Notes from the 2023 Virtual Conference, General Sessions –Kim
In 2022, I visited a full CCDS symposium for the first time. With both my background in neuroscience and my little brother being a CTD patient, I wrote a guide that explained all aspects of CTD in such a way that families without medical or scientific backgrounds could follow. This aimed to bridge the gap between science and society. Since easy-to-read information on this disease was so hard to find, I was convinced about this gap between science and society being present. It was after my visit to the CCDS symposium that I learned little was less true, I had just not been looking in the right places.
At this symposium I met doctors, researchers, and patient families who all had the common goal of helping this patient group. It was heartwarming to see their interactions, discussing research challenges and the serious struggles that parents faced, while the same night having dinner together. Never seemed the gap between science and society so small.The next Scientific + Patient Symposium will be held June 2024, in Utah, US. Here I hope to reconnect with doctors, researchers, and families. And above all, I hope to see the gap shrink even further for more and more families.
Notes from the 2023 Virtual Conference, General Sessions
Summary prepared by Kim Soesbergen and Andrew Marshall
Day 1
Click here for recorded Day 1 sessions.
Sangeetha Iyer
Dr. Sangeetha Iyer shared updates from the ACD, including the approval of GAMT in the United States for recommended universal newborn screening in 2023, the EL-PFDD meeting, and an encouragement for community members to share biosamples for studies currently seeking them. Dr. Iyer also shared ACD’s collaborations to support research of repurposed and novel small molecule therapies, large molecule gene therapies, and refined delivery of the large molecules.
Julia Vitarello
Julia Vitarello shared her story of her daughter Mila and Batten disease, her solo journey into diagnosis, Mila’s treatment, continued advocacy, and how a rare disorder diagnosis has an effect on the family beyond the patient.
Judi Miller
Dr. Miller discussed how the Vigilan natural history study for CTD concluded this year. As the PI, Dr. Miller shared her overall observations on the study’s implications, with a corresponding manuscript being written to be submitted soon. For example, standardized scores are not a good fit for our community, as changes are not reflected when constantly compared to typical improvements. In response, it was proposed that use of individualized curves of growth over time will pick up small changes that will be needed to identify progress and improvements. More general study findings were that patients with CTD have a range of neurologic and gastrointestinal symptoms, and impairments in speech and cognitive abilities. Over time, there are small improvements, but abilities remain impaired.
Dr. Seth Berger
Dr. Seth Berger discussed two patients seen in his clinic with regard to cardiac problems. He discussed a case report of a positive response to creatine supplementation, and the update of HPO resulting in better diagnostic tools. Dr. Berger also discussed how increased cardiovascular risks may lead to additional issues in the drug approval process.
Dr. Samar Rahhal
Dr. Rahhal shared the discovery of elevated amyloid beta peptides and total tau in CTD patient cerebrospinal fluid samples, similar to those seen in Alzheimer’s disease patients.
Dr. Evandro Ferrada
Dr. Ferrada described the study of CTD variants in the interest of understanding the mechanism by which different variants lead to pathogenicity. Through assembling understanding of existing structural data, Dr. Ferrada used software to help predict whether a variant will be pathogenic given the stability of the variants.
Jacklyn Gallagher
Doctoral student Jacklyn Gallagher discussed how small molecule discovery may eventually contribute to treatment and restoration of CTD variants. Specifically, a series of pharmacological, chemical, and genetic analyses has helped inform CTD-related cellular function and targets for pharmacotherapies.
Nicola Longo
Dr. Nicola Longo also discussed the implications of small molecular discovery for treatment of CCDSs, here, for GAMT deficiency. Specifically, Dr. Longo described how AGAT inhibitors may be able to serve as a new therapy for GAMT deficiency. Dr. Longo’s lab is currently working on further refinement of the compounds to help move to preclinical and clinical trials, in that an AGAT inhibitory (along with creatine supplements) may improve the outcomes of patients with GAMT deficiency.
Dr. Peter Axerio-Cilies
Dr. Peter Axerio-Cilies presented on the trajectory of the long-term project aim of identifying a safe FDA-approved oral drug that restores function of SLC6A8 transporters by penetrating the blood-brain barrier. Dr. Axerio-Cilies broke down this process into 4 stages: (1) variant selection and characteristics, (2) identification of drugs that may be effective, (3) evaluation of potentially effective drugs, and (4) movement toward clinical trials, including tests on patients’ fibroblasts. With continued testing on more fibroblasts, the field will get closer to more effective treatments.
Dr. Jenny Goldstein
Dr. Jenny Goldstein updated the CCDS community on work with respect to the Clinical Genome Resource (ClinGen). The primary update was the general classification of sequence variants on a scale from benign to pathogenic. This process is driven by the curation of expert panels, such as one for CCDS (i.e., GAMT, GATM, and SLC6A8). Currently, 160 different classifications have been submitted to ClinVar by the CCDS VCEP, which has been aided by the CreatineInfo registry. Using new criteria/guidance, some of the variants have been reclassified. Ultimately, the goal is to classify all published variants.
Dr. Filippo Ingoglia
Dr. Filippo Ingoglia discussed how functional studies of creatine can benefit diagnoses of CTD. Here, a functional assay permits evaluation of creatine levels in CTD patients’ fibroblasts given creatine supplementation (i.e., incubation), which ultimately helps classify SLC6A8 variants and confirm diagnoses.
Samantha Baxter
Dr. Samantha Baxter provided updates on CCDS prevalence, specifically defining “genetic prevalence” as the approximate proportion of individuals with a causal genotype for a genetic disorder, not the number of individuals with a corresponding diagnosis. Prevalence estimates are influenced by representation (e.g., representation of ancestry groups), curation (e.g., inclusion of misclassified variants), clinical sensitivity, and the disease spectrum. Here, Samantha Baxter presented initial and updated estimates of GAMT genetic prevalence, and how these prevalence estimates may have implications for understanding the total number of individuals across the US (and world) who have GAMT deficiency.
Sylvia Stockler
Dr. Sylvia Stockler explained the principles of the Core Outcome Set (COS). COS is a small set of disease-specific outcomes considered important by parents/caregivers of CTD and GAMT patients and experts. The measurement of these outcomes is needed for assessing the safety and effectiveness of clinical trials. The first step to develop the COS was the collection of a large number of candidate outcomes from literature, patient/caregiver focus groups, and the CreatineINFO registry. To determine which are the most important outcomes, the Delphi Survey was conducted. This international survey gathered opinions from patients, caregivers, and experts in several rounds. In September 2023, after the recording of Dr. Stockler’s talk, round 3 of the survey was launched and a consensus workshop was held to develop a final COS which can be found here.
Emily Reinhardt
Emily Reinhardt updated us on the Creatine Info Patient Registry. At the time, 187 participants were involved in this registry (69% CTD, 30% GAMT, 1% AGAT). Several surveys are used to 1) demonstrate the natural history; 2) facilitate the development of treatments and therapies; and 3) improve diagnostics and screening. Emily provided examples of surveys and explained their relevance by mentioning their use for research or regulation through their many collaborations.
Audrey Thurm
Audrey Thurm explained the importance of outcome measures for clinical trials. The FDA requires information on several domains, including the ‘concepts of interest’, which for example gives information on the patient’s functioning. It is important to find concrete measures that are suitable for measuring over-time and the capabilities of the patients (e.g. speech and IQ).
Day 2
Click here for recorded Day 2 sessions.
Dan Coller
Dan Coller began the day explaining his role on the board and the journey that was taken by him and his family as his son was diagnosed with a CCDS. Dan also provided updates from the ACD board.
Dr. Aloise Mabondzo
Dr. Aloise Mabondzo described work on a pharmacological model on cerebral organoids using fibroblasts of CTD patients. When incubated in creatine, these organoids did not show increased levels of creatine, confirming that lack of the creatine transporter was presented in the model. The data from organoids also suggested potential neurogenesis and synaptogenesis deficits, as well as differential protein expression, in CTD. These results have implications for potential models and treatment testing for CTD.
Dr. Ludovica Iovino
Dr. Ludovica Iovino discussed the potential of gene replacement therapy to treat CTD, using research of mouse models of CTD. Specifically, mouse models of CTD (via gene knockout [KO]) have a similar phenotype (and biochemical creatine transporter expression) to individuals with CTD. However, gene replacement therapy only partially restored the complex phenotype of CTD in studies.
Dr. Laura Baroncelli
Dr. Laura Baroncelli described work on establishing fNIRS as a functional (and objective) biomarker of CCDSs. Notably, the corresponding data correlated well with behavioral data in animal models of younger ages. The next steps in this research program involve collecting similar electrophysiological data from individuals with CTD, some of which have already been collected. Preliminary data show potential differences (as seen in mouse models) (e.g., a higher amplitude of the hemodynamic response in patients with CTD) between individuals with CTD and controls.
Romain Bernasconi
Romain Bernasconi discussed muscular changes in AGAT knockout (KO) vs. GAMT KO mice. To preface, creatine is involved in muscular function. Indeed, there is reduced muscular capacity in AGAT and GAMT KO mice. AGAT KO mice also show muscle atrophy and differences in muscular composition. Interestingly, GAMT KO mice do not show such differences seen in AGAT KO mice.
Dr. Gerry Lipshutz
Dr. Gerry Lipshutz presented on the toxic effects of guanidinoacetic acid (GAA) and the corresponding implications for the brains of those with GAMT deficiency. As background, GAA (along with other compounds) has been shown to be substantially elevated in GAMT KO mice, suggesting that other compounds may also be contributing to the pathology of GAMT deficiency.
Robyn Binsfeld
Graduate student Robyn Binsfeld described the potential for gene replacement therapy as a treatment for GAMT deficiency, given how current treatment for GAMT deficiency involves lifelong supplementation and dietary changes. For this research, Robyn used a mouse model of GAMT deficiency. Indeed, delivery of phGAMT (codon optimized for GAMT cDNA) to cellular models did restore expression and function of GAMT. Similar results were observed in vivo in the mouse model.
Dr. Olivier Braissant
Dr. Olivier Braissant discussed work to develop a more effective rat model of CTD, along with an AAV-based strategy to treat CTD. There are encouraging results thus far, with partial recovery and prevention of CTD symptoms in the rat model of CTD, but more work is needed.
Troy Webster
Graduate student Troy Webster discussed work focused on finding an AAV-based gene therapy for CTD. Here, in the CTD knockout (KO) mice, scAAV9SLC6A8 led to increased levels of creatine in the brain when injected into the brain directly, as well as an increase in body mass. Further, hyperactive behavior in the KO mice was reduced. This research also involved similar injections into the lumbar region, but the same patterns in the data were attenuated.
Dr. Steve Baker
Dr. Steve Baker discussed his work with ACD to form a CCDS research center. His working hypothesis is that patients with CTD have decreased intracerebral creatine content due a failure of neurons to uptake creatine from neighboring oligos and that delivery of both an AGAT and GAMT vector would allow the neuron to synthesize creatine internally. Thus far, preliminary data are promising.
Dr. Maurizio Balestrino
Dr. Maurizio Balestrino discussed MRI and DTI data from individuals with CTD, specifically noting changes in the brain’s left arcuate fasciculus given CTD. The arcuate fasciculus is important for language processing. There was reduced fractional anisotropy (FA) in the arcuate bundle in individuals with CTD, but not in the pyramidal/corticospinal tract. Thus, creatine deficiency may be associated with some structural changes in the brain.
Dr. Saadet Andrews
Dr. Saadet Andrews presented data and a literature review pertaining to AGAT. Dr. Andrews discussed a case report of an individual with Fanconi syndrome due to a heterozygous pathogenic GATM variant (i.e., Fanconi syndrome refers to a condition in which substances normally absorbed into the bloodstream are excreted in urine instead). This individual also had low levels of plasma guanidinoacetate and creatine. Dr. Andrews then described the pathogenesis of Fanconi syndrome in AGAT (GATM). This project’s future directions include treating Fanconi syndrome with creatine supplementation.
Heidi Wallis
Heidi Wallis provided updates on the ACD/CCDS PAReNts project. This project, launched in early 2022, involved monthly capacity building workshops with 24 CCDS caregiver participants and caregiver interviews and presentations, development of a core outcome set for GAMT & CTD, a research paper repository, and a CCDS expert panel meeting series.
CERES Brain Therapeutics (Thomas Joudinaud)
Thomas Joudinaud, on behalf of CERES Brain Therapeutics, provided an update on a therapy to deliver creatine to neurons. Using a drug called CBT101, Thomas reported that creatine could get to neurons through a nasal spray. Preclinical experiments have been conducted in mouse KO models and nonhuman primate models. Thomas shared that CBT101 has also been shown to increase neuroplasticity, improve neurocognition, and restart cerebral metabolism. The next step is clinical trials.
Sebastian Leon
Sebastian Leon discussed therapeutic strategies for CCDS, specifically, a nanoparticle nasal spray solution. During the presentation, Sebastian discussed the development and biochemical diagnostics of this solution.
Interactive Panel
The interactive panel included Drs. Jagdeep Walia, Sylvia Stockler, Laura Baroncelli, and Gerry Lipshutz, and was moderated by Drs. Jonathan Schlebach and Steven Baker. Dr. Walia thinks gene replacement will be the best long-term correction for CCDS. Nanoparticles/small molecule therapies are also a good approach but include some hesitations, as risk for inflammation. Supplements might be used in addition to treatments. Dr. Stockler spoke about how PCORI and patient outcomes might be able to inform clinical trials. Dr. Lipshutz spoke about how CTD will likely be the hardest CCDS to treat, especially as gene therapy might have some toxic side effects. The effects of too much creatine in the brain and the possible risk of toxicity of this was spoken about.
The audience asked about the possibility of using pharmacochaperones for GAMT. The panel answered that chaperones help stabilize a protein and bring it where it should work. So this only works if there is some misfolding, but this is not the case in GAMT. Another topic discussed was enzyme replacement therapy, but Dr. Lipshutz expressed hesitation because of how this therapy may not reduce GAA in the brain as effectively as gene therapy. In addition, the audience asked the panel about the appropriate clinical endpoint for CTD, and Dr. Lipshutz noted that not being able to identify one will prevent FDA approval of therapies. Dr. Stockler suggested that this endpoint will likely be a combination of biomarkers and functional markers, as informed by the core-outcome-set project.
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