Microfluidic formulation of diazoxide-loaded solid lipid nanoparticles as a Novel approach for Friedreich's ataxia treatment

Ilaria Arduino, Antonella Santoro, Silvia De Santis, Rosa Maria Iacobazzi, Angela Assunta Lopedota, Eleonora Paradies, Giuseppe Merla, Sara Anjomani Virmouni, Luigi Palmieri, Carlo Marya Thomas Marobbio, Nunzio Denora, Microfluidic formulation of diazoxide-loaded solid lipid nanoparticles as a Novel approach for Friedreich's ataxia treatment, Journal of Drug Delivery Science and Technology, Volume 97, 2024, 105837, ISSN 1773-2247, doi:10.1016/j.jddst.2024.105837. 

 This study aimed to create solid lipid nanoparticles (SLNs) loaded with DZX by microfluidic technique to improve blood-brain barrier (BBB) penetration and reduce side effects. Employing an in vitro BBB model, SLN-DZX demonstrated enhanced permeability compared to plain DZX. Cell viability assays carried out on FRDA fibroblast cells indicated enhanced viability with 1 μM SLN-DZX. Cellular uptake studies confirmed SLN internalization in FRDA fibroblasts, and subsequent treatment with SLN-DZX significantly reduced both total and mitochondrial ROS levels compared to control and empty SLN-treated cells. These findings suggest SLN-DZX as a potential therapeutic approach for FRDA, mitigating oxidative stress with improved BBB penetration and reduced toxicity.

Phase 2 Trial of Dimethyl Fumarate for Friedrich Ataxia

NeurologyLive. July 17, 2024. Updates in Therapeutic Development: Clinical Trial Readouts to Watch in the Second Half of 2024 

According to a recent interview with Francesco Saccà, MD, PhD, an associate professor of neurology at the University of Naples, the phase 2 study assessing the use of dimethyl fumarate (DMF), an approved product for relapsing multiple sclerosis and psoriasis in Europe, in patients with Friedreich ataxia (FA), potentially anticipates some data, at least the primary and many of the secondary endpoints, by September or October of this year. Saccà also noted that potentially by the end of the year, investigators will close the entire analysis. 

The study, which two sequential 12-week phases, assesses whether DMF can increase the expression of the FXN gene and frataxin protein and ameliorate in-vivo detectable measures of mitochondrial dysfunction in FA. FA, which is typically associated with several developmental features, is caused by a genetic deficiency of frataxin, a small, nuclear-encoded mitochondrial protein. Frataxin deficiency leads to impairment of iron-sulphur cluster synthesis, and consequently ATP production abnormalities.

Lexeo Therapeutics Announces Positive Interim Phase 1/2 Clinical Data of LX2006 for the Treatment of Friedreich Ataxia Cardiomyopathy

NEW YORK, July 15, 2024 (GLOBE NEWSWIRE) -- Lexeo Therapeutics, Inc. (Nasdaq: LXEO), announced positive interim data of LX2006 for the treatment of Friedreich ataxia (FA) cardiomyopathy. Across both the Lexeo SUNRISE-FA Phase 1/2 clinical trial (NCT05445323) and the Weill Cornell Medicine investigator-initiated Phase 1A trial (NCT05302271), LX2006 was well tolerated with no treatment-related serious adverse events, and clinically meaningful improvements in cardiac biomarkers were observed with increasing improvement over time.

Interim Safety Results

• LX2006 was well tolerated with no treatment-related serious adverse events to date in either study
• No signs of complement activation or other immunogenicity observed
• No cardiac or hepatic safety signals observed
• All adverse events were transient and resolved
• No participants discontinued from either study
  

Interim Clinical Results (from 8 participants with > 6-months of follow-up)

• Left ventricular mass index (LVMI): Of participants with elevated LVMI at baseline, 75% achieved >10% reduction at 12 months (n=4). Of all participants, 50% achieved >10% reduction in LVMI at 12 months (n=6).
  • Among the participants with elevated LVMI at baseline, mean reduction in LVMI was 11.4% at 12 months (n=4) and 18.3% at 18 months (n=2).
• Left ventricular (LV) lateral wall thickness: wall thickening, an early indicator of left ventricular hypertrophy, was reduced by 13.6% on average in all participants at 12 months (n=6).
• High-sensitivity Troponin I (hsTnI): troponin I, a biomarker of myocardial injury, was reduced by 53.3% on average in all participants at 12 months (n=5).
• Frataxin protein expression evaluated via myocardial biopsy: observed increased frataxin levels compared to baseline following treatment with LX2006 in all participants evaluated to date utilizing two distinct measurements:
  • LCMS: frataxin increase observed in 3 of 3 evaluable participants.
  • IHC: frataxin increase observed in 2 of 2 evaluable participants.
    

Dosing Update and Next Steps

• As of July 15, 2024, 13 participants dosed to date across two trials:
  • Cohort 1 (1.8x10¹¹vg/kg): n=6
  • Cohort 2 (5.6x10¹¹ vg/kg): n=6
  • Cohort 3 (1.2x10¹² vg/kg): n=1
• SUNRISE-FA independent Data and Safety Monitoring Board endorsed proceeding to Cohort 3 dose level (1.2x10¹²vg/kg). This cohort has started enrollment with 1 participant dosed to date and will include at least 3 participants.
• The Weill Cornell investigator-initiated trial is currently enrolling in Cohort 2.
• Lexeo expects to share further details of these interim results, including an additional cardiac biopsy from Cohort 2, at a scientific conference in Fall 2024.

Anatomical and functional analysis of the corticospinal tract in an FRDA mouse model

Anatomical and functional analysis of the corticospinal tract in an FRDA mouse model. Misa Nishiyama, John Kalambogias, Fumiyasu Imai, Emily Yang, Sonia Lang, Joriene C de Nooij, Yutaka Yoshida bioRxiv 2024.06.28.601178; doi:10.1101/2024.06.28.601178 

Yet, it remains poorly understood how early in the disease cortical spinal neurons (CSNs) show these alterations, or whether CSN/CST pathology resembles the abnormalities observed in other tissues affected by FXN loss. To address these questions, we examined CSN driven motor behaviors and pathology in the YG8JR FRDA mouse model. We find that FRDA mice show impaired motor skills, exhibit significant reductions in CSN functional output, and, among other pathological changes, show abnormal mitochondrial distributions in CSN neurons and CST axonal tracts. Moreover, some of these alterations were observed as early as two months of age, suggesting that CSN/CST pathology may be an earlier event in FRDA disease than previously appreciated. These studies warrant a detailed mechanistic understanding of how FXN loss impacts CSN health and functionality.

Challenges for gene therapy in the financial sustainability of health systems: a scoping review

Ossandon, H., Armijo, N., Vargas, C. et al. Challenges for gene therapy in the financial sustainability of health systems: a scoping review. Orphanet J Rare Dis 19, 243 (2024). doi:10.1186/s13023-024-03249-z

The study identified 279 publications, and after removing duplicates and screening for eligibility, 10 were included in the study. The results show that various financing models have been proposed, including subscription-based payment models, outcome-based payment models, and amortization strategies. However, several barriers to implementing these models were identified, such as deficiencies in informatics systems for data collection, changes in laws or regulations, the lack of accessible clinical endpoints and administrative costs.

SYSTEMIC FRATAXIN DEFICIENCY CAUSES TISSUE-DEPENDENT IRON HOMEOSTASIS ALTERATIONS: IMPLICATIONS FOR FRIEDREICH ATAXIA

SYSTEMIC FRATAXIN DEFICIENCY CAUSES TISSUE-DEPENDENT IRON HOMEOSTASIS ALTERATIONS: IMPLICATIONS FOR FRIEDREICH ATAXIA Maria Pazos-Gil, Marta Medina-Carbonero, Arabela Sanz-Alcázar, Marta Portillo-Carrasquer, Luiza Oliveira, Gonzalo Hernandez, Mayka Sánchez, Fabien Delaspre, Elisa Cabiscol, Joaquim Ros, Jordi Tamarit bioRxiv 2024.07.05.602088; doi:10.1101/2024.07.05.602088 

Our findings demonstrate that frataxin deficiency affects iron homeostasis in a time dependent and tissue-specific manner, and that the pathological mechanisms in FA comprise both iron accumulation and limited iron availability. Understanding this specificity is crucial for the design of iron-related therapeutic interventions aiming to improve FA symptomatology.

Altered calcium responses and antioxidant properties in Friedreich’s ataxia-like cerebellar astrocytes

Altered calcium responses and antioxidant properties in Friedreich’s ataxia-like cerebellar astrocytes Chiara Marullo, Laura Croci, Iris Giupponi, Claudia Rivoletti, Sofia Zuffetti, Barbara Bettegazzi, Filippo Casoni, Ottavio Cremona, Gian Giacomo Consalez, Franca Codazzi bioRxiv 2024.07.19.604129; doi: 10.1101/2024.07.19.604129 

Our findings shed light on cellular changes caused by FXN downregulation in cerebellar astrocytes, which can interfere with their physiological and complex interaction with neurons. The potentially impaired ability to provide neuronal cells with glutathione or to release neuromodulators and bioactive molecules in a calcium-dependent manner could impact neuronal function and contribute to neurodegeneration.

Relative Bioavailability of Omaveloxolone When Capsules Are Sprinkled Over and Mixed in Applesauce Compared With Administration as Intact Omaveloxolone Capsules: A Phase 1, Randomized, Open-Label, Single-Dose, Crossover Study in Healthy Adults

Hynes SM, Goldsberry A, Henneghan PD, et al. Relative bioavailability of omaveloxolone when capsules are sprinkled over and mixed in applesauce compared with administration as intact omaveloxolone capsules: A phase 1, randomized, open-label, single-dose, crossover study in healthy adults. J Clin Pharm. 2024;: 00-00. doi:10.1002/jcph.2482 

Some patients with FA may have oropharyngeal dysphagia or difficulty swallowing whole capsules; therefore, alternate method(s) of administration are needed. A Phase 1 clinical study in 32 healthy volunteers evaluated the relative bioavailability, safety, and tolerability of a single dose of omaveloxolone when capsule contents were sprinkled on and mixed in applesauce compared to when taken as intact capsules. Palatability when sprinkled on and mixed in applesauce was assessed with a questionnaire.