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Citrin Foundation

From EverybodyWiki Bios & Wiki



Citrin Foundation [1] is a research-focused, nonprofit organization dedicated to addressing citrin deficiency (CD). This monogenetic metabolic disorder, and a urea cycle that primarily affects the liver, is caused by mutations in the SLC25A13 gene. This gene encodes citrin, an inner mitochondrial transporter that plays a key role in the malate-aspartate shuttle.

Citrin Foundation
FoundedDecember 2016; 9 years ago (2016-12)[2]
Legal statusCharity (Grantmaker) under the Charities Act 1994[3]
Location
  • Singapore, United Kingdom
Barbara Yu and Yen How Tai[4]
Chair, Scientific Supervisory Board
Sir John E. Walker[5]
Member, Scientific Supervisory Board
Johannes Häberle[6][7]
Websitecitrinfoundation.org

History

Citrin Foundation was established in 2016 by co-founders Barbara Yu and Yen How Tai.[4] The Foundation's mission is to discover effective treatments for citrin deficiency and ultimately find a cure for the disease.[8]

The Foundation allocates resources to fund research initiatives aimed at advancing the understanding of the disease, promoting the development of novel therapies, and extending support to citrin deficiency patients and their families on a global scale. To achieve these goals, it has dedicated US$30 million over the next decade.[9]

Approach and Mission

Citrin Foundation adopts a holistic, research-driven approach to tackling citrin deficiency by bringing together scientists, clinicians, industry partners, and patients to work collaboratively, with the hope to ultimately find a cure.

The Foundation's mission is anchored by two fundamental pillars: the quest for a cure for citrin deficiency and the provision of lifelong support to patients and their families.[10]

Organization

Scientific Supervisory Board

In July 2021, John Ernest Walker FRS, FMedSci, emeritus Director and Professor at the MRC Mitochondrial Biology Unit at the University of Cambridge and Nobel Laureate for Chemistry, was appointed as the Chair of Citrin Foundation's Scientific Supervisory Board. He previously served as a Special Scientific Advisor to the Foundation from 2019 – 2021.

In November 2021, Citrin Foundation appointed Johannes Häberle, MD, paediatrician, neonatologist, intensive care specialist, senior metabolic consultant, and Head of the Metabolic Laboratory at University Children's Hospital Zürich, as a member of the Scientific Supervisory Board.[6]

From May 2022 to May 2024, Citrin Foundation appointed Professor Hannele Yki-Järvinen, MD, FRCP, Professor of Medicine at the Department of Medicine at the University of Helsinki, as a member of the Scientific Supervisory Board.

Current composition of the Scientific Supervisory Board

  • John Walker,FRS, FMedSci, Nobel Laureate for Chemistry, Chairman
  • Johannes Häberle, MD
  • Barbara Yu
  • Yen How Tai

Advisors

The Foundation also appoints a board of international advisors to provide strategic guidance, expertise, and support in various areas.

Activities

Research

The Foundation operates on a financially independent basis and provides grants [9] for projects for up to three years, with applications open year-round. Areas of research include basic science, clinical research and the development of new therapies for citrin deficiency. To date, the Foundation has funded over 25 projects worldwide.

Publications

The following sections detail peer-reviewed publications authored by research groups whose projects were sponsored or partially supported by Citrin Foundation.

2024

A review paper by Kido et al. 2024 titled "Clinical Landscape of Citrin Deficiency: A Global Perspective on a Multifaceted Condition" provides a comprehensive review of the clinical aspects of citrin deficiency, offering an updated global overview and introducing a new nomenclature, adolescent and adult citrin deficiency (AACD), which replaces the earlier term CTLN2.[24] In the same year, a review paper by Vuković et al. 2024, prepared in collaboration with Citrin Foundation titled “The Therapeutic Landscape of Citrin Deficiency” was published. It examines current treatments and explores future therapeutic prospects for citrin deficiency.[25]

2023

A research publication by González-Moreno et al. 2023 examined the levels of citrin and aralar expression in mouse and human livers and assessed the potential of aralar as a substitute for citrin in human therapy.[26] In the same year, a research paper by Kido et al. 2023 entitled “Improved sensitivity and specificity for citrin deficiency using selected amino acids and acylcarnitines in newborn screening for citrin deficiency” [27] was published and proposes an improved method of newborn screening for citrin deficiency.

2022

A review article authored by Tavoulari et al. 2022 offers an updated biochemical overview of citrin deficiency, detailing pathogenic mutations in the SLC25A13 gene and their links to potential structural and functional defects.[28]

2021

A collaboration between the Citrin Foundation, ChromaDex, and Duke-NUS Medical School investigated the in-vitro effects of nicotinamide riboside (NR) on a hepatocyte model of citrin deficiency.[29] The study demonstrated that NR effectively corrected the elevated cytoplasmic NADH/NAD+ ratio and improved defects in glycolysis and fatty acid β-oxidation associated with citrin deficiency.[30] In the same year, studies by Okamoto et al. 2021 [31] and Okano et al. 2021 [32] reported on the food preferences of citrin deficiency patients and examined the daily food energy intake in citrin deficiency patients respectively.

2020

A review article by Saheki et al. 2020 examined the history of identifying SLC25A13 as the causative gene for citrullinemia type 2 (CTLN2) and explored the pathophysiology, animal models, and potential treatments for citrin deficiency.[33]

2019

A research publication by Saheki et al. 2019 demonstrated that L-Ornithine L-Aspartate (LOLA) effectively normalized elevated ammonia and citrulline levels in a mouse model of citrin deficiency.[34] In a collaborative study with Takeyori Saheki, Cao et al. 2019 assessed the pre-clinical efficacy of lipid nanoparticle (LNP)-mRNA therapy for citrin deficiency, showing improvements in both metabolic and behavioral abnormalities in citrin deficiency mouse models.[35] In the same year, a medical protocol by Okano et al. 2019 was developed for citrin deficiency patients as part of a Foundation-sponsored study.[36]

Ongoing Research

The Foundation currently funds multiple research projects with a specific focus on citrin deficiency spanning across disciplines from basic science and clinical studies to translational research focused on therapy development. Selected examples include:

Basic science

  • Understanding the consequences of citrin pathogenic mutations
  • Metabolic flux studies using stable isotope tracers to understand the metabolic consequences of citrin deficiency
  • Develop new cellular and animal research models of citrin deficiency

Clinical studies

  • Improved newborn screening (NBS) methods with better specificity and sensitivity for diagnosing newborns with citrin deficiency
  • Citrin Foundation Global Omics Study to identify citrin deficiency-specific biomarkers from collected patient blood samples
  • Ureagenesis test using orally ingested stable isotope tracers to accurate measure urea cycle function in patients

Therapies development

Clinical Cohorts

The Foundation has identified clinical cohorts in the US, Canada, Malaysia, Japan[37], South Korea, Hong Kong[38], Taiwan, Vietnam[39], the United Kingdom[40] and other countries in Europe.

Events

Citrin Foundation Global Symposia

The Foundation hosts biennial global symposiums that highlight recent research and clinical advancements in citrin deficiency. By bringing together leading scientists, clinicians, and patient advocates, these events aim to foster in-depth discussions, drive innovation, and encourage interdisciplinary collaboration to address the challenges of the condition.

To date, the Foundation has organized two in-person symposia. The first took place in Singapore in November 2019, spanning two days, and gathered participants from across the globe, including researchers, clinicians, and patients and their families.[41] The second symposium, held in Cambridge, UK, in September 2023, consisted of a two-day scientific program and a half-day patient-oriented session. Professionals presented their latest research findings and discussed new ideas over the scientific sessions, further advancing the collective understanding of citrin deficiency. The patient session included a hybrid session, enabling remote participation, extending the symposium's reach to patients and families worldwide.[42]

The Foundation plans to host its next global symposium in Cambridge, UK, in June 2025.

Citrin Deficiency Symposium at the Japan Society of Inherited Metabolic Diseases (JSIMD) Meeting 2023

At the 64th JSIMD Annual Meeting in Osaka, the Citrin Foundation sponsored a symposium on citrin deficiency, highlighting new research advancements and clinical studies supported by the Foundation. The symposium featured prominent international and local speakers and was co-chaired by Johannes Häberle and Kimitoshi Nakamura. Additionally, the Foundation co-hosted a luncheon with regional clinicians to facilitate further discussions on citrin deficiency.

Multi-stakeholder Roundtable at the Society for the Study of Inborn Errors of Metabolism (SSIEM) Meeting 2024

At the 2024 SSIEM Annual Meeting in Porto, the Citrin Foundation hosted a roundtable titled "Multi-Stakeholder Perspectives on the Development of Novel Therapies for Monogenetic Metabolic Diseases".[43] The panel featured prominent regulators like Peter Marks (FDA), Kristina Larsson (EMA), and several key figures from academia and patient advocacy. Discussions focused on challenges in translating preclinical research into clinical trials, optimizing trial design for novel therapies, and the importance of early patient and regulatory involvement. The session highlighted regulatory progress and emphasized the need for global collaboration to advance treatments for rare diseases.

Expert Talks

The Foundation also regularly hosts Expert Talks [44] for its consortium and internal network, inviting speakers who are leading experts in their respective fields. The Expert Talk Series covers a range of topics relevant to citrin deficiency research, with the aim of improving the current understanding of the condition and contributing to the development of effective therapies.

Patient Support

Citrin Foundation provides comprehensive support to patients and families worldwide. With offices in London and Singapore, the Foundation supports a cohort that spans Asia, Europe and North America.

In addition to a patient website [45] with disease management information, patient stories and age-specific resources, the Foundation runs an international peer support group and focuses on building a community for its members. Since 2022, the Citrin Foundation has expanded its online presence across Facebook, X, Instagram and YouTube to provide informational support through a range of multimedia resources.

Patient Committee

In 2024, the Foundation appointed an International Patient Committee[46] with members in the US, Europe and Asia. The committee meets on a quarterly basis to discuss the Foundation's projects and strategize for the future.

Quarterly Newsletter

The Foundation publishes a quarterly newsletter [47]to keep their professional network and patient membership updated on research progress, publications, events and new resources and initiatives.

External links

Further reading

References

  1. ↑ " Citrin Foundation". Entity Search..
  2. ↑ "Singapore Business Directory".Entity Search.
  3. ↑ "Singapore Charity Portal".' 'Charity Status Search.
  4. ↑ 4.0 4.1 "Co-Founders"
  5. ↑ "John E. Walker".
  6. ↑ 6.0 6.1 "Johannes Häberle".
  7. ↑ "[1]".
  8. ↑ "Mission and Vision"
  9. ↑ 9.0 9.1 "Funding Opportunity"
  10. ↑ "Mission & Vision". Citrin Foundation. Retrieved 2025-02-18.
  11. ↑ "Takeyori Saheki". Profile Lookup.
  12. ↑ "Fumio Endo". Profile Lookup.
  13. ↑ "Nicholas Ah Mew". Profile Lookup.
  14. ↑ "Cary O. Harding". Profile Lookup.
  15. ↑ "Marc Hellerstein". Profile Lookup.
  16. ↑ "Edmund Kunji". Profile Lookup.
  17. ↑ "Robin Lachmann". Profile Lookup.
  18. ↑ "Nicola Longo". Profile Lookup.
  19. ↑ "Kimitoshi Nakamura". Profile Lookup.
  20. ↑ "Kimihiko Oishi". Profile Lookup.
  21. ↑ "Jorgina Satrústegui". Profile Lookup.
  22. ↑ "Stephen Leon Yang". Profile Lookup.
  23. ↑ "Masahide Yazaki". Profile Lookup.
  24. ↑ Kido J, Makris G, Santra S, Häberle J (March 2024). "Clinical landscape of citrin deficiency: A global perspective on a multifaceted condition". Journal of Inherited Metabolic Disease. 47 (6): 1144–1156. doi:10.1002/jimd.12722. PMC 11586594 Check |pmc= value (help). PMID 38503330 Check |pmid= value (help).
  25. ↑ Vuković T, Kuek LE, Yu B, Makris G, Häberle J (July 2024). "The therapeutic landscape of citrin deficiency". Journal of Inherited Metabolic Disease. 47 (6): 1157–1174. doi:10.1002/jimd.12768. PMC 11586593 Check |pmc= value (help). PMID 39021261 Check |pmid= value (help).
  26. ↑ González-Moreno L, Santamaría-Cano A, Paradela A, Martínez-Chantar ML, Martín M, Pérez-Carreras M, García-Picazo A, Vázquez J, Calvo E, González-Aseguinolaza G, Saheki T, Arco A, Satrústegui J, Contreras L (June 2023). "Exogenous aralar/slc25a12 can replace citrin/slc25a13 as malate aspartate shuttle component in liver". Molecular Genetics and Metabolism. 35. doi:10.1016/j.ymgmr.2023.100967. PMC 10031141 Check |pmc= value (help). PMID 36967723 Check |pmid= value (help). Unknown parameter |article-number= ignored (help)
  27. ↑ Kido J, Häberle J, Tanaka T, Nagao M, Wada Y, Numakura C, Bo R, Nyuzuki H, Dateki S, Maruyama S, Murayama K, Yoshida S, Nakamura K (September 2023). "Improved sensitivity and specificity for citrin deficiency using selected amino acids and acylcarnitines in the newborn screening". Journal of Inherited Metabolic Disease. 47 (6): 1134–1143. doi:10.1002/jimd.12673. PMID 37681292 Check |pmid= value (help).
  28. ↑ Tavoulari S, Lacabanne D, Thangaratnarajah C, Kunji E (August 2022). "Pathogenic variants of the mitochondrial aspartate/glutamate carrier causing citrin deficiency". Cell, Trends in Endocrinology & Metabolism. 33 (8): 539–553. doi:10.1016/j.tem.2022.05.002. PMC 7614230 Check |pmc= value (help). PMID 35725541 Check |pmid= value (help).
  29. ↑ "ChromaDex and the Citrin Foundation Announce Global Research Collaboration Exploring Citrin Deficiency". Chromadex Investor Relations. March 31, 2021. Retrieved 2024-08-14.
  30. ↑ Yau WW, Chen GB, Zhou J, Francisco JC, Thimmukonda NK, Li S, Singh BK, Yen PM (March 2023). "Nicotinamide riboside rescues dysregulated glycolysis and fatty acid β-oxidation in a human hepatic cell model of citrin deficiency". Oxford Academics, Human Molecular Genetics. 32 (11): 1922–1931. doi:10.1093/hmg/ddad018. PMC 10196666 Check |pmc= value (help). PMID 36881658 Check |pmid= value (help).
  31. ↑ Okamota M, Okano Y, Okano M, Yazaki M, Inui A, Ohura T, Murayama K, Watanabe Y, Tokuhara D, Takeshima Y (September 2021). "Food Preferences of Patients with Citrin Deficiency". MDPI Nutrients. 13 (9): 3123. doi:10.3390/nu13093123. PMC 8468903 Check |pmc= value (help). PMID 34579000 Check |pmid= value (help).
  32. ↑ Okano Y, Okamoto M, Yazaki M, Inui A, Ohura T, Murayama K, Watanabe Y, Tokuhara D, Takeshima Y (May 2021). "Analysis of daily energy, protein, fat, and carbohydrate intake in citrin-deficient patients: Towards prevention of adult-onset type II citrullinemia". Molecular Genetics and Metabolism. 133 (1): 63–70. doi:10.1016/j.ymgme.2021.03.004. PMID 33741270 Check |pmid= value (help).
  33. ↑ Saheki T, Moriyama M, Funahashi A, Kuroda E (July 2020). "AGC2 (Citrin) Deficiency – From Recognition of the Disease till Construction of Therapeutic Procedures". MDPI Biomolecules Journal. 10 (8): 1100. doi:10.3390/biom10081100. PMC 7465890 Check |pmc= value (help). PMID 32722104 Check |pmid= value (help).
  34. ↑ Saheki T, Moriyama M, Kuroda E, Funahashi A, Yasuda I, Setogawa Y, Gao QH, Ushikai M, Furuie S, Yumamura K, Takano K, Nakamura Y, Eto K, Kadowaki T, Sinasac DS, Furukawa T, Horiuchi M, Tai YH (March 2019). "Pivotal role of inter-organ aspartate metabolism for treatment of mitochondrial aspartate-glutamate carrier 2 (citrin) deficiency, based on the mouse model". Nature Scientific Reports. 9 (1). Bibcode:2019NatSR...9.4179S. doi:10.1038/s41598-019-39627-y. PMC 6414645. PMID 30862943. Unknown parameter |article-number= ignored (help)
  35. ↑ Cao J, An D, Galduroz M, Zhuo J, Liang S, Eybye M, Frassetto A, Kuroda E, Funahashi A, Santana J, Mihai C, Benenato K, Kumarasinghe E, Sabnis S, Salerno T, Coughlan K, Miracco E, Levy B, Besin G, Schultz J, Lukacs C, Guey L, Finn P, Furukawa T, Giangrande P, Saheki T, Martini P (July 2019). "mRNA Therapy Improves Metabolic and Behavioral Abnormalities in a Murine Model of Citrin Deficiency". Molecular Therapy. 27 (7): 1242–1251. doi:10.1016/j.ymthe.2019.04.017. PMC 6612659 Check |pmc= value (help). PMID 31056400.
  36. ↑ Okano Y, Ohura T, Sakamoto O, Inui A (July 2019). "Current treatment for citrin deficiency during NICCD and adaptation/compensation stages: Strategy to prevent CTLN2". Molecular Genetics and Metabolism. 127 (3): 175–183. doi:10.1016/j.ymgme.2019.06.004. PMID 31255436.
  37. ↑ Kido, J.; et al. (2022). "Clinical manifestation and long-term outcome of citrin deficiency: Report from a nationwide study in Japan". Journal of Inherited Metabolic Disease. 45 (3): 431–444. doi:10.1002/jimd.12483. PMID 35142380 Check |pmid= value (help).
  38. ↑ Chong, SC.; et al. (2018). "Molecular and clinical characterization of citrin deficiency in a cohort of Chinese patients in Hong Kong". Mol Genet Metab Rep. 17: 3–8. doi:10.1016/j.ymgmr.2018.08.002. PMC 6120422. PMID 30181955.
  39. ↑ Nguyen, MT.; et al. (2023). "The mutation spectrum of SLC25A13 gene in citrin deficiency: identification of novel mutations in Vietnamese pediatric cohort with neonatal intrahepatic cholestasis". J Hum Genet. 68 (5): 305–312. doi:10.1038/s10038-022-01112-2. PMID 36599957 Check |pmid= value (help).
  40. ↑ Pinto, A; et al. (2020). "Dietary Management, Clinical Status and Outcome of Patients with Citrin Deficiency in the UK". Nutrients. 12 (11): 3313. doi:10.3390/nu12113313. PMC 7693899 Check |pmc= value (help). PMID 33137944 Check |pmid= value (help).
  41. ↑ "Citrin Foundation Global Research Symposium 2019". Citrin Foundation Events. February 20, 2020.
  42. ↑ "Citrin Foundation 2nd In-Person Global Symposium 2023". Citrin Foundation Events. November 6, 2023.
  43. ↑ "CF SSIEM Roundtable"
  44. ↑ "Expert Talk"
  45. ↑ "Patient Website"
  46. ↑ "International Patient Committee". Citrin Foundation. Retrieved 2025-02-18.
  47. ↑ "Newsletters". Citrin Foundation. Retrieved 2025-02-18.




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