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Toward Development of A Cure
Toward Development of A Cure
Rare Disease Facts
Rare Disease Facts
More than 10,000 different rare diseases are know today, with additional diseases being discovered over time. More than 30 million people in the United States are living with a rare disease. This equates to 1 in 10 Americans or 10% of the U.S. Population.
The majority (80%) of rare diseases are genetic in origin, and thus are present throughout a person’s life, even if symptoms do not immediately appear. Approximately 50% of rare diseases do not have a disease specific foundation supporting or researching their rare disease.
Despite the number of people affected, fewer than 5% of rare diseases have an FDA approved treatment.
AGU and Drug Development Process
AGU and Drug Development Process
Every new treatment follows a regulated development and FDA review process to determine whether the drug may provide benefits that outweigh its known and potential risks for the intended patient population. To evaluate the potential benefits and risks of a drug or treatment, researchers study the drug, its delivery method, and dose levels in preclinical studies, including animal studies, before submitting an application to test the treatment in humans. This application is called an Investigational New Drug, or IND, application. FDA authorization to proceed under an IND allows the investigational drug to be given to patients in a clinical trial.
Schematic of a drug development steps
Since 2013, Rare Trait Hope Fund has supported the development of two investigational treatment approaches for Aspartylglucosaminuria (AGU): chaperone therapy and gene replacement therapy.
Both approaches require scientific evidence and regulatory review before they can be tested in patients. However, the development paths are different. Chaperone therapy evaluates existing or previously developed medicines for potential use in a new disease, AGU. After testing in patient-derived cultured cells with a specific mutation(s) only, this approach was allowed to proceed into a clinical trial.
Gene replacement therapy required several years of preclinical testing to evaluate the efficacy and safety of the selected investigational gene therapy product. The results of the AGU mouse efficacy study were published in 2021.
Since then, we have:
Manufactured the investigational gene therapy drug (AGA gene + delivery vector) product;
Conducted drug clearance testing and received a Certificate of Analysis for the drug;
Completed large-animal toxicology, dose-determination, and biodistribution studies;
Submitted the Investigational New Drug application to the FDA for AGU gene replacement therapy;
Received FDA clearance to proceed with a first-in-human clinical trial;
Signed a clinical trial agreement with the clinical trial site.
The investigational drug product is filled in vials and remains in frozen storage at the manufacturing facility at UTSW. UTSW still working on:
Certificate of Compliance - confirming that the Products have been manufactured, tested, and stored according to the requirements of the Master Production Record and cGMP criteria.
Deviation/Investigations(s) – report list indicating all product specific deviations (i.e. Product testing record, manufacturing deviation, material deviation).
Environmental monitoring results, and approved deviations/investigations environmental monitoring results, and approved deviations/investigations.
Rare Trait Hope Fund is working to complete the remaining manufacturer payment and clinical trial startup activities needed before the patient dosing can begin.
Rare Trait Hope Fund is now moving from preclinical development and FDA review into clinical trial startup for DANAGALEX, an investigational scAAV9/AGA gene replacement therapy for AGU. The Phase 1/2 clinical trial is designed to evaluate the safety and efficacy of DANAGALEX in adults and children with AGU.
This milestone does not mean the treatment is approved or proven effective. It means that the FDA has reviewed the available preclinical, manufacturing, and clinical trial information and has allowed the investigational treatment to be given to the AGU patients under an IND.
Published Research Funded by Rare Trait
Published Research Funded by Rare Trait
Melanie Meister and Ritva Tikkanen (2014) Endocytic Trafficking of Membrane-Bound Cargo: A Flotillin Point of View. Membranes 2014, 4(3), 356-371. https://doi.org/10.3390/membranes4030356
Banning, A., Gülec, C., Rouvinen, J. et al. Identification of Small Molecule Compounds for Pharmacological Chaperone Therapy of Aspartylglucosaminuria. Sci Rep 6, 37583 (2016). https://doi.org/10.1038/srep37583
Banning, A.; König, J.F.; Gray, S.J.; Tikkanen, R. Functional Analysis of the Ser149/Thr149 Variants of Human Aspartylglucosaminidase and Optimization of the Coding Sequence for Protein Production. Int. J. Mol. Sci. 2017, 18, 706. https://doi.org/10.3390/ijms18040706
Antje Banning, Manuel Schiff, Ritva Tikkanen (2018), Amlexanox provides a potential therapy for nonsense mutations in the lysosomal storage disorder Aspartylglucosaminuria. Biochimica et Biophysica Acta, 1864:668-675. https://doi.org/10.1016/j.bbadis.2017.12.014
Goodspeed, K., Harder, L., Hughes, S., Conger, D., Taravella, J., Gray, S.J. and Minassian, B. (2018), Optical coherence tomography features in brothers with aspartylglucosaminuria. Ann Clin Transl Neurol, 5: 1622-1626. https://doi.org/10.1002/acn3.672
A. Tokola, M. Laine, R. Tikkanen and T. Autti (2019), Susceptibility-Weighted Imaging Findings in Aspartylglucosaminuria. American Journal of Neuroradiology Nov 2019, 40 (11) 1850-1854. https://doi.org/10.3174/ajnr.A6288
Xin Chen, Sarah Snanoudj-Verber, Laura Pollard, Yuhui Hu, Sara S. Cathey, Ritva Tikkanen, Steven J. Gray, Pre-clinical Gene Therapy with AAV9/AGA in Aspartylglucosaminuria Mice Provides Evidence for Clinical Translation, Molecular Therapy, Volume 29, Issue 3, 2021, Pages 989-1000, https://doi.org/10.1016/j.ymthe.2020.11.012.
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