A form of vitamin B3 has shown early promise against
Friedreich's ataxia, a debilitating degenerative disease with no
treatment or cure, in the first human trial of the treatment
involving UCL researchers.
Friedriech's ataxia is thought to be caused by a lack of
frataxin, a protein important in regulating iron levels within
cells. Frataxin deficiency causes iron overload in mitochondria,
the 'batteries' of cells, and problems regulating free radicals
within cells. These damaging effects lead to cellular death.
As the damage builds up, people with the condition suffer from
progressively worsening symptoms including problems walking,
talking, swallowing, seeing and hearing. Many patients are
wheelchair-bound and unable to live independently a decade or two
after symptoms appear and often die of heart disease within 35
years.
In a collaborative effort, researchers from UCL and Imperial
College London gave patients a form of vitamin B3 called
nicotinamide in much higher doses than found in vitamin
supplements. The vitamin has been shown to increase frataxin levels
in the lab, but this was the first test in ataxia patients. The
treatment had minimal side effects and increased patients' frataxin
levels to match those of ataxia carriers who do not experience
symptoms.
Whether restoring frataxin levels will slow or halt the progress
of the disease is still unclear, as the protein's precise role in
the disease is not yet fully understood. Yet as carriers do not
suffer from symptoms, restoring frataxin levels to those seen in
carriers is a significant step.
"We are excited by the prospects of nicotinamide potentially
being developed into a treatment," said Dr Paola Giunti of the UCL
Ataxia Centre, who was instrumental in the trial design and patient
recruitment. "We have developed extensive expertise in trials in
such a rare disorder, Friedreich's ataxia and assembled the largest
cohort of patients in Europe and thus we are in an ideal position
to ensure the success of trials such as this. However 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, Head of the Leonard Wolfson
Experimental Neurology Centre at UCL and former Head of Clinical
Studies at the NIHR/Welcome Trust Imperial College Clinical
Research Facility, 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."
Professor Richard Festenstein of Imperial College London 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."
Epigenetic refers to how the gene is 'packaged' within the
nucleus. DNA wraps around histone proteins to form a
beads-on-a-string pattern known as chromatin. The ends of the
histone proteins are normally labelled as 'active' but at the
Friedreich's ataxia gene this 'active' labelling is removed so that
the gene is abnormally switched off. Nicotinamide prevents these
labels from being removed, switching the gene back on.
Sue Millman, CEO of Ataxia UK, said: "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."
The paper, Epigenetic and neurological effects and safety of high-dose
nicotinamide in patients with Friedreich's ataxia: an exploratory,
open-label, dose-escalation study, is published in The
Lancet.