Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Gene therapy completely corrects hemophilia in laboratory animals

19.04.2005


Newborn mice and dogs with hemophilia A were restored to normal health through gene therapy developed by researchers at Washington University School of Medicine in St. Louis. The technique introduced into the animals’ cells a gene that makes clotting factor VIII, a protein missing because of a genetic defect.



"We are really pleased with the results, because the animals produced about 20 times more factor than has been achieved in prior attempts using gene therapy for hemophilia A in dogs," says senior author Katherine Parker Ponder, M.D., associate professor of medicine and of biochemistry and molecular biophysics.

In addition, the technique using newborn animals had the advantage of not prompting an immune response, which in many other cases eventually blocks the blood clotting activity of introduced factor VIII in hemophilic animals. Since treatment more than a year ago, the blood of the mice and dogs in this study has maintained a normal level of clotting factor activity, and the animals have had no incidents of bleeding. The study will be reported in the April 26 issue of the Proceedings of the National Academy of Sciences.


Hemophilia is an inherited bleeding disorder caused by genetic mutations on chromosome X that prevent normal production of certain blood clotting factors. A defective gene for clotting factor VIII is responsible for hemophilia A, the form occurring in 80 percent of cases. Because females carrying a defective gene can rely on a normal copy of the gene on their second X chromosome, hemophilia almost always occurs in males. One in 5,000 males are born with the disorder.

"Hemophilia greatly restricts patients’ everyday lives," says Ponder, a hematologist at Barnes-Jewish Hospital. "People with the disease don’t heal well after injuries or surgery. Even running can cause bleeding into the joints."

For their own safety, hemophiliacs must be near a refrigerated supply of clotting factor at all times. Over the long term, hemophiliacs suffer from joint damage and other complications related to excess bleeding.

Gene therapy for hemophilia A has been especially challenging because the gene for factor VIII is quite large and therefore hard to fit into viral vectors, which serve as the gene delivery vehicle. The researchers eliminated parts of the factor VIII gene and other genetic components to minimize the material needed and used a large viral vector called gamma retroviral vector.

The viral vector carrying factor VIII genes was injected into the blood of 11 newborn hemophilic mice and two newborn hemophilic dogs. The viral vector also contained a short DNA promoter sequence to make the gene active only in liver cells, one of the sites of factor VIII production in non-hemophiliacs.

The normal mechanisms of viral reproduction enabled insertion of the genetic material from the engineered vectors into cells in the animals. After treatment, blood tests demonstrated all of the treated animals were producing factor VIII. The mice achieved an average of 139 percent of normal factor VIII activity and the dogs an average of 115 percent of normal factor VIII activity in a blood clotting assay. This activity level has remained stable for one and a half years. In comparison, untreated animals with hemophilia A have less than one percent normal factor VIII activity.

"This level of expression of factor VIII in dogs is especially interesting, because in other attempts the results in large animals have not been successful," Ponder says.

The researchers worked with newborn animals for two reasons. First, their livers are still growing. So genes integrated into a liver cell will be reproduced with each new generation of cells, increasing the number of cells containing functional clotting factor genes in the adult animal.

Liver tests done when the animals were about a year old showed that the treated mice had an average of two factor VIII genes per liver cell. In the dogs, an average of one in eight liver cells had the new gene.

Second, newborn mice and dogs have a less mature immune system than do adults, making it less likely they will raise an immune response to the introduced factor VIII. The immune reaction, known as inhibitor formation, diminishes the activity of the clotting factor and has caused failure in previous attempts to correct hemophilia in mice using gene therapy.

The animals in this study have not formed inhibitors against the factor VIII protein after more than a year of follow-up.

"Naturally, the ultimate goal is for gene therapy to work in humans, but humans have a more mature immune system at birth than mice," Ponder says. "In animals more closely related to humans, there will probably be more risk of inhibitor formation, so the next step needs to be gene therapy trials in primates with hemophilia to see if we can prevent inhibitor formation."

Gwen Ericson | EurekAlert!
Further information:
http://www.wustl.edu

More articles from Life Sciences:

nachricht Cryo-electron microscopy achieves unprecedented resolution using new computational methods
24.03.2017 | DOE/Lawrence Berkeley National Laboratory

nachricht How cheetahs stay fit and healthy
24.03.2017 | Forschungsverbund Berlin e.V.

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Giant Magnetic Fields in the Universe

Astronomers from Bonn and Tautenburg in Thuringia (Germany) used the 100-m radio telescope at Effelsberg to observe several galaxy clusters. At the edges of these large accumulations of dark matter, stellar systems (galaxies), hot gas, and charged particles, they found magnetic fields that are exceptionally ordered over distances of many million light years. This makes them the most extended magnetic fields in the universe known so far.

The results will be published on March 22 in the journal „Astronomy & Astrophysics“.

Galaxy clusters are the largest gravitationally bound structures in the universe. With a typical extent of about 10 million light years, i.e. 100 times the...

Im Focus: Tracing down linear ubiquitination

Researchers at the Goethe University Frankfurt, together with partners from the University of Tübingen in Germany and Queen Mary University as well as Francis Crick Institute from London (UK) have developed a novel technology to decipher the secret ubiquitin code.

Ubiquitin is a small protein that can be linked to other cellular proteins, thereby controlling and modulating their functions. The attachment occurs in many...

Im Focus: Perovskite edges can be tuned for optoelectronic performance

Layered 2D material improves efficiency for solar cells and LEDs

In the eternal search for next generation high-efficiency solar cells and LEDs, scientists at Los Alamos National Laboratory and their partners are creating...

Im Focus: Polymer-coated silicon nanosheets as alternative to graphene: A perfect team for nanoelectronics

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are less stable. Now researchers at the Technical University of Munich (TUM) have, for the first time ever, produced a composite material combining silicon nanosheets and a polymer that is both UV-resistant and easy to process. This brings the scientists a significant step closer to industrial applications like flexible displays and photosensors.

Silicon nanosheets are thin, two-dimensional layers with exceptional optoelectronic properties very similar to those of graphene. Albeit, the nanosheets are...

Im Focus: Researchers Imitate Molecular Crowding in Cells

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to simulate these confined natural conditions in artificial vesicles for the first time. As reported in the academic journal Small, the results are offering better insight into the development of nanoreactors and artificial organelles.

Enzymes behave differently in a test tube compared with the molecular scrum of a living cell. Chemists from the University of Basel have now been able to...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

International Land Use Symposium ILUS 2017: Call for Abstracts and Registration open

20.03.2017 | Event News

CONNECT 2017: International congress on connective tissue

14.03.2017 | Event News

ICTM Conference: Turbine Construction between Big Data and Additive Manufacturing

07.03.2017 | Event News

 
Latest News

Argon is not the 'dope' for metallic hydrogen

24.03.2017 | Materials Sciences

Astronomers find unexpected, dust-obscured star formation in distant galaxy

24.03.2017 | Physics and Astronomy

Gravitational wave kicks monster black hole out of galactic core

24.03.2017 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>