Omaveloxolone for the treatment of Friedreich ataxia: clinical trial results and practical considerations.

INTRODUCTION: Omavaloxolone, an NRF2 activator, recently became the first drug approved specifically for the treatment of Friedreich ataxia (FRDA). This landmark achievement provides a background for a review of the detailed data leading to the approval. AREAS COVERED: The authors review the data from the 4 major articles on FRDA in the context of the authors' considerable (>1000 patients) experience in treating individuals with FRDA. The data is presented in the context not only of its scientific meaning but also in the practical context of therapy in FRDA. EXPERT OPINION: Omaveloxolone provides a significant advance in the treatment of FRDA that is likely to be beneficial in a majority of the FRDA population. The data suggesting a benefit is consistent, and adverse issues are relatively modest. The major remaining questions are the subgroups that are most responsive and how long the beneficial effects will remain significant in FRDA patients.

Friedreich ataxia: clinical features and new developments.

Friedreich's ataxia (FRDA), a neurodegenerative disease characterized by ataxia and other neurological features, affects 1 in 50,000-100,000 individuals in the USA. However, FRDA also includes cardiac, orthopedic and endocrine dysfunction, giving rise to many secondary disease characteristics. The multifaceted approach for clinical care has necessitated the development of disease-specific clinical care guidelines. New developments in FRDA include the advancement of clinical drug trials targeting the NRF2 pathway and frataxin restoration. Additionally, a novel understanding of gene silencing in FRDA, reflecting a variegated silencing pattern, will have applications to current and future therapeutic interventions. Finally, new perspectives on the neuroanatomy of FRDA and its developmental features will refine the time course and anatomical targeting of novel approaches.

Friedreich's ataxia (FRDA), mainly referred to as a disorder of balance, is characterized by loss of coordination (ataxia) in the arms and legs and other neurological features, affecting about 1 in 50,000 people in the USA. FRDA also includes serious heart disease, aggressive scoliosis, diabetes and many other disease characteristics. Due to various clinical care needs, disease-specific clinical care guidelines have been created. New developments in FRDA include the advancement of clinical drug trials targeting cell signaling pathways and restoration of the deficient protein found in individuals with FRDA. Additionally, a new understanding of the role of the various genetic factors that contribute to the development of FRDA could affect current and future therapies. Finally, new perspectives on the early developmental features of FRDA will help refine the time course and accelerate new treatments.

Friedreich Ataxia: Multidisciplinary Clinical Care.

Friedreich ataxia (FRDA) is a multisystem disorder affecting 1 in 50,000-100,000 person in the United States. Traditionally viewed as a neurodegenerative disease, FRDA patients also develop cardiomyopathy, scoliosis, diabetes and other manifestation. Although it usually presents in childhood, it continues throughout life, thus requiring expertise from both pediatric and adult subspecialist in order to provide optimal management. The phenotype of FRDA is unique, giving rise to specific loss of neuronal pathways, a unique form of cardiomyopathy with early hypertrophy and later fibrosis, and diabetes incorporating components of both type I and type II disease. Vision loss, hearing loss, urinary dysfunction and depression also occur in FRDA. Many agents are reaching Phase III trials; if successful, these will provide a variety of new treatments for FRDA that will require many specialists who are not familiar with FRDA to provide clinical therapy. This review provides a summary of the diverse manifestation of FRDA, existing symptomatic therapies, and approaches for integrative care for future therapy in FRDA.

New developments in pharmacotherapy for Friedreich ataxia.

Introduction: Friedreich ataxia (FRDA), a rare disease caused by the deficiency of the mitochondrial matrix protein frataxin, affects roughly 1 in 50,000 individuals worldwide. Current and emerging therapies focus on reversing the deleterious effects of such deficiency including mitochondrial augmentation and increasing frataxin levels, providing the possibility of treatment options for this physiologically complex, multisystem disorder. Areas covered: In this review article, the authors discuss the current and prior in vivo and in vitro research studies related to the treatment of FRDA, with a particular interest in future implications of each therapy. Expert opinion: Since the discovery of FXN in 1996, multiple clinical trials have occurred or are currently occurring; at a rapid pace for a rare disease. These trials have been directed at the augmentation of mitochondrial function and/or alleviation of symptoms and are not regarded as potential cures in FRDA. Either a combination of therapies or a drug that replaces or increases the pathologically low levels of frataxin better represent potential cures in FRDA.

Randomized, double-blind, placebo-controlled study of interferon-γ 1b in Friedreich Ataxia.

Objective: In vitro, in vivo, and open-label studies suggest that interferon gamma (IFN-γ 1b) may improve clinical features in Friedreich Ataxia through an increase in frataxin levels. The present study evaluates the efficacy and safety of IFN-γ 1b in the treatment of Friedreich Ataxia through a double-blind, multicenter, placebo-controlled trial. Methods: Ninety-two subjects with FRDA between 10 and 25 years of age were enrolled. Subjects received either IFN-γ 1b or placebo for 6 months. The primary outcome measure was the modified Friedreich Ataxia Rating Scale (mFARS). Results: No difference was noted between the groups after 6 months of treatment in the mFARS or secondary outcome measures. No change was noted in buccal cell or whole blood frataxin levels. However, during an open-label extension period, subjects had a more stable course than expected based on natural history data. Conclusions: This study provides no direct evidence for a beneficial effect of IFN-γ1b in FRDA. The modest stabilization compared to natural history data leaves open the possibility that longer studies may demonstrate benefit.

Cardiac transplantation in Friedreich Ataxia: Extended follow-up.

Friedreich Ataxia (FRDA) is an autosomal recessive neurodegenerative disorder most commonly caused by guanine-adenine-adenine (GAA) trinucleotide repeat expansions in both alleles of the FXN gene. Although progressive ataxia remains the hallmark clinical feature, patients with FRDA are at high risk of developing cardiomyopathy, often resulting in premature death. There is no specific treatment for FRDA-associated cardiomyopathy; even in advanced cardiac failure cardiac transplantation is not commonly pursued. This case series describes extended follow-up of three FRDA cases with end-stage heart failure but mild neurologic disease who underwent successful heart transplantation. We also review and examine the ethical considerations for heart transplantation in the setting of neurodegenerative disease.

Growth Charts for Children With Down Syndrome in the United States.

BACKGROUND AND OBJECTIVES: Children with Down syndrome (DS) have lower birth weights and grow more slowly than children without DS. Advances in and increased access to medical care have improved the health and well-being of individuals with DS; however, it is unknown whether their growth has also improved. Our objective was to develop new growth charts for children with DS and compare them to older charts from the United States and more contemporary charts from the United Kingdom. METHODS: The Down Syndrome Growing Up Study (DSGS) enrolled a convenience sample of children with DS up to 20 years of age and followed them longitudinally. Growth parameters were measured by research anthropometrists. Sex-specific growth charts were generated for the age ranges birth to 36 months and 2 to 20 years using the LMS method. Weight-for-length and BMI charts were also generated. Comparisons with other curves were presented graphically. RESULTS: New DSGS growth charts were developed by using 1520 measurements on 637 participants. DSGS growth charts for children <36 months of age showed marked improvements in weight compared with older US charts. DSGS charts for 2- to 20-year-olds showed that contemporary males are taller than previous charts showed. Generally, the DSGS growth charts are similar to the UK charts. CONCLUSIONS: The DSGS growth charts can be used as screening tools to assess growth and nutritional status and to provide indications of how growth of an individual child compares with peers of the same age and sex with DS.

Longitudinal strain in Friedreich Ataxia: a potential marker for early left ventricular dysfunction.

BACKGROUND: Friedreich's ataxia (FRDA) is a neurodegenerative disorder resulting from deficiency of frataxin, characterized by cardiac hypertrophy associated with heart failure and sudden cardiac death. However, the relationship between remodeling and novel measures of cardiac function such as strain, and the time-dependent changes in these measures are poorly defined. METHODS AND RESULTS: We compared echocardiographic parameters of cardiac size, hypertrophy, and function in 50 FRDA patients with 50 normal controls and quantified the following measures of cardiac remodeling and function: left ventricular (LV) volumes, mass, relative wall thickness (RWT), ejection fraction (EF), and myocardial strain. Linear regression analysis was used to identify significant differences in echocardiographic parameters in FRDA compared with normal subjects. In analyses adjusted for age, sex, and body surface area, significant differences were observed between parameters of remodeling (LV mass, RWT, and volumes) and function in FRDA patients compared with controls. In particular, longitudinal strain was significantly decreased in FRDA patients compared with controls (-12.4% vs. -16.0%, P < 0.001), despite similar and normal left ventricular ejection fraction (LVEF). Over 3 years of follow-up, there was no change in strain, LV size, LV mass, or LVEF among FRDA patients. CONCLUSION: Longitudinal strain is reduced in FRDA despite normal LVEF, indicative of subclinical cardiac dysfunction. Given late declines in LVEF in FRDA, longitudinal strain may provide an earlier index of myocardial dysfunction in FRDA.

Friedreich ataxia clinical outcome measures: natural history evaluation in 410 participants.

Friedreich ataxia is an autosomal recessive neurodegenerative disorder characterized by ataxia, dysarthria, and areflexia. The authors report the progress of a large international noninterventional cohort (n = 410), tracking the natural history of disease progression using the neurologic examination-based Friedreich Ataxia Rating Scale. The authors analyzed the rate of progression with cross-sectional analysis and longitudinal analysis over a 2-year period. The Friedreich Ataxia Rating Scale captured disease progression when used at 1 and 2 years following initial evaluation, with a lower ratio of standard deviation of change to mean change over 2 years of evaluation. However, modeling of disease progression identified substantial ceiling effects in the Friedreich Ataxia Rating Scale, suggesting this measure is most useful in subjects before maximal deficit is approached.

Fusion cell vaccination of patients with metastatic breast and renal cancer induces immunological and clinical responses.

PURPOSE: Dendritic cells (DCs) are potent antigen-presenting cells that are uniquely capable of inducing tumor-specific immune responses. We have conducted a Phase I trial in which patients with metastatic breast and renal cancer were treated with a vaccine prepared by fusing autologous tumor and DCs. EXPERIMENTAL DESIGN: Accessible tumor tissue was disrupted into single cell suspensions. Autologous DCs were prepared from adherent peripheral blood mononuclear cells that were obtained by leukapheresis and cultured in granulocyte macrophage colony-stimulating factor, interleukin 4, and autologous plasma. Tumor cells and DCs were cocultured in the presence of polyethylene glycol to generate the fusions. Fusion cells were quantified by determining the percentage of cells that coexpress tumor and DC markers. Patients were vaccinated with fusion cells at 3-week intervals and assessed weekly for toxicity, and tumor response was assessed at 1, 3, and 6 months after completion of vaccination. RESULTS: The vaccine was generated for 32 patients. Twenty-three patients were vaccinated with 1 x 10(5) to 4 x 10(6) fusion cells. Fusion cells coexpressed tumor and DC antigens and stimulated allogeneic T-cell proliferation. There was no significant treatment-related toxicity and no clinical evidence of autoimmunity. In a subset of patients, vaccination resulted in an increased percentage of CD4 and CD8+ T cells expressing intracellular IFN-gamma in response to in vitro exposure to tumor lysate. Two patients with breast cancer exhibited disease regressions, including a near complete response of a large chest wall mass. Five patients with renal carcinoma and one patient with breast cancer had disease stabilization. CONCLUSIONS: Our findings demonstrate that fusion cell vaccination of patients with metastatic breast and renal cancer is a feasible, nontoxic approach associated with the induction of immunological and clinical antitumor responses.