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Hope for a Cure: FD Hope’s motto and
the motivation behind Dr. Gil Ast’s research. But what exactly
would a cure mean to the hundreds of children and adults with
Familial Dysautonomia (FD)? As Ast envisions it, a cure would
transform the abnormal production of IKAP protein in FD cells
into healthy IKAP protein processing, by manipulating the IKAP
gene. While at first glance, this may sound a bit like science
fiction, the reality is that Ast’s lab has already been able to
produce a 30% success rate in the production of normal IKAP in
FD cells and they are working towards a success rate of 50%,
comparable to IKAP production in healthy FD carriers.
 Ast
is pursuing two avenues for correcting the FD mutation,
anti-sense RNA oligonucleotides (currently in human trials in
China as gene therapy for laryngeal cancer and the area in which
Ast believes actual current achievement in terms of future
therapy lies) and mRNA replication. In the first approach, Ast
is relying on his previously published research (funded by FD
Hope) which revealed that part of the splicing error in FD is a
result of poor binding of a small RNA particle called U1 to the
FD mutation region of IKAP gene. Because U1 cannot bind well,
exon 20 is spliced incorrectly and the protein is cut short.
Anti-sense RNA oligonucleotides are strings of nucleotides that
“match” a specific gene region. Ast has used an anti-sense RNA
oligonucleotide that complements a region next to the FD
mutation and in addition to the specific binding site, this
anti-sense RNA molecule contains a protein binding site. This
protein was shown to enhance U1 binding to the FD mutation
region, thus reversing the mutation’s effect and producing a
normal protein.
The second method, mRNA replication, is
based on the fact that amino acids (the building blocks of
proteins) are encoded by nucleotide triplets (three nucleotides
in a row). A gene (DNA) encodes for mRNA, which in turn encodes
for amino acids. Exon 20 is made up of a number of nucleotides
that is not divisible by three, so when exon 20 is spliced out
of FD mRNA because of the FD mutation, it shifts the “reading”
of the three nucleotide sets and the remaining portion of mRNA
is read incorrectly. Ast determined that the combination of
exons 20 and 21 is a string of nucleotides divisible by three
and since neither exon 20 nor 21 seems to be an essential part
of the protein, removal of exon 21 will ensure normal
translation of the remainder of the gene. This “downstream”
remainder of IKAP is essential to its role in cell stress
signaling and Ast is investigating whether the removal of exon
21 (combined with the abnormal exon 20 splicing as found in FD)
can restore IKAP function.
Ast’s multi-pronged approach to FD
research has driven him to investigate what causes exon 20
skipping in the
nervous system. What other factors influence this selective
expression? Why is exon 20 a suboptimal exon? What is the IKAP
protein’s function in the cell? And does the mutation effect
only IKAP gene expression? What additional effects on other
genes does the mutation cause? Working with other researchers in
Israel, Professor Aharon Razin from the Hebrew University in
Jerusalem and Hadassah’s Dr. Channah Maayan, Ast is working to
obtain a global view of protein synthesis in different tissues,
and under stress conditions, in the cells of individuals with
FD. His work complements the therapeutic studies of Drs. Rubin
and Anderson and promises to hasten the day when the children
and adults with FD need not worry about the progression of FD.
They will have been cured. |
