X-Message-Number: 12402
From: "Robert Moore" <>
Subject: An important medical breakthough!
Date: Sat, 11 Sep 1999 17:54:23 PDT

     The article below heralds a very important medical breakthough.  It 
will probably lead to complete cures of such diseases as sickle cell anemia 
and hemophilia.  The defective cell DNA is repaired, permenantly!  I expect 
that this technique could also possibly be used to eliminate genetic 
predispositions to certain cancers.

A MORE IMPORTANT QUESTION:  (What do the anti-aging experts on Cyronet 
think?)  Could this (chimeraplasty) or a derivative technique be used to 
stop genetically "programmed" aging processes???

======================================================================
Gene repair in rats raises hope for genetic diseases

NEW YORK (Reuters Health) -- Through the use of a novel technique termed 
'chimeraplasty,' researchers have, for the first time, successfully repaired 
the genetic defect associated with Crigler-Najjar syndrome, a rare but 
devastating liver disease, in lab rats.

The finding may lead to gene therapies that cure other genetic diseases such 
as hemophilia and sickle cell anemia, according to the report published in 
the Proceedings of the National Academy of Sciences.

Principal investigator Dr. Clifford Steer, of the University of Minnesota 
School of Medicine in Minneapolis described his team's work in an interview 
with Reuters Health. "We did two things that were important: one, we 
developed a system whereby we could go in and literally rewrite the genetic 
sequence in a specific gene of interest; and two, we developed a technology 
that would do it in the hepatocyte, the type of liver cell that controls the 
major defect (of Crigler-Najjar syndrome)." The syndrome is characterized by 
an innability to properly metabolize bilirubin, a byproduct of normal red
blood cell degradation. The genetic disease features jaundice and 
destructive changes in parts of the brain.

The researchers created a molecule called a chimeraplast, which is based on 
the structure of the defective gene and "targeted to that portion of the 
gene with the mutation," Steer explained. When the molecule is introduced 
into the cell, "it tricks the cell into thinking that there is a defect in 
its DNA sequence for that particular gene and by tricking the cell, the cell 
basically repairs (what it perceives as) its own defect."

What is being accomplished, in essence, is genetic repair without having to 
employ techniques that require "the introduction of new genes (via 
genetically modified viruses) to take the place of the (original 
defective)genes," as is the case in conventional gene therapy, according to 
Steer.

"All we are doing is repairing the genetic defect in a gene that is already 
there," he explained. "And when you think about it, what is really the best 
way to do gene therapy? It would be to go in to correct the defect so that 
the gene is in the right position, controlled and regulated by the 
(appropriate) regulatory elements that would normally control that gene."

An important aspect of this technology is that "once the genetic change is 
made, the repair is permanent," Steer said. And although this work was 
carried out in an animal model, the Gunn rat -- which has a genetic defect 
similar, though not identical, to that seen in human Crigler-Najjar syndrome 
-- Steer "feels very confident that it's going to work in humans. It works 
in animal models, it works in plants, in works in bacteria, it works in any 
structure that has DNA in it."

The type of mutation corrected in the study involves an omission or deletion 
of one "letter" in a specific DNA genetic sequence. DNA is composed of basic 
units called nucleotides, which are designated by specific letters. These 
combine into sequences that "spell out" a genetic code. Changing one 
"letter" into another is easier than replacing a missing letter, Steer said, 
and in the human disease, changing rather than replacement is required to 
correct the defect. Consequently, "we hope that our results will be even 
more exciting in human beings than they were in the rodent model."

Together with his colleagues at the Albert Einstein College of Medicine in 
the Bronx, New York, Steer expects to submit a clinical trial application 
for the technique to the Food and Drug administration early next year.

"We're going to involve 3 to 5 pediatric patients already identified with 
Crigler-Najjar, who live in the Amish country in Pennsylvania," Steer told 
Reuters Health. He commented that the Amish have a very high frequency of 
this disorder and that these particular children all have the same genetic 
defect, a mutation at a single point in the genetic code.

The majority of genetic diseases in human beings are single-point mutations, 
Steer explained, "so we have a technology here that can be applied to many 
different types of disease. The technology is here, it's here to stay, and 
it is very different from gene therapy."

The investigators are already developing a number of other animal models to 
look at potential clinical applications in disease such as Gaucher's 
disease, hemophilia, thalessemia, and sickle cell anemia. Though sickle cell 
anemia's defect originates in the bone marrow, Steer believes that the team 
will be able "to develop a delivery system for the chimeraplasts" that will 
direct them to the marrow, the site of the stem cells from which the 
defective red blood cells in sickle disease originate.

"It's going to be more challenging than liver, only because it's bone marrow 
and the progenitor cells are more difficult to deal with," he noted.

Steer emphasized that though the results achieved thus far are "very, very 
exciting," with potentially "broad-based application," much remains to be 
done. Further developing and refining the technology's seemingly limitless 
possibilities will "keep the medical profession busy for many, many years," 
he predicts.


Source:  Proceedings of the National Academy of Sciences USA
1999;96:10349-10354.


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