Science with Sandra: 2024 in Review and 2025 Preview

Hello and welcome to Science with Sandra! As we are approaching the end of 2024, I would like to look back at the research progress that has been made during this year in our community, and the things we are looking forward to for 2025.

Regarding scientific gatherings, we hosted four Research Roundtables with a wide variety of  topics and guest speakers. The first meeting of the year was on January 23rd and it featured two wonderful members of our research community, Dr. Matthew Gentry and Dr. Hudson Freeze. They talked about brain glucose metabolism and GLUT1 as a fucose transporter.

For our spring Research roundtable, which took place on April 23rd, we had the pleasure of having two great guest speakers: Dr. Abraham Al-Ahmad, who has been part of our community for a long time, and Dr. Elizabeth Radford. They talked about the lessons learned from GLUT1 Deficient human induced pluripotent stem cells and the functional limitations of genetic variants.

Our summer gathering, was on July 23rd and featured two very well known members of our medical and scientific community, Dr. Jörg Klepper and Dr. Juan Pascual who are also members of our advisory board. They shared a summary of the clinical and scientific sessions of the Glut1 Deficiency Summit this past June.

The most recent Research Roundtable, took place on October 22nd, and focused on the ketogenic diet experience in our community and the use of triheptanoin or C7 oil. We had the pleasure to have two expert speakers, Kelly Faltersack, a dietitian and member of our advisory board, and Dr. Juan Pascual. 

Additionally, we hosted our Glut1 Deficiency Summit this past June in Dallas, where we had one and a half days filled with innovative and exciting scientific talks, amazing speakers from our community and speakers new to our community. We were also able to host two research studies on site during the Summit conducted by Dr. Juan Pascual and his team and Dr. Andrea Gropman and her team. 

The Scientific sessions were an excellent opportunity to bring new researchers to our community and to learn about new perspectives that can help develop new and better treatments for Glut1 Deficiency. It was also an opportunity to grow the network of researchers working on our disease that will help open new avenues to advance research progress. Some of the new researchers presented posters of their current investigations in the field. The poster session also featured posters from caregivers in our community and members of our esteemed Patient Advisory Board. Here you can find the abstracts of all the posters presented.

Thanks to the generous donations from our community, we have been able to sponsor a couple of different projects, big and small to help move research forward. One of these projects is the Speech and Language study conducted by the University of Melbourne in collaboration with Murdoch Children’s research Institute and Redenlab in conjunction with the Translational Centre for Speech Disorders at the Royal Children’s Hospital Melbourne (Australia). The goal of this study is to improve the understanding of speech and language in this condition. The researchers hope to improve prognoses, better identify those in need of support and develop targeted strategies. You can read more about this study following this link, and we look forward to sharing an update from the study team in our December newsletter.

Another project we were able to sponsor, thanks to our generous donors, was a project led by Dr. Mattia Bonzanni. The title of the project is “Role of adenosine in Glucose Transporter Type1 Deficiency Syndrome”. The objective of this project is to investigate wether the levels of adenosine are influenced by GLUT1-dependent glucose transport. Dr. Bonzanni shared the results of his project at the poster session of our Glut1 Deficiency Summit this past June. Below you can see the abstract of the poster provided by Dr. Bonzanni: 

“While the energetic implications of glucose metabolism are frequently explored, the relationship between astrocytic glucose uptake and neuromodulator levels remains to be elucidated. Among the neuromodulator, ATP serves as a neurotransmitter and a precursor to adenosine, a significant neuromodulator that inhibits neuronal activity. Astrocytes play a pivotal role in this process by providing ATP for extracellular conversion to adenosine and by facilitating adenosine reuptake, thereby modulating adenosine levels. This regulation becomes crucial during periods of heightened energy demand, such as epileptic seizures, where adenosine acts as a protective signal against abnormal neuronal activity. We thus investigated the hypothesis that astrocytic glucose uptake through GLUT1 influences neuronal activity by modulating adenosine levels. Field potential experiments were conducted on ex vivo hippocampal brain slices from 8-week-old male and female mice to measure net synaptic transmission in the Schaffer collaterals. Astrocytic GLUT1 has been pharmacologically blocked (acute vs chronic) with 50 nM of BAY876. Endogenous occupancy of the adenosine 1 receptor (A1R), which mediates adenosine’s inhibitory action, was assessed by first measuring synaptic transmission under basal conditions (B). Subsequently, a saturating concentration of an A1R inhibitor (I) was added, followed by a saturating concentration of an A1R agonist (A). The occupancy was then calculated using the formula: 100*(I-B)/(I-A). Glucose levels were maintained at a constant level throughout the dissecting, recovery, and recording phases to simulate either fed conditions (10 mM glucose) or normal blood glucose levels (2.5 mM) in the brain. Preliminary findings confirmed a direct dependency on glucose for net synaptic transmission, as demonstrated by a comparison between 10 mM and 2.5 mM levels. Acute pharmacological inhibition of astrocytic GLUT1, at either glucose level, resulted in heightened synaptic transmission. However, chronic exposure to the GLUT1 inhibitor showed a declining trend in synaptic transmission, suggesting long-term remodeling effects of chronic astrocytic GLUT1 blockade. Although basal levels and inhibitory function of adenosine through the adenosine 1 receptor (A1R) were not influenced by glucose levels or chronic inhibition of GLUT1, the responsiveness to adenosine was decreased in the presence of the GLUT1 blocker at 2.5 mM glucose, despite a comparable pre-synaptic probability of neurotransmitter release as evaluated using a paired-pulse facilitation stimulation protocol. This implies that larger fluctuations in adenosine levels, compared to the wild type, are required to achieve equivalent depression of synaptic transmission in the presence of GLUT1 blockage. In summary, should these initial findings be confirmed, they suggest that pharmacologically ablating astrocytic GLUT1 could diminish the responsiveness of the synaptic function to adenosine variations. Consequently, this reduction may compromise the inhibitory effectiveness of adenosine fluctuations during abnormal neuronal activities or stressful conditions such as hypoxia. Future experiments will be repeated with a G1DS murine model, incorporating the neurodevelopmental consequences of G1DS on neuronal activity and adenosine levels”.

Other grants funded included the Million Dollar Bike Ride (MDBR), where we will learn the grantee before the end of this month, as well as a couple of mini grants for researchers interested to acquire Glut1 deficient iPSC cells. Projects that are utilizing these cells are currently ongoing and we will share results with the community as we learn about the findings.

I also wanted to share a great accomplishment for our foundation. This year we published our first peer reviewed publication “The road toward patient-led research in the GLUT1 Deficiency community: a patient organization perspective”. This publication shares information about how the foundation has focused its strategic research plan in the patients and families’ needs and priorities. Additionally, it lists the resources and tools that are available for researchers such as data from the Collective Voices Survey, the Research Compass and a list of disease models available including cells and mouse models. We hope this publication will serve as a guide for researchers towards a better understanding of the disease and the development of better treatments for all the patients in our community.

We continue to learn more and more from the data we are collecting through our Natural History Study, both the Matrix platform and soon we’ll have findings from the Citizen Health project. I’ve been able to share some of the insights from the patient experiences during several presentations this year, and we are learning a lot. I’ll be sharing some of these snapshots at our next Research Roundtable in January, too. We know it takes precious time and effort for already busy families to participate, so we are very grateful for those who do choose to take part and contribute to this critical effort.

Finally, I wanted to mention the things we are really looking forward for next year. First, our inaugural Research Workshop coming up next July 24-25, 2025. The goal of this event is to bring together researchers and clinicians on a mission to drive scientific progress and improve patient care. This event will help our community better strategize the projects that are centered on patients and based on their needs and priorities. There will be two main workgroups, scientific and clinical, and each will have specific topics of focus. The workshop will help establish a collaborative agenda with the goal of continuing working together to accomplish established long term objectives. You can find more information about this workshop following this link, and here you can complete a form to register your interest to participate. 

We are also looking forward to clinical trials in our community, we know they are closer now, and we are preparing for them through our Research Ready Series gatherings. We still have one more virtual gathering next January 18th, 2025, which will be in Spanish and our last in-person gathering, which will be on March 22nd, 2025 in San Diego. Registration is now open and you can find more information and links to register following this link. 

I would like to thank all the researchers and clinicians who presented and participated in our Research Roundtables, our Glut1 Deficiency Summit, as well as the researchers developing projects that help research move forward in our community. A special thank you to all our generous donors for helping us make possible so many different projects that without your support would not have been possible.

Thank you for reading this post and please do not hesitate to contact me if you have any questions at [email protected].