Sarepta Therapeutics to Collaborate With Lexeo on Heart Disease Gene Therapy Pipeline

Aug 28, 2023, NEW YORK – Sarepta Therapeutics has invested an undisclosed sum in Lexeo Therapeutics, and the two companies on Monday said they will explore opportunities to further develop gene therapies in Lexeo's preclinical pipeline for cardiovascular disease.

Halogens engineering-based design of agonists for boosting expression of frataxin protein in Friedreich's ataxia

Naveed, M., Ali, I., Aziz, T., Ain, N., Shabbir, M. A., Javed, K., Alharbi, M., Alshammari, A., Alasmari, A. F., Alharbi, S. A., & Alharbi, M. S. (2023). Halogens engineering-based design of agonists for boosting expression of frataxin protein in Friedreich's ataxia. European review for medical and pharmacological sciences, 27(15), 6972–6984. doi:10.26355/eurrev_202308_33269 

 The selected agonist is one of the most potent compounds in increasing Frataxin protein expression. Furthermore, optimization with halogens can be a productive approach to improve the candidate's drug efficacy. The development of effective medications for the treatment of Friedreich ataxia would be aided by the results of these computational investigations.

The optimized agonist 9-[1-[(1S, 5R)-8, 8-dimethyl-8-azoniabicyclo[3.2.1]octan-3-yl]triazol-4-yl]fluoren-9-ol has higher binding energy of -10.4Kcal/mol with molecular weight of 705.63 g/mol. Drug-like properties are identified through ADMET profiling, having water solubility of about -7.59, skin permeation -7.08 cm/s, bioavailability score 0.17, and high GI absorption. The candidate fulfills the Lipinski rule of five and portrays efficient molecular dynamic stimulations.

Design Therapeutics Reports Initial Results from Phase 1 Multiple-Ascending Dose Study of DT-216 for the Treatment of Friedrich Ataxia

CARLSBAD, Calif., Aug. 14, 2023 (GLOBE NEWSWIRE) -- Design Therapeutics, Inc. (Nasdaq: DSGN), a clinical-stage biotechnology company developing treatments for serious degenerative genetic diseases, today reported initial results from the company’s Phase 1 multiple-ascending dose (MAD) clinical trial of DT-216 in patients with Friedrich ataxia (FA). As of a data cutoff date of August 7, 2023, results showed that DT-216 was generally well-tolerated and achieved a statistically significant and dose-related increase in frataxin (FXN) mRNA levels in skeletal muscle biopsies.

Epidemiological research on rare diseases using large-scale online search queries and reported case data

Zhang, L., Jin, Y., Li, J. et al. Epidemiological research on rare diseases using large-scale online search queries and reported case data. Orphanet J Rare Dis 18, 236 (2023). doi:10.1186/s13023-023-02839-7

 Rare diseases have become a major public health concern worldwide. However, detailed epidemiological data are lacking. With the development of the Internet, search queries have played an important role in disease surveillance. In this study, we explored a new method for the epidemiological research on rare diseases, using large-scale online search queries and reported case data. We distilled search logs related to rare diseases nationwide from 2016 to 2019. The case data were obtained from China’s national database of rare diseases during the same period.

Finding an Appropriate Mouse Model to Study the Impact of a Treatment for Friedreich Ataxia on the Behavioral Phenotype

Bouchard, C.; Gérard, C.; Yanyabé, S.G.-f.; Majeau, N.; Aloui, M.; Buisson, G.; Yameogo, P.; Couture, V.; Tremblay, J.P. Finding an Appropriate Mouse Model to Study the Impact of a Treatment for Friedreich Ataxia on the Behavioral Phenotype. Genes 2023, 14, 1654. doi:10.3390/genes14081654

 The YG8sR mice are Knock-Out (KO) for their murine frataxin gene but contain a human frataxin transgene derived from an FRDA patient with 300 GAA repeats. These mice are used as a FRDA model but even with a low frataxin concentration, their phenotype is mild. We aimed to find an optimized mouse model with a phenotype comparable to the human patients to study the impact of therapy on the phenotype. We compared two mouse models: the YG8sR injected with an AAV. PHP.B coding for a shRNA targeting the human frataxin gene and the YG8-800, a new mouse model with a human transgene containing 800 GAA repeats.

Why Is Design Therapeutics Stock Moving Lower Today?

Aug. 15, 2023, Design Therapeutics planned to reformulate its Friedreich ataxia drug following injection site reactions in a Phase 1 study. The company plans to begin a new multiple-dose Phase 1 study in the second half of 2024, with initial data in the first half of 2025. Based on current methods and procedures, the treatment effect of DT-216 on FXN protein was inconclusive due to high intra-individual variability, consistent with what was seen in the observational study.

Rationale and protocol of a double-blind, randomized, placebo-controlled trial to test the efficacy, safety and tolerability of Dimethyl Fumarate in Friedreich Ataxia (DMF-FA-201)

Chiara Pane1, Alberto M. Marra, Ludovica Aliberti, Mario Campanile, Federica Coscetta, Giulia Crisci, Roberta D'Assante, Angela Marsili, Giorgia Puorro, Andrea Salzano, Antonio Cittadini, Francesco Saccà; Rationale and protocol of a double-blind, randomized, placebo-controlled trial to test the efficacy, safety and tolerability of Dimethyl Fumarate in Friedreich Ataxia (DMF-FA-201). Front. Neurosci. Sec. Neuropharmacology, Volume 17 - 2023 | doi: 10.3389/fnins.2023.1260977 

 Conclusions: this is the first study aimed at exploring the ability of DMF, an already available treatment for MS and psoriasis, to correct the biological deficits of FRDA and potentially improve mitochondrial respiration in-vivo.

Interferon Gamma Enhances Cytoprotective Pathways via Nrf2 and MnSOD Induction in Friedreich’s Ataxia Cells

Luffarelli, R.; Panarello, L.; Quatrana, A.; Tiano, F.; Fortuni, S.; Rufini, A.; Malisan, F.; Testi, R.; Condò, I. Interferon Gamma Enhances Cytoprotective Pathways via Nrf2 and MnSOD Induction in Friedreich’s Ataxia Cells. Int. J. Mol. Sci. 2023, 24, 12687. doi:10.3390/ijms241612687 

The cytokine interferon gamma (IFN-γ) has been shown to increase frataxin expression in FRDA cells and to improve functional deficits in FRDA mice. Currently, IFN-γ represents a potential therapy under clinical evaluation in FRDA patients. Here, we show that IFN-γ induces a rapid expression of Nrf2 and MnSOD in different cell types, including FRDA patient-derived fibroblasts. Our data indicate that IFN-γ signals two separate pathways to enhance Nrf2 and MnSOD levels in FRDA fibroblasts. MnSOD expression increased through an early transcriptional regulation, whereas the levels of Nrf2 are induced by a post-transcriptional mechanism. We demonstrate that the treatment of FRDA fibroblasts with IFN-γ stimulates a non-canonical Nrf2 activation pathway through p21 and potentiates antioxidant responses under exposure to hydrogen peroxide. Moreover, IFN-γ significantly reduced the sensitivity to hydrogen peroxide-induced cell death in FRDA fibroblasts. Collectively, these results indicate the presence of multiple pathways triggered by IFN-γ with therapeutic relevance to FRDA.

Omaveloxolone for the Treatment of Friedreich’s Ataxia

Riley Kessler, Sonal Sharma, David R Lynch, Omaveloxolone for the Treatment of Friedreich’s Ataxia, Published Online: Aug 9th 2023 touchREVIEWS in Neurology. 2023;19(2):Online ahead of journal publication. 

 This review discusses the underlying cellular pathology and proposed mechanism of omaveloxolone in FRDA. The MOXIe study is presented in detail, including a discussion of the challenges faced in clinical trials in FRDA, and rare diseases more broadly. Finally, other therapies under investigation are reviewed briefly.

CRISPR/Cas9 Genome Editing for Tissue-Specific In Vivo Targeting: Nanomaterials and Translational Perspective

Sahel DK, Vora LK, Saraswat A, et al. CRISPR/Cas9 Genome Editing for Tissue-Specific In Vivo Targeting: Nanomaterials and Translational Perspective. Advanced Science (Weinheim, Baden-wurttemberg, Germany). 2023 Jul;10(19):e2207512. DOI: 10.1002/advs.202207512. PMID: 37166046; PMCID: PMC10323670. 

Despite DSBs, they have also been explored through epigenome editing and biosensor applications. However, its in vivo delivery is still a major challenge. Interestingly, ample nonviral nanocarriers have been developed and explored for the in vivo delivery of CRISPR components, but they are limited to some immune-prone organs of the body, such as the liver, lungs, or spleen. 

However, various pharmaceutical companies are showing interest in the CRISPR therapeutics area, and therefore, it will be interesting to watch the progress in this field. Since both ethical and social implications are associated with the usage of CRISPR, we need to move forward very responsibly.