Navigation Links
RNA interference therapy heals growth deficiency disorder in a live animal

A team of Vanderbilt researchers have demonstrated for the first time that a new type of gene therapy, called RNA interference, can heal a genetic disorder in a live animal.

The study, which was published online Nov. 15 by the journal Endocrinology, shows that RNA interference can rescue a strain of mouse that has been genetically engineered to express a defective human hormone that interferes with normal growth. When the gene that produces the defective human growth hormone is inserted into the mouses genome, it also stunts the mouses growth. But when a small snippet of RNA that interferes with the hormones production is also added, the mouse is restored to normal.

It has been very satisfying to figure out the underlying cause of this genetic disorder and then identify a way to prevent it, says John Phillips, the David T. Karzon Professor of Pediatrics at the Vanderbilt University Medical Center, who has been studying human growth deficiency disorders since 1978. He collaborated on the research with graduate students Nikki Shariat and Robin Ryther, who are directed by Professor of Biological Sciences James G. Patton.

Growth hormone deficiency has been estimated to occur in between one in 4,000 to 10,000 children. It has a number of different causes, but one that is genetically inherited is called Isolated Growth Hormone Deficiency type II, and this is the subject of the study.

Children with IGHD-II appear fairly normal at birth but do not gain weight or grow as fast as they should, and their bones do not mature properly. The current treatment consists of daily injections of growth hormone for years until the patients reach their adult height. Not only is this treatment extremely expensive, it also fails to correct the underlying source of the problem: deterioration and death of cells in the pituitary gland that produce growth hormone. As a result, this single hormone deficiency can develop into multi-hormonal deficiency over time.

IGHD-II is what geneticists call a dominant negative disorder. It is caused by a defective form of human growth hormone that not only cant stimulate growth itself but also blocks the action of normal growth hormone. It acts like Aesops dog in the manger which has no use for the hay but keeps the cows from eating, says Phillips. Some other common dominant negative diseases include forms of colon cancer, deafness, muscular dystrophy, brittle bone disease, kidney disease and retinitis pigmentosa.

The blueprint for a protein like growth hormone is genetically encoded in a series of special segments called exons. The instructions in the exons are first copied onto a length of special RNA, called messenger-RNA. The messenger-RNA is moved to a structure in the cell called a ribosome, which links amino acids together in the order specified by the RNA sequence to create the protein.

Normal growth hormone is produced by a series of five exons. The defective hormone is the result of a splicing error: It is made by combining the segments coded by the first two exons and the last two exons, mistakenly skipping the third exon.

A normal person has a very small amount of this defective hormone about 1 percent but people in families with IGHD-II produce 10 to 20 to 50 percent. And the more they make the slower they grow, says Patton.

In 2003, co-author Iain Robinson at the National Institute for Medical Research in London created a transgenic mouse with the human growth hormone gene that duplicated growth hormone deficiency. Although the altered mice still contained the mouse growth hormone genes, he found that high levels of the defective human growth hormone not only stunted their growth but actually killed the cells in the pituitary that produce growth hormone.

This came as a real surprise: We never thought that a splicing error would lead to cell death, says Patton.

Meanwhile, progress in RNA interference research gave Patton and Phillips an idea for a way to correct this disorder.

In the last 15 years, scientists have realized that short pieces of double-stranded RNA, called silencing-RNA, use a pathway that is normally used by cells to regulate genes. This has created an opportunity for developing highly targeted therapies for a number of genetic diseases including macular degeneration in the eye and to block viruses such as herpes and RSV respiratory viruses. To the best of our knowledge, this is the first time it has been used to correct a dominant negative disorder in a living animal, says Patton.

The researchers realized that the messenger-RNA that produced the defective hormone had a unique signature created by skipping the third exon. This allowed the Patton lab to create a specific silencing-RNA, designed to bind uniquely with the defective messenger-RNA.

You might call this the if you dont like the message, kill the messenger approach, Phillips quips.

Having created the special silencing-RNA, the next problem was how to deliver it to the pituitary gland which, in the case of the mouse, is the size of a grain of uncooked rice and is located at the base of the brain. As a proof of concept, the researchers decided to create a second strain of mouse which carried the special silencing-RNA and mate them with the growth deficiency strain. Their offspring should have both the genetic defect that produces the defective growth hormone and the silencing-RNA that should inhibit its production, allowing the mouse growth hormone to act.

The experiment was successful. The offspring grew normally and showed no defects in their pituitaries.

Now the researchers are investigating ways to deliver their silencing-RNA to the pituitary gland that would be suitable for treating humans. The cells that produce growth hormone have special receptors that signal the cells to release their stocks of growth hormone. If they can figure out a way to attach the silencing-RNAs to a compound that binds to this receptor, they should be able to deliver them to the cells where they can interfere with the activity of the defective growth hormone.


Contact: David F. Salisbury
Vanderbilt University  

Related biology news :

1. A new radiation therapy treatment developed for head and neck cancer patients
2. St. Jude finds factors that accelerate resistance to targeted therapy in lymphoblastic leukemia
3. UC health news: molecular pathway may predict chemotherapy effectiveness
4. MIT works toward safer gene therapy
5. Intravenous gene therapy protects normal tissue of mice during whole-body radiation
6. Gene, stem cell therapy only needs to be 50 percent effective to create a healthy heart
7. Fourth Annual International Conference on Cell Therapy for Cardiovascular Diseases
8. Safe and effective therapy discovered for patients with protein-losing enteropathy
9. Ireland Cancer Center researchers advance stem cell gene therapy
10. Dolphin therapy a dangerous fad, Emory researchers warn
11. Cancer and arthritis therapy may be promising treatment for diabetes
Post Your Comments:
Related Image:
RNA interference therapy heals growth deficiency disorder in a live animal
(Date:11/4/2015)... 4, 2015 --> ... published by Transparency Market Research "Home Security Solutions Market - ... 2015 - 2022", the global home security solutions market is expected ... 2022. The market is estimated to expand at a ... to 2022. Rising security needs among customers at homes, ...
(Date:10/29/2015)... 2015 Daon, a global leader in mobile ... a new version of its IdentityX Platform , ... America have already installed IdentityX v4.0 and ... FIDO UAF certified server component as an ... FIDO features. These customers include some of the largest ...
(Date:10/29/2015)... , Oct. 29, 2015 Today, ... announced a partnership with 2XU, a global leader ... deliver a smart hat with advanced bio-sensing technology. ... other athletes to monitor key biometrics to improve ... strategic partnership, the two companies will bring together the ...
Breaking Biology News(10 mins):
(Date:11/26/2015)... CHESHAM , England , November 26, ... Lightpoint Medical, an innovative medical device company specializing in ... Euro grant from the European Commission as part of the ... enabling the company to carry out a large-scale clinical trial ... -->      (Logo: , ...
(Date:11/25/2015)... 25, 2015  PharmAthene, Inc. (NYSE MKT: PIP) announced ... stockholder rights plan (Rights Plan) in an effort to ... (NOLs) under Section 382 of the Internal Revenue Code ... PharmAthene,s use of its NOLs could be substantially limited ... in Section 382 of the Code. In general, an ...
(Date:11/25/2015)... , November 25, 2015 Studies ... and human plaque and pave the way for more effective ... in cats     --> ... commonly diagnosed health problems in cats, yet relatively little was ... Two collaborative studies have been conducted by researchers from the ...
(Date:11/25/2015)... Nov. 25, 2015  Neurocrine Biosciences, Inc. (Nasdaq: ... President and CEO of Neurocrine Biosciences, will be presenting ... New York . ... website approximately 5 minutes prior to the presentation to ... the presentation will be available on the website approximately ...
Breaking Biology Technology: