Layne N Rodden

Bio: Layne N Rodden is an academic researcher from Children's Hospital of Philadelphia. The author has contributed to research in topics: Frataxin & Ataxia. The author has co-authored 1 publications.

Designing phase II clinical trials in Friedreich ataxia.

Abstract: Introduction : Friedreich ataxia (FRDA) is an autosomal recessive disorder caused by deficiency of frataxin, an essential mitochondrial protein involved in iron sulfur cluster biogenesis, oxidative phosphorylation and other processes. FRDA most notably affects the heart, sensory neurons, spinal cord, cerebellum and other brain regions and manifests clinically as ataxia, sensory loss, dysarthria, spasticity and hypertrophic cardiomyopathy. Therapeutic approaches in FRDA have consisted of two different approaches: (1) augmenting or restoring frataxin production and (2) modulating a variety of downstream processes related to mitochondrial dysfunction, including reactive oxygen species production, ferroptosis, or Nrf2 activation. Areas covered : In this review, we summarize data from major phase II clinical trials in FRDA published between 2015 and 2020 which includes A0001/EPI743, Omaveloxolone, RT001, and Actimmune. Expert opinion : A growing number of drug candidates are being tested in phase II clinical trials for FRDA; however, most have not met their primary endpoints, and none have received FDA approval. In this review, we aim to summarize completed phase II clinical trials in FRDA, outlining critical lessons that have been learned and that should be incorporated into future trial design to ultimately optimize drug development in FRDA.

Drug Repositioning in Friedreich Ataxia

Abstract: Friedreich ataxia is a rare neurodegenerative disorder caused by insufficient levels of the essential mitochondrial protein frataxin. It is a severely debilitating disease that significantly impacts the quality of life of affected patients and reduces their life expectancy, however, an adequate cure is not yet available for patients. Frataxin function, although not thoroughly elucidated, is associated with assembly of iron-sulfur cluster and iron metabolism, therefore insufficient frataxin levels lead to reduced activity of many mitochondrial enzymes involved in the electron transport chain, impaired mitochondrial metabolism, reduced ATP production and inefficient anti-oxidant response. As a consequence, neurons progressively die and patients progressively lose their ability to coordinate movement and perform daily activities. Therapeutic strategies aim at restoring sufficient frataxin levels or at correcting some of the downstream consequences of frataxin deficiency. However, the classical pathways of drug discovery are challenging, require a significant amount of resources and time to reach the final approval, and present a high failure rate. Drug repositioning represents a viable alternative to boost the identification of a therapy, particularly for rare diseases where resources are often limited. In this review we will describe recent efforts aimed at the identification of a therapy for Friedreich ataxia through drug repositioning, and discuss the limitation of such strategies.

Perspectives on current models of Friedreich’s ataxia

Abstract: Friedreich’s ataxia (FRDA, OMIM#229300) is the most common hereditary ataxia, resulting from the reduction of frataxin protein levels due to the expansion of GAA repeats in the first intron of the FXN gene. Why the triplet repeat expansion causes a decrease in Frataxin protein levels is not entirely known. Generation of effective FRDA disease models is crucial for answering questions regarding the pathophysiology of this disease. There have been considerable efforts to generate in vitro and in vivo models of FRDA. In this perspective article, we highlight studies conducted using FRDA animal models, patient-derived materials, and particularly induced pluripotent stem cell (iPSC)-derived models. We discuss the current challenges in using FRDA animal models and patient-derived cells. Additionally, we provide a brief overview of how iPSC-based models of FRDA were used to investigate the main pathways involved in disease progression and to screen for potential therapeutic agents for FRDA. The specific focus of this perspective article is to discuss the outlook and the remaining challenges in the context of FRDA iPSC-based models.

Recent Advances on Therapeutic Approaches for Friedreich’s Ataxia: New Pharmacological Targets, Protein, and Gene Therapy

Abstract: Friedreich ataxia (FA) is an inherited autosomal recessive neurodegenerative disorder. The most common mutation in FA is caused by a (GAA)n triplet repeat expansion in the first intron of the frataxin gene. However, in 4% of patients, the disease is caused by a compound heterozygous GAA expansion with a loss of function mutation on the other allele. The genetic defect results in low levels of frataxin, which is an essential gene for mitochondrial function. FA is a multisystemic disorder primarily characterized by progressive sensory and spinocerebellar ataxia. In addition to neurological symptoms, many FA individuals also present a hypertrophic cardiomyopathy and diabetes. In this chapter, we discuss recent therapeutic approaches, including a proof-of-concept study for gene therapy, drug development targeting the affected downstream pathways, paving the way for the first disease-modifying therapeutic approaches.