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The RReSTORe Consortium

RReSTORe logo

The Retinal ganglion cell (RGC) Repopulation, Stem cell Transplantation, and Optic nerve Regeneration (RReSTORe) consortium will advance translational development of vision restoration therapies for glaucoma and other primary optic neuropathies by assembling an international group of more than 100 leading and emerging investigators from related fields.

Goals of the consortium are:

  1. To define and prioritize the most critical challenges and questions related to RGC regeneration over the next five years.
  2. To brainstorm innovative tools and experimental approaches to meeting these challenges while fostering opportunities for collaborative scientific investigation among diverse investigators.
 
 

Why this Initiative is Important

Vision loss in optic neuropathies results from death of RGCs, the retinal projection neurons which transmit visual information from retinal neurons (bipolar cells) to retinothalamic brain targets via the optic nerves and optic tracts. Though some species of fish, birds, and amphibians possess ocular regenerative capabilities, human optic neuropathies cause permanent visual deficits because mammalian RGCs are not spontaneously repopulated. Therefore, vision loss is presently irreversible in patients suffering from a range of primary optic neuropathies including glaucoma, ischemic optic neuropathy, optic neuritis, and other inflammatory, toxic, metabolic, inherited, and traumatic optic nerve diseases.

RGC replacement milestonesFigure 1. RGC replacement milestones, which have been partly achieved in isolation. (1) Develop a reliable source of transplantable RGCs. (2) Deliver donor cells (red) safely. (3) Promote long-term donor RGC survival in the recipient eye. (4) Establish retinal localization and neuritogenesis. (5) Form synaptic connectivity with host retinal interneurons in the inner plexiform layer. (6) Conduct light-evoked, photoreceptor-transduced signals within the visual pathway. (7) Achieve axon growth toward the optic nerve head and into the optic nerve. (8) Develop myelination of new axons. (9) Reinnervate retinorecipient nuclei, including suprachiasmatic nucleus, lateral geniculate nucleus, olivary pretectal nucleus, and superior colliculus. Reprinted from: Zhang KY, Aguzzi EA, and Johnson TV. Retinal ganglion cell transplantation: Approaches for overcoming challenges to functional integration. 2021. Cells. 10(6):1426.

How Can Vision be Restored in Optic Neuropathy?

RGC replacement poses a significant challenge because of the inherent complexity of this neuronal class. Prior work supports the premise that RGC replacement is feasible, as individual milestones in RGC replacement have been attained (Figure 1), including RGC differentiation from stem cells, retinal integration of transplanted RGCs, axonal extension through the optic nerve and into the brain, and RGC axon (re)myelination. However, collaborative efforts among interdisciplinary teams are required to brainstorm new ideas, develop rigorous approaches to execute them, and build teams to bring these ideas to fruition, in order to achieve complete RGC pathway replacement. The National Eye Institute (NIH) has prioritized retinal neuronal replacement as part of its strategic goals and is supporting this challenge through the Audacious Goals Initiative (AGI), which promotes collaborative approaches to retinal regeneration that are necessary given the complexity of this task.

RReSTORe aims to exist to complement other collaboratives efforts. RReSTORe will prioritize inclusion of scientists from diverse backgrounds, especially trainees and early career scientists, and adopt a structure that maximizes collaborative and sustained virtual and in-person discussions to foster interpersonal engagement and innovative approaches to RGC regeneration. Our discussions and our work will focus on five major topics: 

Topics

RGC Development and Differentiation

  1. Stem cell biology and neurogenesis
  2. Transdifferentiation
  3. Organoids and assembloids
  4. RGC subtype identification and specification

Transplantation Methods and Models

  1. Transplantation techniques
  2. In vivo imaging and functional assays
  3. Large animal models of optic neuropathy
  4. Transplant immunology

RGC Survival, Maturation, and Host Interactions

  1. Neuroprotection
  2. Neurovascular coupling
  3. Macroglial interactions
  4. Microglial interactions

Inner Retinal Wiring

  1. RGC migration, tiling, and patterning
  2. RGC dendritogenesis and inner plexiform layer sublaminar targeting
  3. Synaptogenesis in the inner plexiform layer
  4. Functional integration assays

Brain Connectivity

  1. Pathfinding, targeting, projection specificity
  2. Synaptogenesis in the brain
  3. Myelination
  4. Implications for anterograde transsynaptic degeneration
 

Phases

The RReSTORe consortium will be built around a three-phased process founded on active communication and collaboration among diverse investigators to address.

Click the phase number to read more about each.

  • Delineate the most important questions and challenges hindering clinical translation of vision restoration treatments for optic neuropathy though an iterative, inclusive, consensus-based process.

    Participants will self-select into 2 of 5 discussion sections, each co-moderated by a senior & junior investigator: 1) RGC development & differentiation; 2) Transplantation methods & models; 3) RGC survival & host interactions; 4) Inner retinal wiring; and 5) Brain connectivity. Beginning 4 months prior to the RReSTORe workshop, participants will engage in a web-based consensus-building process to identify 5-7 key topics for in-person discussion. Moderators will solicit anonymous feedback from participants, in a manner promoting junior and URM investigator input that prevents group bias based on perceived expertise, seniority, or individual characteristics. Moderators will collate responses and redistribute iteratively to build an agenda for discussion.

  • Share ideas, insights, and data in a collaborative roundtable discussion to identify tools, models, and experiments that will propel clinical translation of vision restoring optic neuropathy treatments.

    On Friday, 4/29/2022, in Denver (prior to ARVO), participants will meet for a 1-day workshop to engage in roundtable discussions based on the questions and challenges identified in Aim 1. Additional stakeholders including clinicians, patients and grant funding agencies will be invited to participate. Moderators will lead subgroup discussions with an effort to ensure input from all attendees, especially emerging vision scientists.

  • Establish a sustainable, collaborative network of investigators who will advance the field of RGC replacement, with an emphasis on maximizing diversity of participants.

    Participant recruitment will prioritize diversity of gender, race, ethnicity, and career stage. Participant slots (≥25%) will be reserved for applications in response to advertisements submitted to trainee programs focusing on underrepresented minorities in science & medicine. We anticipate that conversations between diverse participants will spur new collaborations and scientific opportunities, especially for emerging vision scientists.

    A web-based collaborative platform, facilitating discussions and debriefings, will follow the workshop. A discussion board for conversations and a quarterly webconference will be established and actively moderated for 2 years, and potentially longer.

Impact: We will lay the foundation for a sustainable, interdisciplinary consortium of investigators from diverse backgrounds and all career stages, with emphasis on junior and underrepresented minority scientists, to work collaboratively towards the goal of RGC replacement & regrowth, sustainably beyond the RReSTORe workshop.

 

Organizing Committee

Committee MemberAffilation
Petr Baranov, M.D., Ph.D.Harvard University
Adriana Di Polo, Ph.D.University of Montreal
Kimberly K Gokoffski, M.D., Ph.D.University of Southern California
Jeffrey L Goldberg, M.D., Ph.D.Stanford University
William Guido, Ph.D.University of Louisville
Thomas V Johnson, M.D., Ph.D.Johns Hopkins University
Carol A Mason, Ph.D.Columbia University
Brian C Samuels, M.D., Ph.D.University of Alabama at Birmingham
Thomas A Reh, Ph.D.University of Washington
Ahmara G Ross, M.D., Ph.D.University of Pennsylvania
Derek S Welsbie, M.D., Ph.D.University of California San Diego
Donald J Zack, M.D., Ph.D.Johns Hopkins University

See the full list of workshop participants

Contact Info

Questions, suggestions, or comments may be directed to Thomas Johnson, M.D., Ph.D.

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