Re-activating the Friedreich’s ataxia gene in patients: early promise for a radical treatment 

01/05/2014 00:00 
An essential vitamin commonly known for processing fat and proteins in the body, may hold the key to slowing progression of Friedreich’s ataxia, a condition that currently has no treatment or cure, according to findings published today in The Lancet.

In the first clinical trial of its kind, Dr Paola Giunti (Head of Ataxia Centre at UCL/UCLH), Professor Richard Festenstein (Professor of Neurology at Imperial College London), Dr Vincenzo Libri (Head of the Leonard Wolfson Experimental Neurology Centre at UCL and former Head of Clinical Studies at the NIHR/Wellcome Trust Imperial College Clinical Research Facility) and their research teams, tested the ability of nicotinamide (a form of vitamin B3) to increase levels of frataxin protein that is abnormally low in Friedriech’s ataxia, thereby causing the condition.

The specialist Ataxia Centre at the National Hospital for Neurology and Neurosurgery, part of UCLH, played a pivotal role in the trial which is a continuation of previous research by Professor Festenstein, supported by Ataxia UK and the Medical Research Council.

It showed that a nicotinamide-induced increase in frataxin levels was achievable in cells taken from patients and that the mechanism involved nicotinamide acting on the gene that causes Friedreich’s ataxia by ‘switching it back on’. The result is an increase in production of frataxin protein, and is thought to work by ‘opening up’ the gene making it accessible to the machinery which switches it on.

In this first ever clinical trial involving patients with Friedreich’s ataxia and nicotinamide, the research teams tested the effect of increasing doses of this drug to determine how well it was tolerated and its safety profile. The patients received single and multiple doses of nicotinamide at doses much higher than used for vitamin supplementation. Nicotinamide was generally well tolerated and was shown to increase levels of frataxin protein to the levels found in carriers without symptoms of the condition, when taken daily for up to two months.

Professor Festenstein said, “These results are very encouraging and importantly offer the prospect of a future treatment for this incurable condition. Further studies are needed to determine the safety of high-dose nicotinamide with long-term administration and whether it can increase frataxin levels when given for longer periods. Then we need to know if this will prevent further clinical decline in patients with Friedreich’s ataxia. The study is also exciting because it provides proof-of-concept that aberrant gene silencing can be overcome in humans using an ‘epigenetic* modifier’. This opens the way to a radical approach for other disorders caused by a similar mechanism.”

Dr Paola Giunti contributed to the design of the trial and to the recruitment of the patients through the Ataxia Centre at the National Hospital for Neurology and Neurosurgery. She said: “We are excited by the prospects of nicotinamide potentially being developed into a treatment but it is important to remember that we still need to conduct further trials to confirm the safety over a longer time and to see whether the increase in frataxin actually results in improvements for patients. We are extremely grateful to all the patients who have taken part in this important pilot trial.”

Lead Author Dr Vincenzo Libri said, "Finding a cure for Friedreich’s ataxia is what every researcher in the field dreams about. We're absolutely thrilled by our preliminary results and the hope it offers for the future of patients with this devastating condition and their families. Our results help us understand the key elements of how nicotinamide may work and are important for translating the research from the laboratory into a clinical treatment. However, given the exploratory nature of our investigation, our results should be interpreted with caution and require further substantiation from larger confirmatory studies before we can make our vision of a cure a reality"

Sue Millman, CEO of Ataxia UK “We are really proud to have supported the basic science for this hugely exciting trial and to have moved the research forward to a human trial with such positive early findings. This study was a truly collaborative effort involving ataxia charities in four countries and a number of other funding bodies all recognizing the importance of the study. We now need to push forward towards a larger trial which we hope can eventually be translated into a treatment for patients. That is our goal.”

Dr Giunti added: “The Ataxia Centre was established at the NHNN in 2005 and our aim have always strived to combine excellence in patient care with translational research in order to achieve the aim of finding treatments for this group of  incurable condition.

“We have assembled the largest cohort of patients with Friedreich’s ataxia in Europe and developed extensive expertise - we are in an ideal position to ensure the success of trials such as this. I believe this model that combines cutting edge research within an ataxia specialist centre is important in delivering clinical excellence. The encouraging results of this trial are an important step towards finding a much needed treatment for patients.”

The study was conducted at the NIHR/Wellcome Trust Imperial Clinical Research Facility, Imperial College Healthcare NHS Trust - Hammersmith Hospital.

The trial was funded by a grant from Ataxia UK in collaboration with three other ataxia charities worldwide namely Ataxia Ireland, Association suisse de l'Ataxie de Friedreich and Associazione italiana per la lotta alle sindromi atassiche. It was also supported by the UK National Institute of Health Research, the European Friedreich’s ataxia consortium for translational research and the Biomedical Research Centre of Imperial College London.

More information about the Ataxia Centre can be found on the Ataxia UK website.

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