X-Message-Number: 24350
Date: Tue, 6 Jul 2004 18:59:05 -0700 (PDT)
From: Doug Skrecky <>
Subject: Major advance in treatment of Huntington's disease?

Combination Of Gene Therapy And Gene Silencing Prevents Neurodegenerative
Disease

University of Iowa researchers have shown for the first time that gene
therapy delivered to the brains of living mice can prevent the physical
symptoms and neurological damage caused by an inherited neurodegenerative
disease that is similar to Huntington's disease (HD).

If the therapeutic approach can be extended to humans, it may provide a
treatment for a group of incurable, progressive neurological diseases
called polyglutamine-repeat diseases, which include HD and several
spinocerebellar ataxias. The study, conducted by scientists at the UI Roy
J. and Lucille A. Carver College of Medicine and colleagues at the
University of Minnesota and the National Institutes of Health (NIH),
appears in the August issue of Nature Medicine and in the journal's
advanced online publication July 4.

"This is the first example of targeted gene silencing of a disease gene
in the brains of live animals and it suggests that this approach may
eventually be useful for human therapies," said senior study author
Beverly Davidson, Ph.D., the Roy J. Carver Chair in Internal Medicine and
UI professor of internal medicine, physiology and biophysics, and
neurology. "We have had success in tissue culture, but translating those
ideas to animal models of disease has been a barrier. We seem to have
broken through that barrier."

Davidson and her colleagues used a viral vector (a stripped-down virus)
to deliver small fragments of genetic material (RNA) to critical brain
cells of mice with a disorder that mimics the human neurodegenerative
disease spinocerebellar ataxia 1 (SCA1). The genetic material suppresses
the disease-causing SCA1 gene in a process known as RNA interference.

Mice with the SCA1 gene that were treated with the gene therapy had
normal movement and coordination. The gene therapy also protected brain
cells from the destruction normally caused by the disease and prevented
the build-up of protein clumps within the cells. In contrast, mice with
the SCA1 disease gene that were not treated developed movement problems
and lost brain cells in a manner similar to humans with this condition.

Both SCA1 and Huntington's disease are members of a group of
neurodegenerative disorders caused by a particular type of genetic flaw.
In these dominantly inherited diseases, a single mutated gene inherited
from either parent produces a protein that is toxic to cells. Thus, a
successful therapy must remove or suppress the disease-gene rather than
simply add a corrected version.

"Although we know how to put genes into cells, the difficulty we face in
treating dominant diseases is how to remove or silence genes," Davidson
explained. "With our approach we can marry our gene therapy research
using viral vectors with RNA interference."

Silencing the SCA1 gene with RNA interference inhibited the production of
a neurotoxic protein, suggesting that this technology may also be helpful
against other degenerative neurological diseases caused by neurotoxic
proteins, such as Alzheimer's disease.

In addition to the finding that RNA interference inhibited gene
expression to such an extent that it protected the animals against the
disease, another important finding was that RNA interference in and of
itself does not appear to be toxic to normal brain cells. In the UI
study, neither animal behavior nor brain structures were adversely
affected by RNA interference gene therapy.

Furthermore, the study revealed that specific properties of different
gene therapy vectors can be used to target those cells that are most
involved in causing the disease symptoms. In this case, the UI team
proved that their gene therapy vector, adeno-associated virus 1,
specifically targeted Purkinje cells, which are very important for gait
and coordination.

"Choosing the right vector for the right cells could help us limit gene
expression to those cells where altering expression will have a
beneficial effect," Davidson explained.

Davidson is optimistic about the potential for using RNA interference
gene therapy to treat neurological diseases like HD and spinocerebellar
ataxias in humans.

"This is among the most important work I have done and I am excited about
the prospect of helping to move this approach into clinical trials," she
added.

In addition to Davidson, the team included UI researchers: Haibin Xia,
Ph.D., and Qinwen Mao, Ph.D., who were co-lead authors of the study;
Henry Paulson, M.D., Ph.D.; Steven Eliason; Scott Harper, Ph.D.; and In s
Martins. Harry Orr, Ph.D., at the University of Minnesota, and Linda Yang
and Robert Kotin, Ph.D., at the NIH also were part of the team.

Davidson first presented these findings at the American Society of Gene
Therapy meeting in May, where it was nominated the top abstract.

Rate This Message: http://www.cryonet.org/cgi-bin/rate.cgi?msg=24350