Rare disease research is hard - there are limits and obstacles at nearly every turn. It is critically important that precious time, energy, and resources be spent in the most effective and efficient ways so that we can make progress, together, towards better understanding and better treatments to ensure that brighter future for our patients and families that we envision.
We've brought together stakeholders in our community to help develop a research compass, hoping to help guide the way to the most important problems to solve, biggest questions to answer, widest gaps to fill, and heaviest burdens to ease.
We believe progress will come quickest and easiest not in a straight path or roadmap, but by creating relationships and collaborations across the many scientific corners that touch our disease. We hope this compass helps focus efforts and inspire action on behalf of those who need the answers to these questions - our patients. Thank you for your interest in helping us.
We've brought together stakeholders in our community to help develop a research compass, hoping to help guide the way to the most important problems to solve, biggest questions to answer, widest gaps to fill, and heaviest burdens to ease.
We believe progress will come quickest and easiest not in a straight path or roadmap, but by creating relationships and collaborations across the many scientific corners that touch our disease. We hope this compass helps focus efforts and inspire action on behalf of those who need the answers to these questions - our patients. Thank you for your interest in helping us.
Research Compass
Below you'll find a list of resource tools needed and key questions to answer through research. Our plan as we further develop this resource is to continually add publications, projects, people, and places so that comprehensive information is easily accessible and progress can be followed.
Contribute resources or ideas for inclusion here.
Contribute resources or ideas for inclusion here.
Open Source Research Tools:
Develop the most relevant and reliable tools to use for research and make them easily accessible to any researcher.
Cell Lines and Bio Samples:
Animal Models:
Other Tools:
Clinical Tools:
Develop the most relevant and reliable tools to use for research and make them easily accessible to any researcher.
Cell Lines and Bio Samples:
- cell lines – iPSC to create other relevant cell types
- endothelial cell models - Blood Brain Barrier (BBB)
- organoids – Blood Brain Barrier (BBB), brain
- patient biospecimens – blood, tissue, fibroblasts, CSF, autopsy series
- omics and scRNA-seq data from patient samples
- better classification and characterization of variants
Animal Models:
- Are more mouse models needed?
- Is a pig model needed?
- Is there a role for a zebrafish model?
- omics and scRNA-seq data from animal models
- transcriptomics
- metabolomics
- proteomics
- epigenetic profiling (acetylation, methylation, etc.)
- standardized assays for quantifying functional Glut1
- standardized reagents: antibodies, viral shRNA vectors, others?
Other Tools:
- improved intracerebral glucose and ketone measurements
- better tools to study BBB transport
Clinical Tools:
- consistent and reliable biomarkers
- meaningful outcome measures
- natural history patient data – patient and clinician reported outcomes, electronic health records
- newborn screening tool
Cells:
More clearly define the cell types involved in the disease, their locations in the body, and which ones can and should be targeted for treatment.
More clearly define the cell types involved in the disease, their locations in the body, and which ones can and should be targeted for treatment.
- What cells are clearly and definitively impacted in Glut1 Deficiency? (endothelial, astrocytes, neurons?) others?
- Where are the impacted cells located?
other body areas and systems? muscles? retina? BBB or brain only? what regions of the brain? - What is the right cell model to use for drug screening activities?
- How many cell lines do we need considering the heterogeneity?
Glut1 – the transporter protein:
Better understand the function of Glut1, what influences that function, and how malfunctions can be corrected.
Blood Brain Barrier
Better understand the function of Glut1, what influences that function, and how malfunctions can be corrected.
- What are the other functions of Glut1 besides glucose transport? What are we missing?
- What impacts trafficking, expression, function, and configuration?
- Does Glut1 function and/or expression change over the lifespan?
- Why the familial differences with same variant - what else regulates Glut1?
- How is Glut1 regulated at the transcriptional level and post-transcriptional level?
- How can Glut1 expression or transport be upregulated in the target cells?
- Are there off-target implications of manipulating Glut1 expression?
- Can faulty Glut1 be bypassed? How?
- Can/do other Gluts compensate for impaired Glut1?
- What is the minimum amount of Glut1 needed to prevent disease?
Blood Brain Barrier
- What other factors at the BBB impact Glut1 activities?
- What all is involved in Glut1 regulation at the BBB? Is it different than in other tissues/cells?
- How do we maximize transport of glucose through the BBB?
- Do diet/metabolic therapies alter the BBB?
- Do diet/metabolic therapies change glucose transport at the BBB?
- Can we discover pharmacological approaches that alter transport at the BBB?
- Does exogenous Glut1 behave the same as endogenous at the BBB?
Metabolism:
Better understand the metabolic functions that are impaired by Glut1 Deficiency and identify ways to compensate.
Better understand the metabolic functions that are impaired by Glut1 Deficiency and identify ways to compensate.
- What are the downstream implications of impaired brain glucose transport?
-other substrates?
-other Gluts?
-other molecules ? (BDNF?)
-cycles and pathways (glycolysis, glycosylation, glucogenesis, ATP, lactate shuttle, others)?
- Can these downstream implications be treatment targets?
- What is the role of glycogen in Glut1 Deficiency? Can glycogen metabolism be manipulated for potential utilization?
- What is the role for adenosine in Glut1 Deficiency?
- What about substrate competition vs. utilization?
- How do we better understand the astrocyte/neuronal lactate shuttle?
- What are the astrocytes taking up vs. the neurons? What does each need more of?
- What about substrate driven toxicity?
Genetics:
Identify all the genes that may play a role in Glut1 Deficiency, how defects in the genes contribute to disease, and how their function can be repaired.
Gene Therapy:
Identify all the genes that may play a role in Glut1 Deficiency, how defects in the genes contribute to disease, and how their function can be repaired.
- What are the variants clearly associated with disease?
- What are the functional consequences of those variants?
- What are the genotype/phenotype relationships- what determines or influences a patient’s progression/journey?
- Are other genes or other regions of SLC2A1 implicated in Glut1 Deficiency?
Gene Therapy:
- Does the ketogenic diet expand the therapeutic window of gene replacement?
- Is AAV9 capable of reaching the target cells in the target location?
- Is AAV the optimal capsid for human brain endothelial cells? How durable will it be?
- What other cells types will need to be targeted? Astrocytes?
- What is the optimal route of administration going to be?
- Is there a role for ex vivo gene therapy through autologous bone marrow transplant?
Pathogenesis:
Better define the clinical course of Glut1 Deficiency, what causes the symptoms, and why they change over time.
Better define the clinical course of Glut1 Deficiency, what causes the symptoms, and why they change over time.
- What happens to the human brain with prolonged glucose or Glut1 deficiency? (growth, structure, inflammation)
- What are the mechanisms behind the evolution of the disease and changes from infancy to adulthood?
- What happens to elderly/aged patients?
- What can we learn from studying other Glut1-involved diseases? How can we synergize efforts?
Therapy Development:
Better understand the benefits and limitations of current therapies and develop new and better ones.
Better understand the benefits and limitations of current therapies and develop new and better ones.
- Why/how does ketosis fail to fully resolve symptoms in Glut1 Deficiency?
- What options are there if ketogenic diets fail?
- Can we make ketogenic diets more effective and easier to implement?
- Does genotype/phenotype impact diet efficacy?
- What is the role for MCT’s (oils, triheptanoin, K.Vita)?
- What is the role for ketone esters?
- What level of ketones should we aim for? Does this change over time? Are ketones even important?
- What happens with the need for ketogenic diets into adulthood? Are they less or equally necessary?
- Is there a role for ketogenic diet in patients with Glut1 Deficiency identified before symptoms start (e.g. genetically or due to an affected parent)?
- What is the role for diazoxide? Why?
- What is the role for acetazolamide? Why?
- How can we rescue the movement episodes?
- Which anticonvulsants could help with seizure control? Which ones should be avoided?
- Which movement disorder drugs could help? Which ones should be avoided?
- Are there treatments to target speech and communication symptoms?
- Are there treatments to target cognitive symptoms?
- Is personalized medicine necessary based on level of transport, genotype, and/or phenotype?
- Can Glut1 activity or expression be enhanced by repurposed drugs?
- Can Glut1 Deficiency be cured completely?
- Will there be lingering or return of symptoms with gene therapy?
Clinical Tools:
Develop tools to improve the diagnostic process, support better clinical care, and advance meaningful treatment development.
Develop tools to improve the diagnostic process, support better clinical care, and advance meaningful treatment development.
- How do we improve and best measure cognition and communication outcomes for patients, the top priorities identified by patients for quality of life improvements?
- What are the appropriate endpoints for clinical trials?
- What are the best biomarkers to use?
- Is there a way to use advanced imaging analysis/machine learning for outcome measures?
- Is there a role for continuous glucose monitoring in clinical care?
- Should we incorporate the glucose ketone index into clinical care?
- Should we develop master protocols – what is the optimal therapy for each patient group?
- Newborn screening tool – can we intervene early?
