The invited participants included members of the three NINDS funded RC2 iPSC consortia, representatives from industry, voluntary or not-for-profit organizations, Coriell repository staff, NINDS program staff and other NIH IC program representatives.
Amyotrophic Lateral Sclerosis (ALS) is a rapidly progressive invariably fatal neurodegenerative disorder commonly characterized by muscle weakening, muscle atrophy, and eventual paralysis. When muscles in the diaphragm and chest wall fail, individuals lose the ability to breathe without support of a ventilator. The ALS clinical phenotype is associated with the progressive loss of cortical and spinal motor neurons, as well as a significant loss of local interneurons in the motor cortex and spinal ventral gray regions. The loss of cortical and spinal neurons is accompanied by a dramatic alteration, structurally and functionally, of surrounding astroglia. Mutations in genes such as (SOD1, ALS2, SETX, VAPB, FUS, and TARDPB) account for approximately 5-10% of all ALS cases and in the United States it is estimated that between 10,000-30,000 individuals suffer for idiopathic and familial forms of ALS.
The ALS consortium is directed by Dr. Jeffrey Rothstein (Johns Hopkins University) and is composed of four principal investigators, working in tight collaboration, to generate and evaluate familial ALS (fALS) iPSC lines. The principal investigators include Drs. Kevin Eggan (Harvard University), Chris Henderson (Columbia University), Merit Cudkowicz (Massachusetts General Hospital) and Tom Maniatis (Harvard University).
Huntington’s Disease is an inherited autosomal-dominant neurodegenerative disorder that inevitably leads to death. It is caused by a tri-nucleotide CAG repeat in the HD gene (Htt) that is translated into an extended stretch of glutamines within the Huntington protein (Htt). HD affects populations worldwide and in the US, the risk of disease is approximately 1/10,000. Symptoms appear in mid-life, and include severe motor, cognitive, and psychiatric disability. Progressive loss of medium spiny neurons is the pathologic hallmark of the disease. The length of the polyQ repeat is the primary determinant of the age of onset, however the extent and manifestation of symptoms can vary considerably among patients in a non-repeat dependent manner. Current treatments are palliative and do not modify disease progression. Thus, innovative screening approaches with human cell lines are anticipated to significantly contribute to the drug discovery efforts for HD.
The Huntington’s Disease iPSC consortium is a multiple principle investigator effort lead by Dr. Leslie Thompson from UC Irvine. Members of the consortium include Drs. Steven Finkbeiner (J.D. Gladstone Institute), Jim Gusella (Massachusetts General Hospital), Clive Svendsen (Cedar-Sinai Medical Center) and Chris Ross (Johns Hopkins University), Leslie Lock (UC Irvine), Hongjun Song (Johns Hopkins University), Vanessa Wheeler (Massachusetts General Hospital) and Marcy MacDonald (Massachusetts General Hospital).
Parkinson’s Disease is a slowly progressing neurodegenerative disease characterized by a loss of dopamine neurons in the substantia nigra. The primary motor symptoms of PD include tremor, rigidity, bradykinesia and postural instability. Other non-motor symptoms of PD can include depression, anxiety, irritability, orthostatic hypotension, cognitive changes, sleep disruptions, seborrhea dermatitis, anosmia, and constipation. Mutations in genes such as SNCA, LRRK2, PRKN, DJ1, and PINK1 have been linked to autosomal dominant (SNCA, LRRK2) or autosomal recessive (PRKN, DJ1, PINK1) forms of PD. It is estimated that over one million individuals suffer from PD in the United States, and although medication is available to treat the symptoms of the disease, there are currently no drugs that can delay or stop the progression of PD.
The PD iPSC consortium is a multiple principle investigator effort lead by Dr. Ole Isacson (McLean Hospital). Members of the consortium include Drs. Jim Surmeier (Northwestern University), Ted Dawson (Johns Hopkins University), Jian Feng (University of Buffalo), Karen Marder (Columbia University), Serge Przedborski (Columbia University), Zbigniew Wszolek (Mayo Clinic Jacksonville), Owen Ross (Mayo Clinic Jacksonville), Virginia Lee (University of Pennsylvania) and John Trojanowski (University of Pennsylvania).
Dr. Philip Gregory, Chief Scientific Officer at Sangamo Biosciences Inc. presented data demonstrating the use of zinc finger technology for either the introduction of a reporter gene construct into a safe harbor site in the genome or for the development of isogenic lines representing control or allelic variants of iPSC lines carrying familial mutations of PD, ALS or HD. All consortia members indicated the desire to incorporate reporter gene constructs into iPSC lines for tracking of differentiated phenotypes, and for the eventual derivation of isogenic mutant and wild type iPSC lines.
Presentations from the Amyotrophic Lateral Sclerosis Association, CHDI Foundation Inc., the Hereditary Disease Foundation, the Huntington’s Disease Society of America, the Michael J. Fox Foundation, the Muscular Dystrophy Association, the Parkinson’s Disease Foundation, and the Robert Packard Center for ALS Research emphasized ongoing efforts by these organizations in the area of ESC and iPSC research and the significant contribution of patient participation in these efforts. Dr. Andrea Baruchin, Associate Director for NIH Initiatives at the Foundation for NIH (fNIH) outlined the role of fNIH in coordinating efforts between foundations, industry, and NIH.
Last updated December 23, 2013