LHON Opportunity 1
Patient data and biological samples are the foundation for understanding a disease, its underlying cause(s), natural
progression, and informing hypothesis-driven research and clinical trial design. In LHON, biological samples are rare and
the patient data that exist are fragmented across clinics and patient registries around the world. Among the existing patient data and biological samples, most have been collected without consensus standards or protocols. In our engagement with the LHON field, the need for a coordinated, large, prospective, standardized data set that includes clinician-reported data, patient-reported data, and biological samples—from affected and unaffected carriers—has been a recurrent theme.
LHON Collective has the opportunity to support the build of global repositories to collect clinician and patient-reported data and biological samples from affected and unaffected carriers using common data standards and consensus protocols for collection. Data may include demographics, clinical assessments, symptoms, quality of life surveys, environmental exposures, and other external factors that may modify disease course. Linked patient-derived biological samples could include post-mortem eye tissue, blood, saliva, urine, buccal, or skin and be used to generate genomic data (or other omics data, e.g., metabolomics) and patient-derived cell or organoid models.
Post-mortem human tissues, including eyes, optic nerve, and brain, also have the potential to serve as critical resources to generate omics data, pathology data, or organoid models specifically from the affected cells and microenvironment. These tissues will most efficiently be collected in partnership with brain banks that recognize the value of collecting eye tissue along with brain tissue.
Any data or resources resulting from banked tissue should be shared either through the LHON repository or in another manner that provides open access to researchers. The goal would be to establish a comprehensive repository anchored on foundational data- sharing agreements and systems; the repository data and samples would be made available for research. Through central support and management by LHON Collective, the organization can ensure that researchers around the world have streamlined access to the samples and data, preventing hold-ups based on individual institution policies or competitiveness.
Investing in such a repository will reduce duplication of efforts and data fragmentation and improve the consistency and completeness of the data, which are prerequisites for high-quality research. Patient and clinical data will be used for natural history studies to better understand the course of the disease and to identify secondary factors that predict penetrance and severity, reveal disease subtypes, find biomarkers with clinical and research applications, and inform clinical trial design and outcome measures. Achieving this objective will improve the field’s understanding of the natural disease course and provide patient data as a baseline against which to validate disease models, compare therapeutic interventions, develop data-driven treatment strategies, and foster collaboration among clinicians, researchers, and industry stakeholders.
Approaches to Building Repositories
Following extensive brainstorming during the 2024 LHON retreat, we recommend establishing a unified framework for data and biological sample collection within open-access repositories. Such an initiative will meet the critical need for standardization, increased sample sizes, and greater diversity of samples from affected and unaffected carriers. Formalizing the collection process for both existing data that are currently siloed by institution and geography and new data and biological samples is paramount for conducting comprehensive analyses. Centralizing these resources in regional repositories offers the highest likelihood that the data and biological samples can be linked for downstream research. This nontrivial task necessitates cooperation and endorsement from multiple stakeholder groups, regulatory approval, and data security and privacy considerations.
To establish comprehensive patient data repositories and biorepositories, globally, we recommend the following activities:
1. Establish unified protocols and standards for harvesting, processing, and storing LHON-relevant post-mortem tissues, including the brain, optic nerve, and eyes, within existing brain banks.
Cellular and molecular research for LHON is challenging due to limited adequate animal and cellular models. There is a significant opportunity to build out banks of applicable post-mortem tissue for research purposes. With the need for high-quality fixed and frozen tissue specimens for research, specialized banks will be key for the standardized collection, characterization, storage, and distribution of eye tissue for research purposes. As the eye is part of the brain, brain banks are the optimal frameworks in which to collect eye tissue. In recognition of this, brain banks such as the Netherlands Brain Bank collect postmortem eyes for investigation of eye diseases such as age-related macular degeneration.
A key opportunity in leveraging specialized brain banks lies in the fact that many operate within networks to enhance collaborations, optimize protocols, and increase the ability to fill requests for tissue for research. Examples of successful brain bank networks include BrainNet Europe, UK Brain Bank Network, The National Alzheimer’s Coordinating Centre, NIH NeuroBioBank, and the Australian Brain Bank Network. Notably, the NIH NeuroBioBank combines human post-mortem brain tissue and related biospecimens with medical records and clinical data sets (when available) as well as access to quality metrics and best practices for tissue collection and processing used by each site, combining all critical data types into one open access repository. This framework could serve as a model for LHON Collective to move toward.
Alternatively, LHON Collective and partners could advocate for inclusion of eye tissue within the NIH NeuroBioBank. Most brain banks operate according to best practice guidelines which will need to be established in collaboration with neuro-ophthalmologists should brain banks expand tissues collected to include eyes. Critical needs associated with supporting brain banks and ensuring efficient expansion of tissue types collected include:
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Establishing effective methods of donor recruitment
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Careful training and coordination by brain bank staff to ensure appropriate consent to collect tissue;
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Defining and ensuring standardized tissue collection methods that ensure optimal tissue quality considering the immediate and future uses of the tissue (for example, rapid autopsy and freezing of the optic nerve for pathological and genomic analysis);
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Identifying critical data collection methods that will enable rapid digitization of biological sample data so that human tissue is saved and resulting data can be readily shared through an established LHON data repository (for example, performing DNA and RNA analysis on specific cells or tissues and openly sharing resulting data within a data repository will reduce duplicate requests for tissue to perform such analyses);
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Performing standardized pathological assessment of the tissue collected; and
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Defining a process for tissue requests and disbursement
The development, implementation, and maintenance of a brain bank are extremely costly. Estimates of the cost of brain banking vary between $10,000 and $30,000 per specimen banked and are predominantly related to personnel costs. Importantly, leveraging existing infrastructure and patient autopsies to add new tissue types rather than building independent eye tissue banks has the potential to greatly reduce the cost of collecting eye tissue. Moreover, other eye diseases will benefit from the inclusion of eye tissue collection in brain banks.
Additionally, there is evidence that ocular changes precede neurodegenerative diseases such as Alzheimer’s disease, and researchers are developing eye scan techniques to detect Alzheimer’s disease before major symptoms appear. There is potential for eyes to enable identification of banked brains from patients earlier in the neurodegenerative process, enabling study of pre-symptomatic stages of the disease, a critical time in the development of neurodegenerative diseases. Expansion of brain banking to include eyes is an opportunity to collaborate with organizations that support research efforts for eye and neurodegenerative diseases.
According to their 990, in 2023, the Miracles In Sight non-profit eye bank funded approximately:
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$1.7M in surgical recovery and preservation of donor ocular tissue
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$4.8M in testing, evaluation, and distribution of tissue for transplant and research
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$1.9M in the screening, disclosure, authorization, and tissue recovery process
That year, the organization facilitated over 3,200 donations. Based on these values, the per-donation cost for eyes can be estimated at approximately $2,500. The ultimate cost will vary depending on the type of tissue collected, the analysis performed on the tissue, and the processing and preservation of the tissue. Importantly, if eye donations can be aligned with brain donations, there is potential to share surgical recovery and screening costs and further reduce the cost of eye banking.
2a. Identify and Gather Existing Patient Data Worldwide to Build a Unified Retrospective Data Set
Existing data can be used as a baseline to set standards and consensus protocols and identify data gaps that should be addressed in future data collection. The most immediate way to do this is to build a data committee to landscape the current data ecosystem and conduct a data needs assessment. A data committee will prepare a template and request investigators/institutions with existing data contribute to its completion. A cost estimate for assessing the data landscape includes $1,000 per contributor to ensure timely and accurate sharing of available data, $1,000 per member of a data committee to support time spent on identifying the information to be requested of data contributors and coordinate a landscape analysis and development of a publication, and approximately $2,000 to publish the data landscape as a consensus statement and call to action for the field to standardize data and biological sample collection. Overall, this effort should not exceed $25,000 and the final cost will be dependent on the number of institutions that collect LHON patient data and/or biosamples.
2b. Establish open-access data and biorepositories across global regions to gather longitudinal clinician and patient-reported data alongside biological samples from both affected and unaffected carriers
Researchers should use standardized data practices and consensus protocols (2a) for collection of new data to fill LHON data gaps and increase data quantity. The amount of capital required for establishing and maintaining repositories for patient data and biological samples will vary based on location, the number of patients and samples involved, and the project’s stage; initial setup and data and sample collection typically incur higher costs compared to ongoing maintenance. Leveraging existing repositories with established sharing policies and infrastructure would significantly reduce the cost of collecting, storing, and sharing data. Based on the data landscape performed (2a), there is the potential for LHON Collective to identify data and/or biorepositories that are already collecting and sharing patient data and biosamples from LHON or other mitochondrial diseases or optic neuropathies with the potential to expand with dedicated funding.
An open or targeted grant funding opportunity has the potential to optimize LHON data and sample collection without requiring the costly initial build of repository infrastructure. We recommend a funding opportunity of up to $500,000 to support the expansion of one or two existing repositories to fill data and sample gaps for LHON. This opportunity is not an immediate requirement if preceded by the development of a brain bank. Once processing and digitization of brain bank tissues is initiated and investigators begin to collect molecular patient data, tissue samples for model development, and process post-mortem tissue donations, an open-access repository that can collect and share samples, models, and data will be beneficial to the research community. Additionally, this opportunity can be scaled up over time or allow for the selection of additional global sites within a network to further enhance the volume of data and samples collected.
The collection, storage, and sharing of patient data requires care in consenting and collection, safeguards on data storage, and establishment of frameworks and systems that ensure patient protection from concerns such as identification and discrimination. Below, we consider two different options for the collection of LHON patient and carrier data:
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Solidify and optimize LHON Collective’s partnership with RARE-X to manage data from multiple sources and identify a biorepository partner (recommended)
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Partner with a research institution to establish a patient data and biorepository
Both of the above options include a biorepository component, as outlined above. What differentiates the options is the type of organization that holds the patient data; either RARE-X, an organization with a preexisting relationship with LHON Collective and has an existing framework for collection of both patient-supplied and clinical data, or an institution or collaborative network capable of holding both data and biosamples.
Partnership with RARE-X
Based on current LHON Collective relationships and efforts, we recommend that LHON Collective prioritizes collection of patient clinical and natural history data in partnership with RARE-X. RARE-X collects research-grade data from patients using disease ontologies (i.e., controlled vocabularies for standardization) based on consultation with clinicians. RARE-X can collect both patient-reported and clinician-reported data, but they do not have the infrastructure to store or manage biosamples.
In our conversations with RARE-X, we discussed two major hindrances to data collection in the LHON community:
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Lack of funding to build out a data collection platform accessible to patients with low or no vision
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Lack of consensus among experts on the most useful data to collect.
The LHON Data Collection Program at RARE-X has collected data from more than 120 LHON patients around the world, and addressing the previously noted challenges has the potential to significantly increase the number of participants in the repository.
RARE-X is a philanthropy-funded organization, and we recommend that LHON Collective provide targeted support and connections to experts in the field to create a LHON data and patient advisory committee to rapidly scale the expansion of the RARE-X LHON database. This database has the potential to provide information on patient trajectory, LHON plus symptoms, and natural history. All of which will be important to industry as clinical trials are pursued. Patient enrollment, therapeutic window, and endpoints can all be bolstered with enough appropriate data.
As such, there is potential for industry to support efforts with RARE-X once preliminary benefit has been demonstrated. Compensation for advisory committee time should be provided by LHON Collective (approximately $1,000 per advisor for up to eight advisors). Appropriate contributions toward improvements in RARE-X platform accessibility and the addition of data types as determined by the advisory committee will need to be determined in collaboration with RARE-X. Information on individual organizational contributions toward RARE-X efforts are not listed in their 990 but estimates of improving accessibility range from $3,000 to $50,000. We would anticipate funding support to RARE-X not to exceed $50,000.
If LHON Collective is interested in pursuing RARE-X as a patient data repository, a biological sample repository site will need to be identified as biosamples are collected from patients. As RARE-X collaborates with the Broad Institute on data collection, data governance, and data sharing, it may be worth exploring options for building a biorepository at the Broad Institute or another organization with the capabilities to analyze and store samples and leverage or link RARE-X data. The appropriate partner could either be identified using a targeted grant mechanism or through field-wide discussion at repository-focused meetings.
Partner with a Research Institution
Academic medical centers and research institutes have the necessary infrastructure, expertise, and access to diverse patient populations to effectively collect, manage, and analyze patient data and biological samples. Patients and clinicians trust reputable institutions, which helps to lower one of the primary barriers to participation in research. As outlined above (2b), a research institution or network with the capability to house both clinical data and biosamples and data resulting from molecular assessment of those samples could be selected from among the institutions that are currently collecting LHON patient and tissues and express the capacity to expand their efforts with dedicated funding.
Partnership Considerations
To ensure efficient management and maximize impact, we recommend, as a first step, partnering with other eye disease and neurodegenerative disease organizations to expand tissue collection within either a single or network of brain banks to include eye, optic nerve, and other appropriate tissue as identified by researchers. The brain bank can serve as a foundation for tissue collection but will benefit from additional funding to support tissue processing, pathological analysis, storage, and distribution.
As a first step, we recommend identifying brain banks with the willingness and capabilities to collect, process, and store eye tissue. Standardized collection methods can be established and a core set of analyses for tissue can be identified. Once a critical mass of healthy and affected and/or carrier eyes are banked, clustered DNA, RNA, pathology, and other analyses identified as important by researchers can be performed and data can be digitized and shared with researchers broadly. Digitization of data will ensure the protection of critical biosamples for future analyses as molecular technologies evolve.
Moreover, a linked data repository will be necessary as tissues are processed and data are digitized. There is significant potential for digitized pathology to provide ample data that can be processed and analyzed using artificial intelligence methods.
In concert with brain bank efforts, we recommend convening clinicians and investigators experienced in LHON patient data collection to establish consensus guidelines and protocols for patient data and biological sample collection. This convening may also be used to prioritize sample and data collection, set clinical leads who will be responsible for protocol development for each sample or data type, and weigh biorepository and data network requirements to establish specific criteria for participation to vet potential partners.
As natural history data will be an immediate benefit to industry, it will be a key need for early funding streams. Early optimization of the RARE-X platform for the collection of LHON data will enable expansion of that data set. Early successes, such as benefits to patient recruitment for clinical trials or identification of meaningful endpoints will signal the utility of this resource to industry and likely result in additional supportive funding from that sector.
Once the LHON data landscape has been clarified and data collection priorities have been set, established repositories can be identified through either a competitive or targeted application process to receive funding for LHON-specific efforts to support data and biosample expansion. Ultimately, any new therapeutic development will benefit from patient samples, so in establishing repositories, a stipulation of funding should be that data and samples are accessible to both academia and industry.
Data management and curation are essential to the quality and utility of a repository. Challenges often arise with data and sample sharing between clinicians and scientists, potentially necessitating funding for multiple centers in different geographic regions. The complexity of data management will escalate with the addition of more centers, necessitating an increase in the number of regulatory sponsors and data access agreements. It can be challenging for investigators outside a medical center or research institute to access internal data and biological samples for research; it is imperative that data sharing and access agreements guarantee open access.
Partnering with a pharmaceutical company as a financial sponsor or co-funder may be worth pursuing. Leveraging NIH programs for natural history studies may offer additional financial support for investigators in subsequent phases of research.
