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FARAFARA Cure FA

Research Resources

FARA-funded research has facilitated the discovery and development of research resources such as animal models, cell models, antibodies, biorepositories, etc.

We are grateful to the discovery scientists who have worked hard to bring us these important assets and continue to give to the community by sharing their results, knowledge, expertise and resources. It is our goal to promote collaboration throughout the research community by communicating with the discovery, translational and clinical scientists and facilitating their access to such resources.

Friedreichs Ataxia Transgenic Mouse Model Now Available Through The Jackson Laboratory.

Early in 2008, the Friedreich’s Ataxia Research Alliance (FARA) engaged The Jackson Laboratory (JAX) to discuss opportunities to have Friedrich's Ataxia (FA) mouse models brought into JAX and made available to the research community. Academic researchers who have created and developed these models have generously shared their models with JAX for establishing colonies for distribution and formed a task force to guide additional work at JAX to further optimize and characterize these models.

This partnership between JAX and FARA will provide many benefits to the FA research community, including the following:

  • Access to novel gold standard, genetically defined, well characterized, specific-pathogen-free JAX® Mice FA models
  • Detailed genotypic and phenotypic information about FA models in the JAX® Mice Database
  • Efficient distribution of FA models from JAX
  • Reduced burden of animal husbandry and distribution for the researchers, allowing them to focus on developing new models and advancing new discoveries
  • Accelerated pace of FA research

For inquiries about these mouse models, direct contact at JAX:

   Cathleen M Lutz Ph. D
   Associate Director, Mouse Repository
   Genetic Resource Science
   The Jackson Laboratory
   Bar Harbor, ME 04609
   Tel (207) 288-6341
   Cat.Lutz@jax.org

B6.Cg-Fxntm1Mkn Tg(FXN)YG8Pook/J

Mice that are homozygous for the Fxntm1Mkn (frataxin) targeted allele and hemizygous for the Tg(FXN)YG8Pook (frataxin, human) transgene, display an age dependent, tissue specific expansion of the GAA repeat, with expansion accumulation in the CNS (particularly cerebellum), similar to the human pathology of Friedreich Ataxia. This strain is maintained heterozygous for the targeted mutation and hemizygous for the transgene.

http://jaxmice.jax.org/strain/012253.html

B6.Cg-Fxntm1MknFxnTm1Pand/J

Animals bearing a (GAA)230 expansion repeat “knock in” targeted to the endogenous Fxn locus coupled with an Fxn Fxn targeted “knock out” mutation allele disrupting exon 4, known as knockin/knockout mice or “KIKO” mice are viable and fertile. Analysis of frataxin levels in tissues from KIKO mice demonstrate a reduction of frataxin to 25-36% of wildtype controls. KIKO animals up to 1 year of age perform equivalent to wild type controls on rotarod test. Total iron concentration in tissues was similar in KIKO mice and their wild type littermates except in pancreas, where iron levels were significantly lower in KIKO mice. No iron deposits and only mild collagen staining around the vessels of the heart were observed in both year old KIKO mice and wild type controls. In contrast to FRDA patients, no detectable change in GAA repeat size was found over six studied generations, moreover, no evidence of somatic cell instability was noted as GAA repeat expansion size was the same in all analyzed tissues.

http://jaxmice.jax.org/strain/014162.html

B6.129-Fxntm1.1Pand/J

Similar to stock 008470, these mice express a (GAA)230 expansion repeat from the endogenous Fxn locus. Homozygotes produce an average of 75% of wild-type levels of frataxin protein, as assayed by Western blot densitometry analysis. The GAA repeat size was found to be stable over the 6 generations studied. Mice that are homozygous for the targeted mutation are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. These mice do not carry the neo selection cassette. This mutant mouse strain may be useful in studies of Friedreich's ataxia.

http://jaxmice.jax.org/strain/011113.html

B6.129-Fxntm1Pand/J

These mice express a (GAA)230 expansion repeat from the endogenous Fxn locus. Homozygotes produce an average of 75% of wild-type levels of frataxin protein, as assayed by Western blot densitometry analysis. The GAA repeat size was found to be stable over the 6 generations studied. Mice that are homozygous for the targeted mutation are viable, fertile, normal in size and do not display any gross physical or behavioral abnormalities. This mutant mouse strain may be useful in studies of Friedreich's ataxia.

http://jaxmice.jax.org/strain/008470.html

STOCK Fxntm1Mkn Tg(FXN)YG8Pook/J

Mice that are homozygous for the Fxntm1Mkn (frataxin) targeted allele and hemizygous for the Tg(FXN)YG8Pook (frataxin, human) transgene, display an age dependent, tissue specific expansion of the GAA repeat, with expansion accumulation in the CNS (particularly cerebellum), similar to the human pathology of Friedreich Ataxia. This strain is maintained heterozygous for the targeted mutation and hemizygous for the transgene.

http://jaxmice.jax.org/strain/008398.html

STOCK Fxntm1Mkn Tg(FXN)YG22Pook/J

Mice that are homozygous for the Fxntm1Mkn (frataxin) targeted allele and hemizygous for the Tg(FXN)YG22Pook (frataxin, human) transgene, display an age dependent, tissue specific expansion of the GAA repeat, with expansion accumulation in the CNS (particularly cerebellum), similar to the human pathology of Friedreich Ataxia. Mice that are homozygous for the targeted allele and hemizygous for the transgene exhibit progressive retinal degeneration, impaired and decreased locomotor activity and coordination, an increase in body weight, and neurodegeneration. This strain is maintained heterozygous for the targeted mutation and hemizygous for the transgene.

http://jaxmice.jax.org/strain/010963.html

For a complete list of resources available through JAX or to place an order: Jax Mice

Friedreich’s ataxia lymphoblast and fibroblast cell lines are available at the Coriell Cell Repository:
http://ccr.coriell.org/Sections/Search/Search.aspx?PgId=165&q=frda
Note: Several researchers have reported problems working with the fibroblast lines from Coriell (they have been passaged many times) and there are only a few lines available.

Friedreich’s ataxia derived iPS cells are now available at Coriell Cell Repository:
http://ccr.coriell.org/Sections/Search/Sample_Detail.aspx?PgId=166&Ref=GM23404
http://ccr.coriell.org/Sections/Search/Sample_Detail.aspx?PgId=166&Ref=GM23913

These cell lines were established by the Gottesfeld laboratory at The Scripps Research Institute.
Coriell provides a Certificate of Analysis.

Reference -
Ku S, Soragni E, Campau E, Thomas EA, Altun G, Laurent LC, Loring JF, Napierala M, Gottesfeld JM
Friedreich's ataxia induced pluripotent stem cells model intergenerational GAA·TTC triplet repeat instability
Cell stem cell7:631-7 2009     PubMed ID: 21040903

A repository of >40 Friedreich Ataxia fibroblasts established in collaboration between Dr. Napierala (University of Alabama at Birmingham) and Dr. David Lynch (Children’s Hospital of Philadelphia) laboratories.

Repository-FA-Fibroblasts-2016.pdf

Requests for cells can be sent directly to mnapiera@uab.edu or lynchd@mail.med.upenn.edu

Access the FARA Cell Line Database

FARA is working closely with several investigators in the United States, Europe and Australia who are developing FA neuronal and cardiac cell models by differentiation of induced pluripotent stem (iPS) cells derived from patient fibroblasts (e.g. Generation of Induced Pluripotent Stem Cell Lines from Friedreich Ataxia Patients, Liu J, Verma PJ, Evans-Galea MV, Delatycki MB, Michalska A, Leung J, Crombie D, Sarsero JP, Williamson R, Dottori M, Pébay A, Stem Cell Rev and Rep 2010 Dec 22 22 and Friedreich's ataxia induced pluripotent stem cells model intergenerational GAA⋅TTC triplet repeat instability.Ku S, Soragni E, Campau E, Thomas EA, Altun G, Laurent LC, Loring JF, Napierala M, Gottesfeld JM. Cell Stem Cell. 2010 Nov 5)

Some of these models are available for sharing and some FA iPS cells are being banked for greater access to researchers worldwide.

Other cellular models have been developed from a variety of approaches, with different defining features, e.g., Dr. Helene Puccio and colleagues developed murine cellular models for FRDA that have all the biochemical phenotypes associated with FA; making this model ideal for drug discovery. The first cellular models based on frataxin missense mutations that reproduce spontaneously the defects associated with Friedreich ataxia Nadège Calmels, Stéphane Schmucker, Marie Wattenhofer-Donzé, Alain Martelli, Nadège Vaucamps, Laurence Reutenauer, Nadia Messaddeq, Cécile Bouton, Michel Koenig, Hélène Puccio. PlosOne July 24, 2009

Several other investigators have developed high throughput assays for drug discovery in FA. These assays vary significantly – some assays developed focus on readouts of mitochondrial function, some focus on direct measurements of frataxin (e.g. genetically-derived assays that carry the expanded GAA repeats in the FRDA gene).

If you would like to learn more about these cellular models or assays or be connected directly to these discovery scientists please contact: Jane Larkindale at jane.larkindale@curefa.org.

Through the Collaborative Clinical Research Network in FA, small biorepositories of DNA, RNA, plasma and serum from FA patients have been established. In addition investigators in the CCRN in FA are willing to collaborate with researchers who need fresh biological samples from FA patients for translational and clinical research studies, please contact Jane Larkindale at jane.larkindale@curefa.org.

Tissue Bank - Dr. Arnulf Koeppen, VA Medical Center in Albany, New York

To make valuable tissues available to FA investigators everywhere, FARA supports an autopsy and tissue donation program at the VA Medical Center in Albany, New York. The program's principal investigator, Dr. Arnulf Koeppen, is a neurologist and neuropathologist and has made significant contributions to our understanding of FA and other ataxias. This tissue bank has fixed and frozen tissues from brain, spinal cord, heart, sural nerve, and pancreas of 30 individuals with FA. Requests for these tissues can be made directly to Dr. Koeppen.

Dr. Arnulf H. Koeppen
VA Medical Center
113 Holland Ave
Albany, N.Y. 12208
Phone: (518) 626-6391  or  (518) 626-6377
Fax: (518) 626-6369
email: arnulf.koeppen@va.gov

Frataxin antibodies are available from various sources. Below are a few references.

Mito Sciences has anti-frataxin monoclonal antibodies and/or protein immunoassays In addition, MitoSciences has a wide range of reagents and assays that can be used to assess the downstream consequences of altered frataxin expression on enzyme levels, enzymatic activities, and expression pattern of proteins that depend on iron-containing prosthetic groups for activity and assembly.

http://www.mitosciences.com/frataxin.html

SantaCruz Biotechnology has frataxin monoclonal and polyclonal antibodies.

Mouse monoclonal IgG1, 100µg/ml, recommended for detection of Frataxin of human origin by WB, IP and ELISA
Goat or rabbit polyclonals, recommended for detection of Frataxin of mouse, rat and human origin by WB, IF and ELISA

In addition, Santa Cruz has Frataxin specific siRNA, sHRNA Plasmid and shRNA Lentiviral Particles gene silencers are also available.

http://www.scbt.com/table-frataxin.html

UC Davis/NIH NeuroMab Facility – NeuroMab has a monoclonal frataxin antibody. Monoclonal antibody info: Mouse strain: Balb/C Myeloma cell: SP2/0 Mouse Ig Isotype: IgG2b NeuroMab Applications: Immunoblot and Immunocytochemistry Species Reactivity: human, mouse

http://neuromab.ucdavis.edu/datasheet/N191_7.pdf

http://neuromab.ucdavis.edu/catalog.cfm

Millipore has frataxin monoclonal and polyclonal antibodies.

Polyclonal anti-frataxin derived from rabbit - http://www.millipore.com/catalogue/item/ab15080

Monoclonal anti-frataxin derived from mouse, recognizes only isoforms of frataxin containing exon 4. - http://www.millipore.com/catalogue/item/mab1594

FARA is working with Dr. Giovanni Coppola at UCLA and the Coordinated Clinical Research Network (CCRN) and other to develop a database of gene expression data from FA patients and from mouse models of the disease.  The database is available from Dr. Coppola’s website at https://coppolalab.ucla.edu/account/login/.  You will need to register for a password to access the database.  Array data is available for some patients who have taken part in natural history studies through the CCRN, so clinical data can be accessed.  Additional data is still being added over time, and additional analyses are underway.  For more information, please contact Jane Larkindale at jane.larkindale@curefa.org.

The National Institute of Neurological Disorders and Stroke (NINDS), National Institutes of Health (NIH), has developed Friedreich’s Ataxia (FA) Common Data Elements (CDEs) for use in clinical research. The NINDS recently assembled an external working group of experts, the FA CDE Working Group, to develop “Version 1.0” of the Friedreich’s Ataxia CDEs and they are now ready for use in Friedreich’s Ataxia clinical research community.

Friedreich's Ataxia CDE Standards Version 1.0

The NINDS CDE Web site fully describes the NINDS CDE Project and its goals. In summary, the CDE Project aims to develop content standards, both generic and disease-specific, that enable clinical investigators to systematically collect, analyze, and share data across the research community. The NINDS first convened the Friedreich’s Ataxia CDE Working Group in June 2010. Over a one-year period the Friedreich’s Ataxia CDE Working Group identified and defined a catalog of CDEs investigators can choose from when assembling their clinical study materials. The Friedreich’s Ataxia CDE Working Group has not attempted to define the complete universe of variables a clinical study will collect; rather, their goal has been to isolate elements that will be useful across multiple FA clinical studies.

To develop the Friedreich’s Ataxia (FA) CDEs, the FA CDE Working Group divided into subgroups to focus on identifying and defining data elements in the domains of:

  • Ataxia and Performance Measures
  • Biomarkers
  • Cardiac and Clinical Outcomes
  • Demographics, Medical History/ Prior Health Status, Laboratory Tests/ Vital Signs

Scientific Reference
Mov Disord. 2012 Dec 12. doi: 10.1002/mds.25201. [Epub ahead of print]
Common data elements for clinical research in Friedreich's ataxia
Lynch DR, Pandolfo M, Schulz JB, Perlman S, Delatycki MB, Payne RM, Shaddy R, Fischbeck KH, Farmer J, Kantor P, Raman SV, Hunegs L, Odenkirchen J, Miller K, Kaufmann P

FA Common Data Elements (full text - PDF)

FARA encourages all investigators doing clinical research studies in FA to consult these guidelines. The FA CDEs include case report form (CRF) modules, standardized data element definitions, and instructions intended to expedite the development of data collection tools. There is also significant gain from the ability to share and compare data across studies – these common data elements are a platform ensuring uniformity in data collection across multiple distinct studies so that later comparative analyses may be performed.