Effect of Nicotinamide in Friedreich's Ataxia

• Significant upregulation of Frataxin (FXN) in patients with Friedrich ataxia using an antibody dipstick assay (interventional part) [ Time Frame: Daily administration up to 9 weeks ] [ Designated as safety issue: No ]
  Low levels of Frataxin (FXN) (<30% of normal) cause Friedrich ataxia. The trial will determine the effect of oral nicotinamide in upregulating FXN. Therefore the primary outcome is upregulation of Frataxin levels above baseline. This will be measured using an antibody dipstick assay (Mitosciences) and chromatin immunoprecipitation studies.
  
  

• Assessment of impact on clinical phenotype using the SARA scale to measure degree of ataxia (interventional part of the study) [ Time Frame: Daily administration up to 9 weeks ] [ Designated as safety issue: No ]
  Assessment of impact on clinical phenotype using the SARA scale to measure degree of ataxia
  
  
• Use of novel highly-sensitive technology to capture clinical deficit (non-interventional part) [ Time Frame: 6-9 months ] [ Designated as safety issue: No ]
  Investigate the use of novel, highly-sensitive technology to capture clinical deficit and measure subtle changes in the activities of daily living over a 6-9 month period without nicotinamide.
  
  
• Correlate functional changes to levels of expression of Frataxin protein and the epigenetic structure of the Frataxin gene over a 6-9 month period without nicotinamide (non-interventional part). [ Time Frame: 6-9 months ] [ Designated as safety issue: No ]
  Correlate functional changes to levels of expression of Frataxin protein and the epigenetic structure of the Frataxin gene over a 6-9 month period without nicotinamide (non-interventional part).
  
  
• Assessment of additional FRDA biomarkers using gene expression profiling (interventional study). [ Time Frame: Daily administration up to 9 weeks ] [ Designated as safety issue: No ]
  Assessment of additional FRDA biomarkers using gene expression profiling (interventional study).
  
  
• Chromatin immunoprecipitation (interventional study) [ Time Frame: Daily administration up to 9 weeks ] [ Designated as safety issue: No ]
  Further assessment of efficacy by means of chromatin immunoprecipitation to look for epigenetic changes at the Frataxin locus compatible with transcriptional upregulation. Such information might also be useful in identifying patients more likely to respond to this therapy by upregulating FXN (interventional study).
  
  
• Determine the safety and tolerability of nicotinamide in FRDA patients (interventional study). [ Time Frame: Daily administration up to 9 weeks. ] [ Designated as safety issue: Yes ]
  Determine the safety and tolerability of nicotinamide in FRDA patients (interventional study).
  
  

Friedreich's ataxia (FRDA) is caused by a GAA repeat expansion in the Frataxin gene causing its repression which resembles the archetypal epigenetic phenomenon of Position Effect Variegation and hence can be modulated by chromatin modifiers The investigators have now confirmed that a similar form of silencing occurs in cells from FRDA patients. Based on these findings histone deacetylase (HDAC) inhibitors which can overcome such silencing have been identified. The investigators have extended this result by showing that the classical Class III HDAC inhibitor, nicotinamide, can relieve silencing in cells from patients. Nicotinamide is a vitamin and a registered drug and has been previously administered to humans with no significant ill effects.

In the interventional study, the investigators will perform pharmacodynamic studies on nicotinamide in humans with FRDA to investigate whether the investigators can upregulate Frataxin and if so, to determine an optimum dosing regimen. Nicotinamide will be administered orally following a standard drug escalation regimen and blood samples taken to measure Frataxin level and chromatin structure of the Frataxin gene. The end-point of the study is to achieve significant upregulation of Frataxin in patients providing a potential therapy for this currently untreatable condition.

In the non-interventional study, we will investigate the use of novel, highly-sensitive technology to capture clinical deficit and measure subtle changes in the activities of daily living and correlate functional changes to levels of expression of Frataxin protein and the epigenetic structure of the Frataxin gene over a 9-12 month period without nicotinamide. Healthy volunteers as comparators will be included in this part of the study. HVs will undergo the same assessments as participants with Friedreich ataxia once.