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Wolfram syndrome is a rare, genetic, and fatal neurodegenerative disease that progressively impacts multiple organs and systems. Wolfram is characterized by childhood-onset diabetes mellitus, optic nerve atrophy, deafness, diabetes insipidus, and neurodegeneration, eventually resulting in premature death.1-5

There are currently no approved therapies for the approximately 3,000 people in the U.S., and more around the world, living with Wolfram. The majority of people with Wolfram carry mutations in the WFS1 gene, which encodes a protein called wolframin that spans the membrane of the endoplasmic reticulum (ER). Loss of wolframin function leads to ER stress and impaired mitochondrial dynamics, which in turn leads to dysfunction and apoptosis of cells. Because of the clear link between WFS1 mutations and ER stress, Wolfram syndrome is considered a prototypical ER stress disorder.1, 5-9

AMX0035 is hypothesized to reduce neuronal cell death in Wolfram by simultaneously mitigating ER stress and mitochondrial dysfunction. Preclinical studies have provided evidence that AMX0035 may reduce cell death and improve cellular function.10

As part of our commitment to explore the full potential of AMX0035 in neurodegenerative diseases, we initiated HELIOS (NCT05676034), a Phase 2 clinical trial designed to evaluate if AMX0035 slows progression of diabetic, visual, and other measures in people with Wolfram syndrome, and to evaluate safety and tolerability.

  1. Urano F. (2014). Wolfram syndrome iPS cells: the first human cell model of endoplasmic reticulum disease. Diabetes, 63(3), 844–846. https://doi.org/10.2337/db13-1809
  2. Pallotta, M. T., Tascini, G., Crispoldi, R., Orabona, C., Mondanelli, G., Grohmann, U., & Esposito, S. (2019). Wolfram syndrome, a rare neurodegenerative disease: from pathogenesis to future treatment perspectives. Journal of translational medicine, 17(1), 238. https://doi.org/10.1186/s12967-019-1993-1
  3. Lee EM, Verma M, Palaniappan N, Pope EM, Lee S, Blacher L, Neerumalla P, An W, Campbell T, Brown C, Hurst S, Marshall B, Hershey T, Nunes V, López de Heredia M and Urano F (2023) Genotype and clinical characteristics of patients with Wolfram syndrome and WFS1-related disorders. Front. Genet. 14:1198171. http://doi.org/10.3389/fgene.2023.1198171
  4. Leslie M. (2021). A revealing flaw. Science (New York, N.Y.), 371(6530), 663–665. https://doi.org/10.1126/science.371.6530.663
  5. Matsunaga, K., Tanabe, K., Inoue, H., Okuya, S., Ohta, Y., Akiyama, Urano F. (2016). Wolfram Syndrome: Diagnosis, Management, and Treatment. Current diabetes reports, 16(1), 6. https://doi.org/10.1007/s11892-015-0702-6
  6. Fraser FC and T Gunn. J Med Genet.1977;14(3): 190-193. http://doi.org/10.1136/jmg.14.3.190
  7. Silvestri, F., Tromba, V., Costantino, F., Palaniappan, N., & Urano, F. (2022). Two Cases of Wolfram Syndrome Who Were Initially Diagnosed With Type 1 Diabetes. AACE Clinical Case Reports, 8(3), 128-130. https://doi.org/10.1016/j.aace.2022.01.001
  8. Mishra, R., Chen, B. S., Richa, P., & Yu-Wai-Man, P. (2021). Wolfram syndrome: new pathophysiological insights and therapeutic strategies. Therapeutic advances in rare disease, 2, 26330040211039518. https://doi.org/10.1177/26330040211039518
  9. Samara A, Rahn R, Neyman O, Park KY, Samara A, Marshall B, Dougherty J, Hershey T. Developmental hypomyelination in Wolfram syndrome: new insights from neuroimaging and gene expression analyses. Orphanet J Rare Dis. 2019 Dec 3;14(1):279. http://doi.org/10.1186/s13023-019-1260-9
  10. Kitamura, R. A., Maxwell, K. G., Ye, W., Kries, K., Brown, C. M., Augsornworawat, P., Hirsch, Y., Johansson, M. M., Weiden, T., Ekstein, J., Cohen, J., Klee, J., Leslie, K., Simeonov, A., Henderson, M. J., Millman, J. R., & Urano, F. (2022). Multidimensional analysis and therapeutic development using patient iPSC–derived disease models of Wolfram syndrome. JCI Insight, 7(18). https://doi.org/10.1172/jci.insight.156549

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