X-Message-Number: 26001
Date: Mon, 11 Apr 2005 20:35:44 -0700 (PDT)
From: Doug Skrecky <>
Subject: reversal of progeria (in vitro)

[A "cure" for this premature aging syndrome may become available in the
not-too-distant future.]

Nat Med. 2005 Apr;11(4):440-5. Epub 2005 Mar 6.
Reversal of the cellular phenotype in the premature aging disease
Hutchinson-Gilford progeria syndrome.
  Hutchinson-Gilford progeria syndrome (HGPS) is a childhood premature
aging disease caused by a spontaneous point mutation in lamin A (encoded
by LMNA), one of the major architectural elements of the mammalian cell
nucleus. The HGPS mutation activates an aberrant cryptic splice site in
LMNA pre-mRNA, leading to synthesis of a truncated lamin A protein and
concomitant reduction in wild-type lamin A. Fibroblasts from individuals
with HGPS have severe morphological abnormalities in nuclear envelope
structure. Here we show that the cellular disease phenotype is reversible
in cells from individuals with HGPS. Introduction of wild-type lamin A
protein does not rescue the cellular disease symptoms. The mutant LMNA
mRNA and lamin A protein can be efficiently eliminated by correction of
the aberrant splicing event using a modified oligonucleotide targeted to
the activated cryptic splice site. Upon splicing correction, HGPS
fibroblasts assume normal nuclear morphology, the aberrant nuclear
distribution and cellular levels of lamina-associated proteins are
rescued, defects in heterochromatin-specific histone modifications are
corrected and proper expression of several misregulated genes is
reestablished. Our results establish proof of principle for the
correction of the premature aging phenotype in individuals with HGPS.

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