Strategies for increasing frataxin expression in Friedreich's ataxia: modulation of the epigenome and proteome

Thesis

Friedreich's ataxia is a rare and fatal childhood neurodegenerative disease that causes shrinkage of the spinocerebellar tracts and the progressive loss of neurons in the dorsal root ganglia. This leads to awkward, unsteady movements and impaired sensory function, leaving sufferers wheelchair bound. It is caused by the expansion of a trinucleotide repeat region within the first intron of the FXN gene, leading to reduced production of the essential mitochondrial protein frataxin. The average life expectancy of sufferers is 37 years old, and there is currently no available treatment.

Reduced frataxin production is thought to be the result of a host of epigenetic changes at the FXN locus that cause heterochromatin-induced gene silencing. Recently, the histone lysine methyltransferase SUV4-20 has been implicated in heterochromatin formation. Pharmacological inhibition with SUV4-20 chemical probe A-196 leads to an increase in frataxin production, however its substantial metabolic instability precludes its use in vivo. This thesis describes attempts to design and synthesise analogues of A-196 with improved metabolic stability, enabling their testing in animal disease models and continued preclinical development. It also examines the development of a novel approach to disease treatment through the use of a heterobifunctional molecule to induce frataxin stabilisation.

Chapter 1 evaluates the challenges facing drug discoverers in the context of rare disease treatment and provides an overview of Friedreich’s ataxia. It also examines key pharmacokinetic concepts and strategies for their modulation. Chapter 2 describes the design and synthesis of analogues of A-196, culminating in the development of a compound with a nine-fold improvement in stability that will permit its evaluation in vivo. Chapter 3 describes the conceptualisation and efforts towards the development of a novel, heterobifunctional small molecule for induced frataxin stabilisation via deubiquitination.

Authors: Quinlan, R

• DOI: 10.5287/ora-54g4n8mwe
• Type of award: DPhil
• Level of award: Doctoral
• Awarding institution: University of Oxford
• Language: English
• Keywords: Friedreich's ataxia; epigenetics; histone methyltransferase
• Subjects: Epigenetics; Pharmaceutical chemistry; Drug discovery