The RReSTORe Consortium will sponsor a number of periodic virtual symposia aimed at maintaining collaborative discussions surrounding our collective work on vision restoration for optic neuropathies.
The RReSTORe Consortium
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 200 leading and emerging investigators from related fields.
Goals of the consortium are:
- To define and prioritize the most critical challenges and questions related to RGC regeneration over the next five years.
- To brainstorm innovative tools and experimental approaches to meeting these challenges while fostering opportunities for collaborative scientific investigation among diverse investigators.
RReSTORe Workshop Travel Grants
Thank you to the organizations that have funded travel grants to many of our participants. RReSTORe travel grants have been awarded to the following participants:
- Zhang, Jingliang
- Naguib, Sarah
- Guy, Brian
- Valenca, Viviane
- Peng, Micalla
- Huang, Kang-Chieh
- El Hajji, Sana
- Saleem, Meher
- Ufongene, Claire
- Silva-Lepe, Ariadna
- Sharma, Tasneem
- Fouda, Adbelrahman
- Abed, Sadaf
- Jauregui, Alexa
- Askary, Amjad
- Clark, Brian
- Woodworth, Mollie
- Samuel, Melanie
- Luo, Ziming
- Shiga, Yukohiro
- Keuthan, Casey
- Marina, Pavlou
- Tian, Feng
- Soucy, Jonathan
- Gomes, Catia
- Peterson, Sheri
- Jalligampala, Archana
- Balasubramanian, Revathi
- Rudzitis, Christopher
- Hu, Mengming
- Preston, Kiam
- Sivyer, Ben
- McGregor, Juliette
- Alarcon-Martinez, Luis
- Dharmarjan, Subramanian
- Lozano, Diana
- Wang, Xuewei
- Todd, Levi
- Aguzzi, Erika
- Wohlschlegel, Juliette
- Alapure, Bhagwat
- Monavarfeshani, Aboozar
- Das, Arupratan
- Chang, Kun-Che
- Emmerich, Kevin
- Villafranca-Baughman, Deborah
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.
Figure 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
- Stem cell biology and neurogenesis
- Transdifferentiation
- Organoids and assembloids
- RGC subtype identification and specification
Transplantation Methods and Models
- Transplantation techniques
- In vivo imaging and functional assays
- Large animal models of optic neuropathy
- Transplant immunology
RGC Survival, Maturation, and Host Interactions
- Neuroprotection
- Neurovascular coupling
- Macroglial interactions
- Microglial interactions
Inner Retinal Wiring
- RGC migration, tiling, and patterning
- RGC dendritogenesis and inner plexiform layer sublaminar targeting
- Synaptogenesis in the inner plexiform layer
- Functional integration assays
Brain Connectivity
- Pathfinding, targeting, projection specificity
- Synaptogenesis in the brain
- Myelination
- 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.
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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 self-selected 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 engaged in a web-based consensus-building process to identify 5-7 key topics for in-person discussion. Moderators solicited anonymous feedback from participants, in a manner promoting junior and URM investigator input that prevented group bias based on perceived expertise, seniority, or individual characteristics. Moderators collated responses and redistributed iteratively to build an agenda for discussion.
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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 Saturday, 4/30/2022, in Denver (prior to ARVO), participants met 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 were invited to participate. Moderators lead subgroup discussions with an effort to ensure input from all attendees, especially emerging vision scientists.
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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 prioritizes diversity of gender, race, ethnicity, and career stage. Participant slots (25%) are reserved for applications in response to advertisements submitted to trainee programs focusing on underrepresented minorities in science & medicine. Conversations between diverse participants 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 web-conference 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 Member | Affiliation |
|---|---|
| Thomas V Johnson, M.D., Ph.D. - Chairman | Johns Hopkins University |
| 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 |
| 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 |
| Brad Fortune, O.D., Ph.D. | Devers Eye Institute |
| Yvonne Ou, M.D. | University of California, San Francisco |
| Alex Kolodkin, Ph.D. | Johns Hopkins University |
Thank You
Funding for the RReSTORe Workshop and Travel Grants for Emerging Vision Scientists were made possible by the following organizations: