Topic 2.2. Potential targets for therapies

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This chapter of the Clinical Management Guidelines for Friedreich Ataxia and the recommendations and best practice statements contained herein were endorsed by the authors and the Friedreich Ataxia Guidelines Panel in 2022.

Topic Contents

2.2 Potential targets for therapies
2.2.1 Therapies that decrease oxidative stress and enhance mitochondrial function
2.2.2 Anti-inflammatory therapy
2.2.3 Modulators of frataxin-controlled metabolic pathways
2.2.4 Therapies that increase FRDA gene expression
2.2.5 Frataxin replacement, stabilizers or enhancers

Disclaimer / Intended Use / Funding

The Clinical Management Guidelines for Friedreich ataxia (‘Guidelines’) are protected by copyright owned by the authors who contributed to their development or said authors’ assignees.

These Guidelines are systematically developed evidence statements incorporating data from a comprehensive literature review of the most recent studies available (up to the Guidelines submission date) and reviewed according to the Grading of Recommendations, Assessment Development and Evaluations (GRADE) framework © The Grade Working Group.

Guidelines users must seek out the most recent information that might supersede the diagnostic and treatment recommendations contained within these Guidelines and consider local variations in clinical settings, funding and resources that may impact on the implementation of the recommendations set out in these Guidelines.

The authors of these Guidelines disclaim all liability for the accuracy or completeness of the Guidelines, and disclaim all warranties, express or implied to their incorrect use.

Intended Use
These Guidelines are made available as general information only and do not constitute medical advice. These Guidelines are intended to assist qualified healthcare professionals make informed treatment decisions about the care of individuals with Friedreich ataxia. They are not intended as a sole source of guidance in managing issues related to Friedreich ataxia. Rather, they are designed to assist clinicians by providing an evidence-based framework for decision-making.

These Guidelines are not intended to replace clinical judgment and other approaches to diagnosing and managing problems associated with Friedreich ataxia which may be appropriate in specific circumstances. Ultimately, healthcare professionals must make their own treatment decisions on a case-by-case basis, after consultation with their patients, using their clinical judgment, knowledge and expertise.
Guidelines users must not edit or modify the Guidelines in any way – including removing any branding, acknowledgement, authorship or copyright notice.

The authors of this document gratefully acknowledge the support of the Friedreich Ataxia Research Alliance (FARA). The views and opinions expressed in the Guidelines are solely those of the authors and do not necessarily reflect the official policy or position of FARA.

2.2 Potential targets for therapies

George Wilmot, Caterina Mariotti, David Lynch, Geneieve Tai and Massimo Pandolfo

The research of therapies that could have clinically meaningful results leading to a cure for the disease is continuing, with new compounds and new clinical trials being designed, commenced and currently ongoing. The research of new strategies is still based on the evaluation of potential therapeutic effects of drugs that are already commercially available and approved for other diseases, as well as new compounds specifically intended for the cure of FRDA and not available for other indications.

2.2.1 Therapies that decrease oxidative stress and enhance mitochondrial function

The pathology of FRDA is characterized by mitochondrial dysfunction and oxidative stress, demonstrated in both cell and animal models of FRDA (6, 14). Respiratory chain dysfunction, accumulation of iron in the mitochondria and impaired antioxidant responses lead to increased production of reactive oxygen species (15). The use of antioxidants has therefore been investigated as a potential therapy for FRDA.

2.2.2 Anti-inflammatory therapy

Inflammation contributes to the pathology of FRDA and has been detected in animal models as well as in tissues of people with FRDA (16, 17). The anti-inflammatory properties of steroids may play a role in altering oxidative damage caused by frataxin deficiency. This hypothesis arose after an improvement in neurological symptoms was reported in an individual with FRDA following corticosteroid treatment (18). Methylprednisolone has thus been explored as a treatment in FRDA (19).

2.2.3 Modulators of frataxin-controlled metabolic pathways

FRDA is caused by the reduced expression of frataxin, a protein found mostly in the mitochondria (20, 21), where it acts as an activator of iron-sulfur (Fe-S) cluster biosynthesis. The resulting Fe-S deficiency impairs the activity of many cellular proteins, including respiratory chain subunits and Krebs cycle enzymes in the mitochondria, and triggers a homeostatic response that increases cellular and mitochondrial iron uptake (22). However, as the Fe-S cluster biosynthetic pathway is impaired, iron eventually accumulates in mitochondria where it may engage in redox reactions generating toxic free radicals, activate signaling pathways leading to neurodegeneration (23), and trigger cell death, in particular by ferroptosis (24).

It has been proposed that frataxin is also involved in various other pathways, including iron metabolism, transport and storage (25), as well as regulation of apoptosis (26). Furthermore, several metabolic pathways are perturbed because of frataxin deficiency, in particular those that control antioxidant responses and mitochondrial biogenesis. Therapies that modulate such pathways include nuclear factor erythroid-derived 2-related factor 2 (Nrf2) activators and peroxisome proliferator activated receptor (PPAR)-γ agonists.

2.2.4 Therapies that increase FRDA gene expression

Approximately 96% of individuals with FRDA have a homozygous mutation consisting of the expansion of GAA trinucleotide repeats within the first intron of the FXN gene (20), leading to the formation of heterochromatin (27). As a result, transcription of FXN mRNA is reduced (28, 29). Agents that counter heterochromatin formation can upregulate FXN mRNA, including histone deacetylase (HDAC) inhibitors (30, 31). Other agents directly boost FXN expression regardless of the presence of expanded GAA repeats. Those clinically tested include erythropoietin and derivatives, Interferon gamma (12, 32).

2.2.5 Frataxin replacement, stabilizers or enhancers

Frataxin replacement therapy has been proposed by pairing synthetic frataxin protein with a delivery system using a protein fragment called a trans-activator of transcription (TAT) to enable frataxin delivery into the mitochondria (33, 34). Another method of frataxin supplementation is through delivery of a normal copy of the FXN gene via gene replacement therapy (35-37).

Gene replacement and editing

Gene replacement therapy is perhaps the most promising in terms of correcting frataxin loss in FRDA, with numerous strategies currently being explored ( FRDA presents as a favorable candidate for gene replacement therapy due to several factors. About 96% of individuals with FRDA have the same single gene mutation which leads to gene silencing and a reduction of the frataxin protein levels. Because individuals with FRDA already produce frataxin, it is less likely that an immune response will be produced. Furthermore, while carriers for FRDA possess one faulty copy of the gene and produce half the normal frataxin levels, these individuals do not exhibit any symptoms, indicating that even a small increase of frataxin has the likelihood to be beneficial.

There are several approaches to gene therapy (38). Adeno-associated viruses (AAV) are viral vectors that do not integrate into the host genome, avoiding genotoxicity. Their DNA persists for a long time in transfected cells as an episome, potentially lifelong. This makes AAV a vector of choice for perennial tissues such as the brain, spinal cord, and heart, which are most affected in FRDA. The potential efficacy of AAV-based gene therapy for FRDA was first demonstrated in a conditional cardiac and skeletal muscle FXN knockout mouse model (Mck-Cre-FxnL3/L mice) that was treated intravenously with adeno-associated virus rh10 vector expressing human FXN, leading to prevention of cardiac disease onset if given early, as well as a complete reversal of cardiomyopathy when given after the development of symptoms (36). In a separate study, a parvalbumin-conditional FXN knockout mouse model (Pvalb cKO) with FXN delivered through an AAV9 vector resulted in a complete reversal of sensory ataxia but not of manifestations of central nervous system (CNS) disease (37).

There are, however, several issues that need to be resolved before AAV-based gene therapy becomes a reality in FRDA. Some naturally occurring AAVs, such as AAV9, can effectively cross the blood-brain barrier (BBB) after systemic administration, but only for a limited time after birth. For this reason, while AAV9-based gene therapy has been effective in treating diseases such as spinal muscular atrophy (SMA), that affects babies, there are ongoing efforts to generate new capsids that can penetrate the CNS in older children and adults after systemic administration (39). However, this may require very high intravenous doses of the vector, which, at least in the case of AAV9 and related capsids, may trigger a severe reaction with liver toxicity and cytokine release. While this reaction could be potentially lethal, it is at least partially preventable with immune suppressive treatment with steroids (40). Furthermore, an inflammatory reaction with neuron loss in the dorsal root ganglia (DRG) has been observed in some animal models (40). This is a particularly worrisome complication in FRDA, where DRG pathology is already present. Acquired immunity to AAVs, a common occurrence in the general population, is another problem, as neutralizing antibodies may inactivate the gene therapy vector and T cells may attack transfected cells presenting capsid fragments on their surface. This is also a major obstacle to re-administer AAV to patients who have previously received it. Overall, these difficulties impose the development of new capsids with improved biodistribution and ability to cross the BBB, as well as of strategies to control innate and acquired immune responses, allowing administration to individuals carrying anti-AAV antibodies and re-administration of a therapeutic vector if needed (41).

Proper control of transgene expression is also necessary. Frataxin expression must reach heterozygous carrier levels at least, but cannot be excessive, as it has demonstrated that very high levels are toxic, causing mitochondrial dysfunction and cardiac toxicity in mouse models (42). This requires a combination of appropriate vector biodistribution and promoter choice.

The possibility of dual routes of administration is an emerging option for what we may consider the first-generation gene therapy for FRDA, while “optimal” vectors are being developed. This approach aims at reaching peripheral organs (heart, pancreas, DRG, peripheral nerves, muscle) via a relatively low dose systemic administration, and the CNS via intrathecal or intraparenchymal administration, targeting key affected structures as the dentate nuclei in the cerebellum.

Other approaches may involve different viral vectors, such as Herpes virus-based, or non-viral vectors such as lipid nanoparticles. These are still in an early-preclinical phase.

Delivery of brain-derived neurotrophic factor (BDNF) is another approach to gene therapy in FRDA (43). BDNF has numerous neuroprotective properties including anti-apoptosis, antioxidation and autophagy suppression (44). The stargazer mouse model with severe cerebellar ataxia exhibited improved ataxia and motor impairment when crossed with mice overexpressing transgenic BDNF (45). In another study, a gene encoding BDNF was delivered via a herpesviral amplicon vector to a knockout mouse model which prevented the onset of cerebellar neuropathology and ataxia (46).  Overexpression is an issue with BDNF as well, having been shown to cause learning and short-term memory impairment (47).

A lack of animal models that accurately depict FRDA is another barrier in the development of gene therapy in FRDA. Conditional knockout mouse models are useful in providing proof-of-concept, but models with a pathologically low systemic frataxin expression, as is the case in the human disease, are still unsatisfactory. A YG8JR mouse model carrying a human FXN gene with 800 GAA repeats has recently been developed and is the most genetically alike to individuals with FRDA. However, the phenotype of this model, as of other GAA repeat expansion-carrying mouse models, appears to be late disease onset and mild disease presentation. There is also a lack of models in larger animals which may be more useful with respect to translation to humans.

David Lynch, MD, PhD
Professor of Neurology and Pediatrics, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA

Caterina Mariotti, MD
Neurologist, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milan, Italy

Massimo Pandolfo, MD
Professor (Clinical), McGill University, Montreal, Quebec, Canada

Geneieve Tai, BBiomedSc(Hons)
Research Assistant, Murdoch Children’s Research Institute, Parkville, Victoria, Australia.

George Wilmot, MD, PhD
Associate Professor, Department of Neurology, Emory University, Atlanta, Georgia, USA

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These Guidelines are systematically developed evidence statements incorporating data from a comprehensive literature review of the most recent studies available (up to the Guidelines submission date) and reviewed according to the Grading of Recommendations, Assessment Development and Evaluations (GRADE) framework © The Grade Working Group.

This chapter of the Clinical Management Guidelines for Friedreich Ataxia and the recommendations and best practice statements contained herein were endorsed by the authors and the Friedreich Ataxia Guidelines Panel in 2022.

It is our expectation that going forward individual topics can be updated in real-time in response to new evidence versus a re-evaluation and update of all topics simultaneously.