Funding opportunities

Derivation and characterization of human ES cells from FSHD embryos

Funding Type: 
SEED Grant
Grant Number: 
Principle Investigator: 
Funds requested: 
$632 500
Funding Recommendations: 
Grant approved: 
Public Abstract: 
Statement of Benefit to California: 
Review Summary: 
SYNOPSIS: This proposal aims at isolating novel human embryonic stem cell lines from facioscapulohumeral muscular dystrophy (FSHD) homozygotic embryos. This proposal has two specific aims. The first is the derivation and characterization of FSHD hES cells. The second specific aim is the comparative analysis of normal and FHSD ES cells. FSHD has been proposed to result from a reduction in the number of repeats of a subtelomeric DNA sequence called D4Z4 on chomosome 4Q, but no direct evidence supporting this claim is given. Thus, isolation of FSHD hES cells will provide an opportunity to dissect the initial molecular cascades involved in FSHD. SIGNIFICANCE AND INNOVATION: This proposal is extremely significant, as it tackles head-on the global analysis of diseased FSHD embryonic stem cells. The basic understanding of human embryonic stem cells, as well as their potential for clinical application depends on studies that will involve either the type of proposed by the author here, or by SCNT, where the nucleus of a patient is cloned into a human embryonic, upon which stem cells are derived. As SCNT technology still requires tremendous improvement, this approach is the most powerful and useful way to approach hESC studies. STRENGTHS: This proposal has strength on many levels. First, is the quality of the investigator and his dedication to solving this problem. The second is the fact that this investigator has a connection with Dr. Jeanne Loring at the Burnham Institute. Dr. Loring, according to her letter of collaboration, has collected more than 1,000 human embryos with a nice collection of FSHD diagnosed embryos. As no FSHD cell line has been established, if successful this approach will provide the first of such lines for both basic and clinical studies. The third level of strength is the fact that FSHD seems to be a “heterochromatic abnormality disease” connecting the regulation of epigenetic programs to specific disease states. Overall the proposal is well written, and clearly presented. WEAKNESSES: The major weakness of the proposal is its lack of preliminary data especially in terms of differentiating hES cells into skeletal muscle. The success of this proposal hinges on the ability to produce myotubes and myofibers from hES cells ad thus some indication that they can do so would seem almost necessary. Moreover, only certain muscles are affected in patients with FSHD and there is no strategy outlined for directing the differentiation of hES cells into those muscle types. In fact, there is no mention of markers to distinguish different skeletal muscles (i.e. thigh muscle, facial muscle, upper arm muscle) from one another.. DISCUSSION: The first aim, if succesfully realized would result in a resource useful world-wide. Noted that although investigator did not make clear in application how would monitor for the differentiation into the muscle types affected in FSHD, that this investigator was the best qualified to define way to assay for said muscle types as is a leader in the FSHD field. Noted that FSHD has very variable age of onset and this could be a difficulty. However another reviewer commented on 'tricks ' to changing the speed of differentiation (eg making human/mouse chimerias at embroid body stage). Also noted that there may be instances where a disease phenotype manifesting late may be a consequence of an early expression event

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