Gene Therapy - Scientist clears hurdles for muscular dystrophy therapy

Scientist clears hurdles for muscular dystrophy therapy
New studies demonstrate effective way to deliver gene therapy; MU scientist proves therapy can be beneficial for the heart

COLUMBIA, Mo. — Approximately 250,000 people in the United States have some form of muscular dystrophy. Duchenne muscular dystrophy (DMD) is the most common type of the disease, predominantly affecting males. Boys with DMD will lose the ability to walk by their teens and typically die before the age of 30. For years, scientists have studied the use of gene therapy as a possible way to correct the muscle deterioration, but hurdles such as the need to treat all muscles in the body, including both skeletal muscle and heart muscle, have challenged researchers looking for an effective therapy until now.

In recent studies, published in Molecular Therapy and Human Gene Therapy, a team of University of Missouri researchers, led by Dongsheng Duan, associate professor of molecular microbiology and immunology, has found not only a delivery method that can reach every muscle of the body in a large animal model, but a therapy that will work on both skeletal muscle, the type found in arms and legs, and cardiac muscle, such as the heart.

"The difficult challenge with treating Duchenne muscular dystrophy, and other types of muscle-related diseases, is that the therapy must reach almost every muscle throughout the body," Duan said. "We have found that our new therapy, which uses a particular virus to deliver the gene therapy, reaches all of the muscles in large animals. This development raises the hope of whole body correction of Duchenne muscular dystrophy."

Patients with Duchnne muscular dystrophy have a gene mutation that disrupts the production of a protein known as dystrophin. Absence of this protein starts a chain reaction that eventually leads to muscle cell degeneration and death. Eventually, the damaged muscle tissue is replaced by fibrous, bony or fatty tissue and loses function. In the heart, this leads to severe heart disease and can place severe limitations on individuals afflicted with the disease.

In gene therapy, mutated genes are replaced with healthy genes. However, even with gene therapy, the healthy genes must reach every muscle in the body. Previously, scientists, including Duan's team, have experimented using viruses to deliver the healthy genes. However, these earlier studies were conducted in mice. Duan's team has now proven that this delivery system will reach every muscle in larger animals, such as dogs.

"Between 40 percent and 60 percent of the body weight is muscle, so it's vital that we find a way to deliver the therapy to every muscle in the body," Duan said. "Since dogs are 250 times the size of mice, but only nine times smaller than a human on average, we have taken a significant step in understanding if this therapy can work."

Duan's team has not stopped with just that discovery. In gene therapy, it is not feasible to fix every cell in the heart. Previously, scientists were uncertain whether partial correction could benefit patients. In an earlier study, Duan's research team demonstrated that heart tissue could be corrected enough to sustain a healthy life if only 50 percent of the tissue was affected by the therapy. Following the success with heart tissue, Duan's team has demonstrated for the first time that this result also is true with live heart muscle.

The Mizzou researchers delivered the therapy to the hearts of newborn mice with muscular dystrophy and found that gene therapy corrected many of the electrocardiogram abnormalities in these mice.

New tests have been developed to screen newborns with a high risk of muscular dystrophy. With few treatments available, the screening has not been widely accepted, but that may change if Duan's therapy proves to be effective.

"If you can treat an infant before they develop symptoms, you can treat the patient before they experience muscle loss," Duan said. "If you wait until symptoms start to appear, the muscle has already started to deteriorate. It's very difficult to treat when there is no muscle there."

###

Duan's research has been supported by grants from the Muscular Dystrophy Association, the National Institute of Arthritis and Muscular Skeletal and Skin Diseases, and the National Institute of Neurological Disorders and Stroke.

Views: 189

Reply to This

Replies to This Discussion

ofelia brings up a good point: "If you can treat an infant before they develop symptoms, you can treat the patient before they experience muscle loss," Duan said. "If you wait until symptoms start to appear, the muscle has already started to deteriorate. It's very difficult to treat when there is no muscle there."

well, that is something that has actually bothered me since my sons diagnosis.

let's say they find a cure for DMD...ok, FANTASTIC!!!

but what about the lost muscle? to my limited knowledge, scientist have not yet found a way to get the atrophied muscle to regenerate.

So, yes, my son would be saved with the cure, but what about all the muscle that was lost? How will that all be replaced?

Does anyone here that researches web sites and documentation for DMD treatments/cures know of any sites we can look at that is researching muscle regeneration?

I would imagine parapalegics follow these things closely.
I received a very kind email back from Christian Basi. He said that there are no plans to get this out to humans in any way anytime soon.... But, for some reason I found it really reassuring that he also mentioned that his child has Down's syndrome. I'm still new at this whole game, only having gotten a diagnosis a few months ago. But somehow knowing that the research is progressing, however slowly and that the researchers are personally vested in finding real cures that work, that helps somehow. I know that my son will probably never see a cure, but maybe my carrier daughter will have one for her sons.
Thanks a lot for sharing the response! I also sent an email to him but have not gotten a response yet. I know this does not seem encouraging for now, but as you mentioned it would probably help future generations.
Christian,

Two things come to my mind as having potential for older patients. Cossu's stem cell treatment (if it works) and Jerry Mendell's follistatin (http://medicalhealthcenter.org/2008/08/gene-therapy-study-in-mice-s...). Cossu seems to be ready for trials, just waiting approvals to start; Mendell said that they will test it in LGMD patients first if I remember correctly.

Ofelia

MicahsDaddy said:
ofelia brings up a good point: "If you can treat an infant before they develop symptoms, you can treat the patient before they experience muscle loss," Duan said. "If you wait until symptoms start to appear, the muscle has already started to deteriorate. It's very difficult to treat when there is no muscle there."

well, that is something that has actually bothered me since my sons diagnosis.

let's say they find a cure for DMD...ok, FANTASTIC!!!

but what about the lost muscle? to my limited knowledge, scientist have not yet found a way to get the atrophied muscle to regenerate.

So, yes, my son would be saved with the cure, but what about all the muscle that was lost? How will that all be replaced?

Does anyone here that researches web sites and documentation for DMD treatments/cures know of any sites we can look at that is researching muscle regeneration?

I would imagine parapalegics follow these things closely.
I am not able to recall the paper but there was a stem cell study done where is single stem cells multiplied to produce glowing muscles in mice. This would proove that stem cells will actually regenerate the muscle tissue even if the original tissue is not there.

However I am not sure about Coccu's research. Cossu related articles very clearly call out that his study involves immuno suppression. The paper at http://www.mdsa.org.za/Documents/new_therapies_dmd.pdf talks about clinical trials in 2008. My understanding is the immuno supression is not a long term solution since the stem cells needs to be given at regular intervals.

This leads to some new papers from last month. We know that iPS can be reprogrammed into the stem cells for muscles. We need to get clean muscle stem cells. Some new studies in this area are in the following papers

1. This paper tells on how to not use cancer and tumor causing chemicals for stem cell reprogamming
http://www.ncbi.nlm.nih.gov/pubmed/18849973?ordinalpos=2&itool=...


2. This papers tells how to reprogram stem cells with neutral viruses
http://www.ncbi.nlm.nih.gov/pubmed/18818365?ordinalpos=1&itool=...


3. This paper tells on how embryonic stem cells were reprogrammed without any viruses
http://www.ncbi.nlm.nih.gov/pubmed/18818365?ordinalpos=1&itool=...


After all this detail the stem cell approach looks promising even for older patients. However its still in the exploratory phases and needs lots of funding to actually narow down on the exact approach to make muscle stem cell.
I contacted the team that is currently conducting the following gene therapy clinical trials. *Transfer of dystrophin genes by intramuscular injection -- phase 1 >> safety trial in DMD* They are currently recruiting new patients( but she indicated that depending on the mutation, you may not be allowed to participate. In our case, she indicated that my son will not be eligible and I am not sure why this is mutation specific. None the less, I asked them about the latest discovery and whether this team is planning on clinical trials in the furture using this method. Here is her response on the study and the second paragraph about the question on the new discovery:

"This study has started 2 years ago and 6 patients have been enrolled so far.
>> We are in the process of enrolling 3 more patients to test a higher dose of
>> the transgene. This study aims at injecting a small muscle of the foot, with
>> the transgene on one side and a placebo on the other side (without knowing
>> which gets what). After 6 weeks, the muscles will be removed during a biopsy
>> procedure and analyzed to see if the transgene helped the production of
>> dystrophin. It won't benefit the patient since one single muscle is
>> injected (and removed) but our goal is to deliver the transgene in the
>> circulation to target several muscles of the legs. However, and despite very
>> good results in animal models, we cannot move forward until we complete the
>> single muscle injection study.
>> We can enroll patients 5 years and older. The mutation in the dystrophin
>> gene is a very specific criterion, and I need to know it to let you know if
>> we can consider the patient as a potential candidate or not."

"You are correct, our team is working on vascular delivery of the transgene:
the transgene will be injected in the artery in the groin, targeting all the
muscles of the leg. We still need to show that the dose of the transgene we
will use will be safe and will work."
did they say how long before results would be published, is this Dr Mandells gene therapy trial that started two years ago?
Her response on what mutations can participate and timelines.

"We can include patients with mutation between exon 15 and exon 49, and exon 52 and exon 57. We may be moving to the vascular delivery within the next 2 years."
This is Mendell's mini-dystrophin trial correct? I was under the impression that this is not mutation specific. They don't have that in the description here: http://clinicaltrials.gov/ct2/show/NCT00428935?term=Muscular+Dystro...
Very strange. The timeline doesn't look good either.



Godbless said:
Her response on what mutations can participate and timelines.

"We can include patients with mutation between exon 15 and exon 49, and exon 52 and exon 57. We may be moving to the vascular delivery within the next 2 years."
Yes, it is the same Mendell's trial. Even I thought that the mutation does not matter. I asked coordinator(Laurence.Viollet@NationwideChildrens.org) and she responded with the following reason.

"As you know, there are 3 types of mutation:
-one (or several) exon(s) can be missing: that is a deletion
-one (or several) exon(s) can be repeated: that is a duplication
-there can be a stop sign in one exon, so the protein is truncated.
In every case, the gene is not read properly and the protein is not functioning.

Your son's body doesn't "know" the part of the protein that corresponds to exon 12 because exon 12 is lacking in his gene. Exon 12 is part of the transgene and will be expressed in the muscle, bringing a "new" protein (at least for the part that is exon 12). Your son may have an immune response to this part and it may destroy the whole protein. We can include patients with mutation between exon 15 and exon 49, and exon 52 and exon 57."
I do not know what to say about this. I thought that the mini-gene has parts of exon 17, exons 18-59 and exons 70-79 deleted. So if the concern is immune response because one exon already exists why do they exclude deletions in the interval 50-51 for example? Those exons are not in the transgene.

Godbless said:
Yes, it is the same Mendell's trial. Even I thought that the mutation does not matter. I asked coordinator(Laurence.Viollet@NationwideChildrens.org) and she responded with the following reason.

"As you know, there are 3 types of mutation:
-one (or several) exon(s) can be missing: that is a deletion
-one (or several) exon(s) can be repeated: that is a duplication
-there can be a stop sign in one exon, so the protein is truncated.
In every case, the gene is not read properly and the protein is not functioning.

Your son's body doesn't "know" the part of the protein that corresponds to exon 12 because exon 12 is lacking in his gene. Exon 12 is part of the transgene and will be expressed in the muscle, bringing a "new" protein (at least for the part that is exon 12). Your son may have an immune response to this part and it may destroy the whole protein. We can include patients with mutation between exon 15 and exon 49, and exon 52 and exon 57."
Also the link on the clincal trials says the trial is not recruiting. where as they are recruiting additional 3 patients. Here is the link about this trial on the MDA site.

http://www.mda.org/research/view_ctrial.aspx?id=212

Reply to Discussion

RSS

Need help using this community site? Visit Ning's Help Page.

Members

Events

© 2021   Created by PPMD.   Powered by

Badges  |  Report an Issue  |  Privacy Policy  |  Terms of Service