In this issue: Recap of publication on Ataluren to pave the path for clinical trials. Learn more about how it works in this post.
Welcome to our timely updates on all things SDS, Science, and Advocacy. We bring you a digest of recent scientific publications, conferences, and other newsworthy content - all relevant to SDS - with links to more details and learning opportunities. Are you interested in anything specific? Did we miss something? Let us know. Email genetics@SDSAlliance.org or message us on Facebook! This is all for you!
An update on the development of Ataluren, a therapeutic approach targeting the c.183_184TA>CT mutation in the SBDS gene
Over the past few years, important research has been ongoing in Dr. Valentino Bezzerri and Dr. Marco Cipolli’s laboratory in Italy to investigate the use of Ataluren to treat individuals with SDS. We previously wrote about this work, including a detailed summary by Dr. Bezzerri in a SDS & Science Snapshot edition from May 2022 and October 2023.
This week, the publication has finally hit the shelves and is now available for free online. It expands the pre-clinical laboratory based research to solidify the rationale to enable clinical trials for Ataluren for a subset of SDS patient. The authors show, that
Ataluren improved ribosome assembly and total protein synthesis in SDS-patient-derived cells in the lab
Restored myelopoiesis in myeloid progenitors in the lab
Improved neutrophil chemotaxis in an experimental model
Reduced neutrophil dysplastic markers in the lab.
Restored full-length SBDS protein production in osteoblasts (bone producing cells) donated by patients, suggesting that its beneficial role may go beyond the blood producing stem cells.
The authors summarize: "Altogether, our results strengthened the rationale for a Phase I/II clinical trial of ataluren in SDS patients who harbour the nonsense mutation".
Dr. Bezzerri also shared his work at the 2023 SDS POPS summit in May and joined us for a lively discussion at our first ever Ask-an-Expert Community Chat. It was fantastic. Check out the recording, below.
As previous highlighted, the group tested the effect of Ataluren in the laboratory on cells of individuals with SDS who harbor the c.183_184TA>CT mutation in their SBDS gene. These preclinical studies showed:
Improved SBDS protein levels and improved ribosome assembly and total protein synthesis;
Reduced the elevated levels of p53 protein, which is found in excess in SDS tissues; and
Improved migration of neutrophils, important cells in the immune system frequently reduced in individuals with SDS.
These results are promising for Ataluren and its use as a "personalized medicine" approach for treating SDS patients carrying nonsense variants, such as c.183_184TA>CT. These preclinical results support the idea of developing of a Phase I/II clinical trial in the future for Ataluren in SDS patients who have a nonsense mutation. The SDS Alliance team will remain in communication with the SDS community about these trials when/if they become available. Be sure to sign up for updates!
The figure below summarizes the findings published in the current article. The top of the figure shows what normally happens in SDS cells that harbor a nonsense variant. The bottom panel shows the mechanism of Ataluren and the improvements it makes on the cellular environment.
What is the significance of the c.183_184TA>CT mutation in SBDS gene?
A large percentage of SDS patients carry the variant (i.e., mutation), c.183_184TA>CT, in addition to the most common “splice site” variant. For instance, the c.183_184TA>CT variant is present in more than half of SDS patients. This genetic change leads to the generation of a premature stop in building the SBDS protein, similar to inserting a period in the middle of a sentence. These types of variants, known as nonsense variants, generally result in unstable protein intermediates and are rapidly degraded in the cell or produce a protein that has lost its function.
What is Ataluren?
Ataluren (PTC124) was launched in 2007 by PTC Therapeutics (NJ, USA), which promotes careful attention to “incorrect punctuation” in cells (e.g., an extra period in the middle of a sentence). This attention allows for more selective synthesis of proteins with normal structure (i.e., proteins without the extra period in the middle of the sentence). Furthermore, Ataluren has shown less toxicity and better safety than other drugs used for similar purposes. The use of Ataluren as a potential therapeutic agent for genetic disorders has been proposed for the treatment of Duchenne Muscular Dystrophy (DMD) and Cystic Fibrosis (CF). Most importantly, Ataluren has been approved for the treatment of DMD in Europe (but not in the US). Data from clinical trials showed that chronic Ataluren treatment is beneficial to DMD patients undergoing standard care, because it delays the progression of ambulation impairment and the worsening of pulmonary and cardiac functions. Interestingly, clinical studies revealed that the best results are observed in younger individuals, suggesting major benefits of early ataluren administration.
Why is Ataluren not widely used?
Despite promising pre-clinical results, Ataluren unfortunately failed in clinical studies for CF and was therefore discontinued. This early work suggested there may be highly variable clinical benefits in using Ataluren to treat individuals with CF. Because of such variable levels of effectiveness of Ataluren, it is important to perform extensive preclinical testing using cells in the laboratory, such as the recent work published by Cipolli et al., before trying Ataluren in people with SDS in clinical trials.
Find additional information about Ataluren and its treatment of individuals with DMD by watching this YouTube video.
Ataluren improves myelopoiesis and neutrophil chemotaxis by restoring ribosome biogenesis and reducing p53 levels in Shwachman-Diamond syndrome cells.
Cipolli M, Boni C, Penzo M, Villa I, Bolamperti S, Baldisseri E, Frattini A, Porta G, Api M, Selicato N, Roccia P, Pollutri D, Marinelli Busilacchi E, Poloni A, Caporelli N, D'Amico G, Pegoraro A, Cesaro S, Oyarbide U, Vella A, Lippi G, Corey SJ, Valli R, Polini A, Bezzerri V.Br J Haematol. 2024 Jan;204(1):292-305. doi: 10.1111/bjh.19134. Epub 2023 Oct 24.
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