New project: Identification of the E3 ligase that ubiquitinates frataxin

Identification of the E3 ligase that ubiquitinates frataxin
Principal researcher: Dr Roberto Testi, Department of Experimental
Medicine,
University of Rome, 'Tor Vergata,' Italy
Scientific summary
Understanding whether and how frataxin is normally degraded might
provide insights
on possible strategies aimed at preventing frataxin degradation in FRDA
patients,
thus allowing frataxin accumulation and increasing frataxin
bioavailability. We
observed that frataxin is degraded via the ubiquitin-proteasome system
and that by
preventing the degradation process, frataxin levels in fact rise in FRDA
cells. We also
identified the lysine responsible for ubiquitination. In fact, a
frataxin lacking the critical
lysine cannot be ubiquitinated and has a longer half life. We now plan
to identify the
E3 ligase(s) that interacts with frataxin and mediates frataxin
ubiquitination. This
information should reveal new potential pharmacological targets for
FRDA.
Lay summary
FRDA is caused by the low levels of the protein frataxin in cells of
affected
individuals, due to scarce production. Since normally all proteins are
constantly
produced and degraded, one way to possibly increase frataxin levels is
to slow down
its degradation. We therefore started to understand the mechanisms by
which
frataxin is degraded in human cells. The aim of this project is to
refine our
understanding of the modalities of frataxin degradation and to further
elucidate the
molecular mechanisms. This information could be instrumental in
developing new
therapeutic approaches focused on preventing frataxin degradation.
This project is co-funded with the Friedreich's ataxia Society Ireland
(FASI).
For more support or information please contact: Ataxia UK, Lincoln
House,
Kennington Park, 1 – 3 Brixton Road. London SW9 6DE
Website: www.ataxia.org.uk.
Helpline: 0845 644 0606 Tel: +44 (0)20 7582 1444 Fax: +44 (0)20 7582
9444
Email: helpline@ataxia.org.uk.

FARA Press Release

FOR IMMEDIATE RELEASE
EPI-A0001 Improves Neurological Outcome Endpoint in 28-Day Phase 2A
Double-Blind Placebo-Controlled Clinical Trial in Friedreich's Ataxia
Clinical trial being designed to confirm encouraging results
FARA, June 11, 2011 – In its release issued Friday, Edison
Pharmaceuticals, Inc.
announced that EPI-A0001 significantly improved neurological function as
assessed by the
Friedreich's Ataxia Rating Scale (FARS). The trial did not show
significant improvement in
the primary endpoint of glucose disposition index (a measure of the
body's glucose
handling). The three arms of the trial consisted of placebo, low dose
and high dose of
EPI-A0001. The FARS scores improvements were reported to be
statistically significant in
both the low and high dose groups when compared to the placebo group.
There were no
differences between the placebo group and the two drug-treated groups in
the rates of
drug-related adverse events.
Dr. David Lynch, the principal investigator of the trial, said, "We are
working closely with
Edison, the U.S. Food and Drug Administration (FDA) and our colleagues
in FARA's
Collaborative Clinical Research Network in Friedreich's Ataxia to design
extended duration
clinical trials to verify this encouraging data." FARA President Ron
Bartek added, "FARA
would like to thank the patients and patient families who participated
in this very
promising clinical trial. We look very much forward to working with the
FA patient
community, Edison and the clinical investigators as EPI-A0001 takes its
next steps through
clinical development toward the treatment goal for which we are all
striving together."
FARA has been involved in the development of EPI-A0001 from its
pre-clinical
development stage. In 2006, Dr. Robert B. Wilson, Edison Pharmaceuticals
and FARA as
co-applicants were accepted into the National Institutes of Health Rapid
Access to
Intervention Development (RAID) Pilot Program. Support by this NIH
program accelerated
EPI-A0001 clinical development. Additionally, FARA has awarded multiple
grants to Edison
for the development of both EPI-A0001 and EPI-743. FARA will continue
working hand-inhand
with Edison, the investigator team, and the patient and physician
community to
begin implementation of further EPI-A0001 prospective trials.
About FA
FA is a rare, degenerative, life-shortening neuro-muscular disorder that
affects children
and adults and involves the loss of strength and coordination usually
leading to wheelchair
use; diminished vision, hearing and speech; scoliosis (curvature of the
spine); increased
risk of diabetes, and a life-threatening heart condition. There are
currently no effective
treatments.
About FARA
The Friedreich's Ataxia Research Alliance (FARA) is a 501(c)(3),
non-profit, charitable
organization dedicated to accelerating research leading to treatments
and a cure for
Friedreich's ataxia. www.CureFA.org
Contact:
Jennifer Farmer
Executive Director, Friedreich's Ataxia Research Alliance
(484) 879 6160
info@curefa.org

important press release and HOPE

Hi everyone,

here is an exciting press release, and WHY fundraising dollars are so
important.

cheers

Laurel

Letter from Ron Bartek re press release

Hello all,

We know we do not want to put all our research eggs in any one basket -
we want as many really promising eggs as we can incubate in as many
baskets (FA disease mechanisms) as we can identify.

The disease baskets we are carrying right now include:
1. The mitochondrial dysfunction basket - the shortage of frataxin
protein in FA patients leads to their mitochondria producing far less
energy and far more oxidative stress that kills their cells. The eggs
we have been incubating in this basket include CoQ10, Idebenone, A0001
and EPI-743,as well as Pioglitazone and Resveratrol, each of which has
been aimed at improving mitochondrial function in cells with reduced
frataxin protein. The CoQ10 and Idebenone eggs have not hatched
successfully. We continue to support advancement of the other
mitochondrial agents in hopes that they will hatch by showing in
"pivotal" (phase 2B/phase 3) trials that they are safe and capable of
increasing energy and reducing oxidative damage in our patients so they
can be approved as treatments for FA. The FDA has awarded both A0001
and EPI-743 "orphan drug designation" which means that the FDA judged
that:

a. FA is an orphan disease (fewer than 200,000 U.S. patients), and
b. the applications for both A0001 and EPI-743 presented sufficient
evidence/data that the drug holds potential for benefitting FA patients.

Orphan drug designation also carries significant incentives for the drug
company. For example, if an application for drug approval is submitted
to the FDA following the pivotal trial, the review of the application is
expedited (the review might take six months rather than 18 months). If
the drug is approved, the company would receive seven years of
exclusivity in the market for that drug for treatment of that
disease. The company would also be given tax breaks amounting to up to
50 percent of the funds it expended in developing the drug.

The FDA's approval of additional "Expanded Access" for the treatment of
"seriously ill" patients with mitochondrial disorders refers to the
emergency treatment of about forty patients so far with various late- or
final-stage conditions (two with FA, the others seriously ill
with different mitochondrial dysfunction disorders). Today's
announcement indicates that some additional patients that are seriously
ill with such late- or final-stage conditions will be eligible for such
emergency treatment with EPI-743. FARA is seeking guidance as to how,
when and where such treatments are to be managed.

2. The other disease mechanism baskets we are all carrying together
right now include the efforts to increase the frataxin protein levels
available to FA patients (HDAC inhibitor, EPO, CEPO, TAT-Frataxin,
gene-replacement, etc.), and the efforts to reduce the amount of toxic
iron in the mitochondria (for example, the iron chelator Deferiprone).

With everybody's continued support and participation in the clinical
research, FARA's plan is to keep filling the pipeline with promising
drug discoveries and to keep pushing the clinical development of those
drugs until we all achieve the treatments and cure to which the FA
family is committed.

Hope that helps,
Ron

Ronald J. Bartek
President
Friedreich's Ataxia Research Alliance (FARA)
P. O. Box 1537
Springfield, VA 22151
Tel (703) 426-1576
FARA website: http://www.CureFA.org
Email: fara@CureFA.org
Please register in the FARA Patient Registry at
http://www.curefa.org/registry/ and for e-news at
http://visitor.constantcontact.com/email.jsp?m=1101190303489

FARA press release

Hi everyone, FARA has released this press release on the status of
EPI-743/

I will also send through an email from Ron Bartek, explaining what this
means.

FARA Pipeline

Hi.

here is a link to the current FARA research pipeline.... its worth
having a look and see just how international the effort is.

http://www.curefa.org/pipeline.html

Anesthetic management of a patient with spinocerebellar degeneration

http://www.joacp.org/article.asp?issn=0970-9185;year=2011;volume=27;issue=2;spage=249;epage=252;aulast=Vadhanan

Utilisation of Advance Motor Information is Impaired in Friedreich Ataxia

yet another example of the good work our aussie team are doing!

http://www.springerlink.com/content/b820227u40193562/