Xinhong Chen & Beth Walker & Claire Tebbutt & Yujie Fan & Damien A. Wolfe & Cynthia M. Arokiaraj & Erin E. Sullivan & Xiaozhe Ding & Ting-Yu Wang , 2024. "Human cell surface-AAV interactomes identify LRP6 as blood-brain barrier transcytosis receptor and immune cytokine IL3 as AAV9 binder," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    3. Ayano Matsushima & Sergio Sebastian Pineda & Jill R. Crittenden & Hyeseung Lee & Kyriakitsa Galani & Julio Mantero & Geoffrey Tombaugh & Manolis Kellis & Myriam Heiman & Ann M. Graybiel, 2023. "Transcriptional vulnerabilities of striatal neurons in human and rodent models of Huntington’s disease," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Shuang Luo & Hao Jiang & Qingwei Li & Yingfei Qin & Shiping Yang & Jing Li & Lingli Xu & Yan Gou & Yafei Zhang & Fengjiang Liu & Xiao Ke & Qiang Zheng & Xun Sun, 2024. "An adeno-associated virus variant enabling efficient ocular-directed gene delivery across species," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    2. Leonardo D. Garma & Lisbeth Harder & Juan M. Barba-Reyes & Sergio Marco Salas & Mónica Díez-Salguero & Mats Nilsson & Alberto Serrano-Pozo & Bradley T. Hyman & Ana B. Muñoz-Manchado, 2024. "Interneuron diversity in the human dorsal striatum," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    3. Valentina Cigliola & Adam Shoffner & Nutishia Lee & Jianhong Ou & Trevor J. Gonzalez & Jiaul Hoque & Clayton J. Becker & Yanchao Han & Grace Shen & Timothy D. Faw & Muhammad M. Abd-El-Barr & Shyni Var, 2023. "Spinal cord repair is modulated by the neurogenic factor Hb-egf under direction of a regeneration-associated enhancer," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    4. BaDoi N. Phan & Madelyn H. Ray & Xiangning Xue & Chen Fu & Robert J. Fenster & Stephen J. Kohut & Jack Bergman & Suzanne N. Haber & Kenneth M. McCullough & Madeline K. Fish & Jill R. Glausier & Qiao S, 2024. "Single nuclei transcriptomics in human and non-human primate striatum in opioid use disorder," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60000-3. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.