Groundbreaking Organoid Vision Clinical Study: Takahashi Q&A

Clinical trials using organoids are still rare and a Clinicaltrials.gov search for such organoid work largely brings up in vitro studies. A new clinical study in Japan where organoid material will actually be transplanted into patients is causing a lot of excitement.

Masayo Takahashi (高橋 政代) is a pioneer in stem cell-based clinical trial work and more specifically induced pluripotent stem cell (IPSC)-based trials. Her new clinical study is another groundbreaking step in that it is organoid based, in this case for Retinitis pigmentosa.

Today’s post is my Q&A interview with Dr. Takahashi on her new organoid clinical study. You can see an image below from their foundational mouse transplant work. and I would point readers to this pub as well.

Then later in the post I have included a timeline that Dr. Takahashi sent me of the efforts and she noted that sub-team leader Dr. Michiko Mandai MD, PhD is doing a great deal of this work.

Mandai et al Stem Cell Reports, 2017
Mandai et al Stem Cell Reports, 2017.

PK: This is the trial in the world to use a IPS cell derivative for Retinitis pigmentosa, correct? What preclinical work went into the foundation for this?

MT: Yes. First transplantation utilize organoids and first obvious reconstruction of CNS.

Some past related work on retinal differentiation and organoids from pluripotent cells are below:

  • Assawachananont et al Stem Cell Reports 2014  
  • Fujii et al Sci Rep., 2016   
  • Mandai et al Stem Cell Reports, 2017
  • Iraha and Tu et al  Stem Cell reports, 2018
  • Tu and Watanabe et al  EbioMedicine, 2019
  • Akiba et al. eCollection  2019 

PK: What is the rationale for using a retinal organoid as opposed to a sheet or suspension of retinal cells?

MT: We will use tiny retinal progenitor cell sheets cut from retinal organids.

For more than 10 years from the 2006 Nature paper, it had been believed that cell suspension transplant works well in the retina.  But it was proved to be cytoplasmic transfer in 2016 or so.

We believed from the beginning that tissue transplantation is necessary to reconstruct the photoreceptor layer. Our papers were right.

3D retinal organoid transplantation research
3D retinal organoid transplantation research timeline. Takahashi team.

PK: Are there other cells present in the organoids besides photoreceptors? Does the purity matter? What organoid protocol is being used and how long are the organoids allowed to develop?

MT: We will transplant organoids that consists of only retinal progenitors. It will maturate in the patients eye for several months to generate mature photoreceptors. There are other types of retinal cells, but still it is OK to recover the visual function in the completely photoreceptor degenerated retinal

PK: How will the organoids be deployed? Are they surgical implanted in the retina? How organoids used per eye?

MT: Cut tiny sheets from the organdies and transplant into the subretinal space.

PK: Do you predict the organoids will integrate into the eye and the cellular and neural network?

MT: We vigorously confirmed this for nearly 10 years using electrophysiology and behavior tests, which you can see in our papers.

PK: How many patients will be transplanted and how long will the follow-up be?

MT: The plan is 2 patients to start and 1 year of observation. A clinical trial is planned by a company after this study.

7 thoughts on “Groundbreaking Organoid Vision Clinical Study: Takahashi Q&A”

  1. Masayo Takahashi

    Dear Stella,

    Thank you for your comment. This is Masayo.
    I am sorry that we cannot describe about cells QC in detail, since the cells are made by pharmaceutical company and they do not like to share in detail.

    # We will replace degenerated photoreceptors only this time. We will find the cases that is suitable for that kind of treatment. We also plan to do next clinical study using only RPE . And in the future combined sheet transplantation in the future for the cases that need both.

    # The following is the list of articles that show our history of retinal cells and organdies development from pluripotent stem cells.
    Mainly they are done by the members of Dr. Sasai’s lab.

    1. Generation of Rx+/Pax6+ neural retinal precursors from embryonic stem cells.
    Ikeda H, Osakada F, Watanabe K, Mizuseki K, Haraguchi T, Miyoshi H, Kamiya D, Honda Y, Sasai N, Yoshimura N, Takahashi M, Sasai Y.
    Proc Natl Acad Sci U S A. 2005 Aug 9;102(32):11331-6. doi: 10.1073/pnas.0500010102. Epub 2005 Aug
    2. Toward the generation of rod and cone photoreceptors from mouse, monkey and human embryonic stem cells.
    Osakada F, Ikeda H, Mandai M, Wataya T, Watanabe K, Yoshimura N, Akaike A, Sasai Y, Takahashi M.
    Nat Biotechnol. 2008 Feb;26(2):215-24. doi: 10.1038/nbt1384. Epub 2008 Feb 3.
    3. In vitro differentiation of retinal cells from human pluripotent stem cells by small-molecule induction.
    Osakada F, Jin ZB, Hirami Y, Ikeda H, Danjyo T, Watanabe K, Sasai Y, Takahashi M.
    J Cell Sci. 2009 Sep 1;122(Pt 17):3169-79. doi: 10.1242/jcs.050393. Epub 2009 Aug 11.
    4. Self-organizing optic-cup morphogenesis in three-dimensional culture.
    Eiraku M, Takata N, Ishibashi H, Kawada M, Sakakura E, Okuda S, Sekiguchi K, Adachi T, Sasai Y.
    Nature. 2011 Apr 7;472(7341):51-6. doi: 10.1038/nature09941.
    5. Self-formation of optic cups and storable stratified neural retina from human ESCs.
    Nakano T, Ando S, Takata N, Kawada M, Muguruma K, Sekiguchi K, Saito K, Yonemura S, Eiraku M, Sasai Y.
    Cell Stem Cell. 2012 Jun 14;10(6):771-785. doi: 10.1016/j.stem.2012.05.009.
    6.Generation of a ciliary margin-like stem cell niche from self-organizing human retinal tissue.
    Kuwahara A, Ozone C, Nakano T, Saito K, Eiraku M, Sasai Y.
    Nat Commun. 2015 Feb 19;6:6286. doi: 10.1038/ncomms7286.
    7. Preconditioning the Initial State of Feeder-free Human Pluripotent Stem Cells Promotes Self-formation of Three-dimensional Retinal Tissue.
    Kuwahara A, Yamasaki S, Mandai M, Watari K, Matsushita K, Fujiwara M, Hori Y, Hiramine Y, Nukaya D, Iwata M, Kishino A, Takahashi M, Sasai Y, Kimura T.
    Sci Rep. 2019 Dec 12;9(1):18936.

    1. Dear Masayo, thank you for taking the time to reply and for the information. I fully understand the confidentiality issues. Interestingly, my colleagues at the University of Dresden and the German Center for Neurodegenerative Diseases have also developed an organoid system in the last years, but with the aim of generating mature photoreceptors in quantity. Combined with an existing efficient RPE generating protocol, the aim is to transplant both cell types into RP patients (eventually).

      The whole organoid transplantation idea would appear to be simpler but the architecture of the organoids I have seen would not be appropriate for this – they are far away from Dr. Sasai´s eye cups! So it is necessary to isolate, sort, clean, QC, combine, show functional coupling with RPE and then transplant into mouse models. It seems you have done all of this so I have some reading to do!

      I look forward to hearing how the first patients fare, and if the photoreceptors are able to function after transplantation.

      1. Masayo Takahashi

        Thank you for your comments. The results of hESC-RPE transplantation is encouraging. It works in the photoreceptor remained region. You can see the cell body layer (ONL) of photoreceptors was remained before transplantation. Regenerated layer is the outer segments (a portion of photoreceptor cells). It is good that the outer plexiform layer (synaptic layer) was also recovered beautifully.
        Completely degenerated area needs not only RPE but photoreceptor transplantation.

  2. The multicellular concept makes sense for the retina, and has done so since Yoshiki Sasai grew optic cups from ESC back in 2012. But I would have thought there are a huge number of questions to answer before clincal trials, e.g. are all cells post-mitotic, is photoreceptor-RPE coupling sufficient or will you just get another RPE degeneration syndrome in the transplanted tissue. Their publications only address some basic toxicology and differentiation parameters. Maybe there is unpublished information, but I can´t imagine how the FDA would approach this – good job they are in Japan! Fingers crossed.

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