End of 2013 With Promising Developments in Research and Trials of HIBM/GNE Myopathy

Dear friends, family and readers:
I wish you a joyful conclusion to 2013 and  may 2014 bring you joy, good tidings, and peace. I continue to forge ahead  with my participation in a clinical trial for HIBM.
There has been some progress with the clinical trials conducted by NIH and Ultragenyx Pharmaceutical.  NIH concluded the phase 1 trial with ManNac and will be starting phase 2 in the near future.  Ultragenyx Pharmaceutical has concluded extended phase 2 with the Sialic Acid Extended Release SA-ER tablets and has started patients on Sialic Acid Immediate Release (SA-IR) in addition to the SA-ER tablets.  The total dose per day is 12,000 mg. In addition to the 46 patients who were in the trial already, they are recruiting 10 new patients -"treatment naïve subjects" (those who have never taken sialic acid)  for this current trial.  Here is the link with the details.

http://clinicaltrials.gov/ct2/show/NCT01830972?term=hibm&rank=5


Ultragenyx Pharmaceutical  found the following based on preliminary data in phase 2 trial which is quite promising.
"Similar to the results observed at the 24-week interim analysis, at 48 weeks the
comparison of the upper extremity composite of muscle strength for the combined
group of patients on 6 grams showed a modest increase and a statistically significant
difference relative to the decline in strength observed in the combined groups on 3
grams. In the 6-gram cohort treated for 48 weeks, the modest increase in upper 
extremity strength observed at 24 weeks was sustained relative to a further decline in 
the comparable 3-gram group. These changes were more pronounced in those patients
that have less advanced disease as assessed by a greater walking ability at baseline, a
predefined subset. The lower extremity composite did not show a statistically significant
difference between the dose groups, but neither group showed a significant decline
during the treatment period."

“These 48 week data suggest that 6 grams per day of SA-ER is mitigating the normally 
expected decline in upper extremity muscle strength,” said Emil Kakkis, M.D., Ph.D.,
Chief Executive Officer of Ultragenyx. “The maintenance of this effect from the 24-week
data is encouraging. Given the difference between the dose groups and good safety
profile, we plan to test an even higher dose of sialic acid in these patients who have no
other approved treatment options.”

I have attached the link of their complete press release here.

http://www.ultragenyx.com/index.php?ht=a/GetDocumentAction/i/17531


The acronym HIBM (Hereditary Inclusion Body Myopathy) has been widely used to describe the muscle wasting disease and  also has been confused with another disease, therefore the name of HIBM is now changed to GNE myopathy which more accurately defines this disease as it is on this gene - GNE where the deficiency happens. I will gradually change my blog name to "Tara Talks GNE Myopathy". Here is some discussion on this topic.

"There is confusion in some circumstances with the very similar names of two quite different medical disorders; Inclusion Body Myositis and Hereditary Inclusion Body Myopathy. This press release is to advise that Inclusion Body Myositis is NOT THE SAME as HIBM (myopathy). Because of this confusion, NZP supports the name change of Hereditary Inclusion Body Myopathy (HIBM) to “GNE myopathy” (see; http://dx.doi.org/10.1016/j.ymgme.2012.10.011).
Myositis is a mostly inflammatory muscle disease and mostly occurring sporadically in elderly people. There is no inflammation in HIBM/GNE myopathy and GNE myopathy has a much earlier onset than myositis. Also HIBM/GNE myopathy is a genetic disease, while for Inclusion Body Myositis no common genetic component has been identified.
 
To make the names more confusing, inclusion body myositis is abbreviated as sIBM (sporadic inclusion body myositis). More about sIBM can be found at: http://omim.org/entry/147421.
In some publications, Inclusion Body Myositis is called IBM1 and HIBM/GNE myopathy is called IBM2."

http://www.nzp.co.nz/index.php/news/7-news/79-ibm-hibm-and-gne-myopathy.html

"GNE myopathy, previously termed hereditary inclusion body myopathy (HIBM), is an adult-onset neuromuscular disorder characterized by progressive muscle weakness. The disorder results from biallelic mutations in GNE, encoding UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, the key enzyme of sialic acid synthesis. GNE myopathy, associated with impaired glycan sialylation, has no approved therapy. "

http://www.sciencedirect.com/science/article/pii/S1096719212003794


Best wishes for 2014.

A Profoundly Touching Video of a Friend with HIBM

This is quite a moving video of a friend who also has HIBM.  She gave this speech at the annual fundraising gala event for the Neuromuscular Disease Foundation.  http://www.ndf-hibm.org/

The video is about thirteen minutes long.  In her speech Jennifer poignantly describes what it is like to inhabit  a body that suffers from HIBM. She has effectively encapsulate  the whole spectrum of feelings of HIBM patients and their daily challenges.

Please take the time to watch this video, and visit the NDF web site.
Thank you Jennifer. 
http://vimeo.com/79357093

A More Functional Sleek Designed Wheel Chair With Reviews From Gizmodo

Finally, a wheel chair is coming on the market with functionality and "good looks" for people with disabilities.  I feel this company has done it's research in how people could more effectively use a wheel chair that assists in maintaining proper posture, ease in getting up, and sitting down. I had the pleasure of meeting one of it's founder and I am impressed with their vision to create this chair. Check out the wheel technology and the turning radius.  I do not know the cost for such a chair yet and if and when Medicare will cover it.  Please feel free to contact the company.
Best wishes to all my readers.  May your light continue to shine.
Tara

http://whill.jp/

Type-A is classified as a non-medical device. So, people will need to buy WHILL Type-A out of pocket... We plan to receive FDA clearance with our future model and already got started with it.

Review of this chair by Gizmodo
http://gizmodo.com/this-professor-x-approved-futuristic-wheelchair-is-arri-1450704347

Friend from Japan with HIBM/gne Myopathy, Japanese Registry, and Recent Research on HIBM

 I recently had the pleasure of meeting a friend from Japan who like me has HIBM. Yuriko travelled to the United States to visit  the National Institutes of Health in Bethedsa, Maryland and attend a HIBM symposium held in San Francisco, California. Yuriko started noticing weakness associated with HIBM in her early twenties and is the only one in her family affected.  She currently uses  a wheel chair and is getting weaker as this disease progresses.  She is the vice president for  the Patients Association for Distal Myopathies or PADM in Japan. This is a patient organization which is very active in pursuing a treatment for HIBM.  There are over 130 members in this  association which is quite a high number for a rare disease. There are two well known researchers of HIBM  (Dr. I. Nishino and Dr. I. Nonaka)  on their Academic Advisory board.

It was very insightful to meet Yuriko and her husband.  I find Yuriko  brave to travel such a long distance, as in my experience  with my disability a flight of only five hours is my limit.  There are many barriers at the airports, getting on and off  the plane for one to overcome when using a wheelchair.  It was  quite insightful for me to meet another patient with HIBM and observe how gracefully Yuriko is able to manage her disability.

Link for the PADM association.
http://enigata.com/index_e.html

There is a Japanese GNE myopathy registry which was set up in 2012. 
 http://www.remudy.jp/dmrv/index.html

A research abstract recently published on Japanese patients.
I find this  information quite interesting from this abstract that there were able to profile 212 patients as with rare diseases it is quite difficult to get that many patients.. "Here, we report the mutation profile of the GNE gene in 212 Japanese GNE myopathy patients, which is the largest single-ethnic cohort for this ultra-orphan disease. We confirmed the clinical difference between mutation groups. However, we should note that the statistical summary cannot predict clinical course of every patient."
http://europepmc.org/abstract/MED/24027297

Just a personal note to my friends from far and near,  I continue to participate in a clinical trial in the U.S and I am well.

Conglomeration of Articles, Updates, and Announcements

This is an article from the New York Times discussing the effects of exercise on muscles. Since our muscles deteriorate with HIBM, I think this is a well written article which discusses "epigenetics" and muscles.  It also lists the research being done in this area.

Exercise promotes health, reducing most people’s risks of developing diabetes and growing obese. But just how, at a cellular level, exercise performs this beneficial magic — what physiological steps are involved and in what order — remains mysterious to a surprising degree.
Several striking new studies, however, provide some clarity by showing that exercise seems able to drastically alter how genes operate.
Genes are, of course, not static. They turn on or off, depending on what biochemical signals they receive from elsewhere in the body. When they are turned on, genes express various proteins that, in turn, prompt a range of physiological actions in the body.
One powerful means of affecting gene activity involves a process called methylation, in which methyl groups, a cluster of carbon and hydrogen atoms, attach to the outside of a gene and make it easier or harder for that gene to receive and respond to messages from the body. In this way, the behavior of the gene is changed, but not the fundamental structure of the gene itself. Remarkably, these methylation patterns can be passed on to offspring – a phenomenon known as epigenetics.
What is particularly fascinating about the methylation process is that it seems to be driven largely by how you live your life. Many recent studies have found that diet, for instance, notably affects the methylation of genes, and scientists working in this area suspect that differing genetic methylation patterns resulting from differing diets may partly determine whether someone develops diabetes and other metabolic diseases.
But the role of physical activity in gene methylation has been poorly understood, even though exercise, like diet, greatly changes the body. So several groups of scientists recently set out to determine what working out does to the exterior of our genes.
The answer, their recently published results show, is plenty.
Of the new studies, perhaps the most tantalizing, conducted principally by researchers affiliated with the Lund University Diabetes Centre in Sweden and published last month in PLoS One, began by recruiting several dozen sedentary but generally healthy adult Swedish men and sucking out some of their fat cells. Using recently developed molecular techniques, the researchers mapped the existing methylation patterns on the DNA within those cells. They also measured the men’s body composition, aerobic capacity, waist circumference, blood pressure, cholesterol levels and similar markers of health and fitness.
Then they asked the men to start working out. Under the guidance of a trainer, the volunteers began attending hourlong spinning or aerobics classes approximately twice a week for six months. By the end of that time, the men had shed fat and inches around their waists, increased their endurance and improved their blood pressure and cholesterol profiles.
Less obviously, but perhaps even more consequentially, they also had altered the methylation pattern of many of the genes in their fat cells. In fact, more than 17,900 individual locations on 7,663 separate genes in the fat cells now displayed changed methylation patterns. In most cases, the genes had become more methylated, but some had fewer methyl groups attached. Both situations affect how those genes express proteins.
The genes showing the greatest change in methylation also tended to be those that had been previously identified as playing some role in fat storage and the risk for developing diabetes or obesity.
“Our data suggest that exercise may affect the risk for Type 2 diabetes and obesity by changing DNA methylation of those genes,” says Charlotte Ling, an associate professor at Lund University and senior author of the study.
Meanwhile, other studies have found that exercise has an equally profound effect on DNA methylation within human muscle cells, even after a single workout.
To reach that conclusion, scientists from the Karolinska Institute in Stockholm and other institutions took muscle biopsies from a group of sedentary men and women and mapped their muscle cell’s methylation patterns. They then had the volunteers ride stationary bicycles until they had burned about 400 calories. Some rode strenuously, others more easily.
Afterward, a second muscle biopsy showed that DNA methylation patterns in the muscle cells were already changing after that lone workout, with some genes gaining methyl groups and some losing them. Several of the genes most altered, as in the fat cell study, are known to produce proteins that affect the body’s metabolism, including the risk for diabetes and obesity.
Interestingly, the muscle cell methylation changes were far more pronounced among the volunteers who had ridden vigorously than in those who had pedaled more gently, even though their total energy output was the same.
The overarching implication of the study’s findings, says Juleen Zierath, a professor of integrative physiology at the Karolinska Institute and senior author of the study, is that DNA methylation changes are probably “one of the earliest adaptations to exercise” and drive the bodily changes that follow.
Of course, the intricacies of that bogglingly complex process have yet to be fully teased out. Scientists do not know, for instance, whether exercise-induced methylation changes linger if someone becomes sedentary, or if resistance training has similar effects on the behavior of genes. Nor is it known whether these changes might be passed on from one generation to the next. But already it is clear, Dr. Ling says, that these new findings “are additional proof of the robust effect exercise can have on the human body, even at the level of our DNA.”   http://well.blogs.nytimes.com/2013/07/31/how-exercise-changes-fat-and-muscle-cells/?smid=fb-share&_r=0

The registry for HIBM being conducted by Ultragenyx has added a new site in addition to the British and Canadian sites, they added a U.S. site (although not recruiting). I attended a webinar yesterday on the "Registry" process of rare diseases.  I learned  from the presenters that we as patients need to be included in the design of the "natural history", questionnaires and testing procedures. Please refer to this link:  http://clinicaltrials.gov/ct2/show/NCT01784679?term=hibm&rank=2

To those who are interested in knowing what the doctors and researchers are  finding out about muscles, there will be a World Muscle Society "congress"  to be held from October 1-5th.


 Here is the link to the announcement:   http://www.worldmusclesociety.org/news/read/105

Phase 2 of the Extension Clinical Trial of Sialic Acid - Extended Release Tablet Recruiting Participants

For those who are interested Ultragenyx has now  opened the extension of Phase 2 study or SA-ER. Seems like you have had to participate in Phase 2 to qualify for this study.  For those interested, please contact the  sites listed.

An Open Label Phase 2 Extension Study of(SA-ER)Tablet

This study is currently recruiting participants.

Verified July 2013 by Ultragenyx Pharmaceutical Inc

Sponsor:

Ultragenyx Pharmaceutical Inc

Information provided by (Responsible Party):

Ultragenyx Pharmaceutical Inc

ClinicalTrials.gov Identifier:

NCT01830972

First received: April 10, 2013

Last updated: July 3, 2013

Last verified: July 2013

History of Changes

• Full Text View
• Tabular View
• No Study Results Posted
• Disclaimer
• How to Read a Study Record

  Purpose

GNE myopathy or hereditary inclusion body myopathy (HIBM) is a severe progressive metabolic myopathy caused by a defect in the biosynthetic pathway for sialic acid(SA). The purpose of the study is to measure long term safety and the effects of Sialic Acid-Extended Release (SA-ER) pills.

Condition	Intervention	Phase
GNE Myopathy HIBM	Drug: SA-ER tablets	Phase 2

Study Type:	Interventional
Study Design:	Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	An Open-label Phase 2 Extension Study to Evaluate the Long Term Safety and Efficacy of Sialic Acid-Extended Release (SA-ER) Tablets in Patients With GNE Myopathy or Hereditary Inclusion Body Myopathy

Further study details as provided by Ultragenyx Pharmaceutical Inc:

Primary Outcome Measures:

• Assess long-term safety of 6000 mg/day SA-ER in HIBM subjects [ Time Frame: approximately 3 years ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	45
Study Start Date:	June 2013
Estimated Primary Completion Date:	June 2016 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: open label, 6000 mg/day	Drug: SA-ER tablets

Detailed Description:

GNE myopathy or hereditary inclusion body myopathy (HIBM) is a severe progressive metabolic myopathy caused by a defect in the biosynthetic pathway for sialic acid (SA). Substrate replacement therapy is a potential therapeutic strategy based on the success of replacing missing SA and reducing muscle disease in a relevant mouse model of the human disease (Malicdan et al., 2009). Successful use of SA replacement therapy in humans is believed to depend upon providing steady long-term exposure to the compound in an extended release form (such as Sialic Acid-Extended Release [SA-ER]), given SA's short half-life. Following a Phase 1 study to establish the pharmacokinetics for SA-ER and an ongoing Phase 2 study to assess the pharmacodynamic effect of restoring sialylation of muscle by treatment over 48 weeks, Ultragenyx is conducting this study to evaluate the long term safety and efficacy of SA-ER treatment for up to 36 additional months.

  Eligibility

Ages Eligible for Study:	18 Years to 65 Years
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

• Enrollment in and successful completion of the UX001-CL201 protocol. Must be willing and able to provide written, signed informed consent after the nature of the study has been explained, and prior to any research-related procedures.
• Must be willing and able to comply with all study procedures
• Sexually active subjects must be willing to use an acceptable method of contraception while participating in the study.
• Females of childbearing potential must have a negative pregnancy test at Baseline and be willing to have additional pregnancy tests during the study.
• Females considered not of childbearing potential include those who have been in menopause for at least two years, or have had tubal ligation at least one year prior to Baseline, or who have had total hysterectomy.

Exclusion Criteria:

• Pregnant or breastfeeding at Baseline or planning to become pregnant (self or partner) at any time during the study
• Use of any investigational product (other than SA-ER tablets) to treat HIBM
• Ingestion of ManNAc or similar SA producing compounds
• Has had any hypersensitivity to SA or its excipients that, in the judgment of the investigator, places the subject at increased risk for adverse effects
• Have any co-morbid conditions, including unstable major organ-system disease(s) that in the opinion of the Investigator, places the subject at increased risk of complications, interferes with study participation or compliance, or confounds study objectives.

  Contacts and Locations

Please refer to this study by its ClinicalTrials.gov identifier: NCT01830972

Locations

United States, California
UCLA Medical Center	Recruiting
Los Angeles, California, United States
Contact: Perry Shieh, MD     310-994-5142     pshieh@mednet.ucla.edu
Principal Investigator: Perry Shieh, MD
United States, New York
NYU Medical Center	Recruiting
New York, New York, United States, 10016
Contact: Heather Lau, MD     212-263-8344     Heather.Lau@nyumc.org
Contact: Pankaj Patel     212-263-0139     pankaj.patel@nyumc.org
Principal Investigator: Heather Lau, MD
Israel
Hadassah Univeristy Hospital	Recruiting
Jerusalem, Israel
Contact: Yoseph Caraco, MD     972-2-6778584     caraco@hadassah.org.il
Principal Investigator: Yoseph Caraco, MD

Sponsors and Collaborators

Ultragenyx Pharmaceutical Inc

  More Information

No publications provided

Responsible Party:	Ultragenyx Pharmaceutical Inc
ClinicalTrials.gov Identifier:	NCT01830972     History of Changes
Other Study ID Numbers:	UX001-CL202
Study First Received:	April 10, 2013
Last Updated:	July 3, 2013
Health Authority:	United States: Food and Drug Administration

ClinicalTrials.gov processed this record on July 04, 2013

http://clinicaltrials.gov/ct2/show/NCT01830972?term=hibm&rank=5

Breaking News from Ultragenyx; the Company Conducting the Sailic Acid Trial for HIBM

Ultragenyx released their  preliminary findings for the Sialic Acid Extended Release tablet for phase 2 clinical trial.  I have been participating in this study and have just finished my one year on this medicine. I have my personal anecdotal findings , however here is what Ultragenyx have found and it is very encouraging to see that this medicine is showing some hope and improvement in muscle strength.  It is  stated in their News Release:  

"The data showed dose-dependent improvement in muscle strength relative to placebo in some muscle groups, particularly in the upper extremities at the 6-gram dose. These changes were statistically significant or trended towards significance, and were more pronounced in those patients that had greater walking ability at baseline, a predefined subset."

Here is a copy of their complete release.


Transforming good science into great medicine for rare genetic diseases
www.ultragenyx.com
Contact Ultragenyx Pharmaceutical Inc.
For Investor inquiries, Shalini Sharp, Chief Financial Officer
415-483-8800
ssharp@ultragenyx.com
For Media inquiries, Susan Kinkead of Kinkead Communications
415-751-3611
skinkead@kinkeadcomm.com
FOR IMMEDIATE RELEASE:
Ultragenyx Announces a Positive Signal in Interim Data from Phase 2 Study of UX001
in Hereditary Inclusion Body Myopathy
Study to continue to 48 weeks, followed by extension study testing higher dosage
Novato, CA—July 3, 2013—Ultragenyx Pharmaceutical Inc., a biotechnology company focused on developing treatments for rare and ultra-rare genetic disorders, announced interim 24-week data from a 48-week Phase 2 clinical study of UX001 in 47 patients with hereditary inclusion body myopathy (HIBM), a progressive muscle-wasting disease. The study compared treatment with a total daily dose of 6 grams or 3 grams of UX001 with placebo. UX001, an oral sialic acid extended-release (SA-ER) tablet, is designed to replace the deficient sialic acid substrate in patients with HIBM.
The data showed dose-dependent improvement in muscle strength relative to placebo in some muscle groups, particularly in the upper extremities at the 6-gram dose. These changes were statistically significant or trended towards significance, and were more pronounced in those patients that had greater walking ability at baseline, a predefined subset. Other clinical endpoints did not reveal changes at this interim assessment. Creatine kinase levels showed a trend to improvement in the 6-gram dose group compared with placebo. UX001 appeared to be well tolerated with no serious adverse events observed to date in either dose group.
“These early data suggest a modest dose-dependent improvement in muscle strength in HIBM patients treated with UX001 compared to a decline in placebo-treated patients,” said Emil Kakkis, MD, PhD, Chief Executive Officer of Ultragenyx. “We need to evaluate whether the observed treatment effect is sustained or increased over a longer 48-week period, and if higher dosing might further enhance the efficacy signal observed.”
The primary objective of the Phase 2 study is to evaluate safety, dose and potential pharmacodynamic effect of restoring sialylation of muscle in patients with a confirmed genetic mutation for HIBM. The study is also evaluating clinical measures of muscle strength, mobility, function, self-reported disability, and changes in quality of life. The study is taking place at four sites in the United States and Israel. Patients were randomized to receive placebo, 3 grams, or 6 grams per day of UX001, in three divided doses. At 24 weeks, placebo patients were randomized and crossed over into either of the two dose groups on a blinded basis. Patients will be evaluated again at 48 weeks,with final data anticipated around year-end. Following the 48-week analysis, the company plans to continue to treat these patients in an extension study with an increased dosage of UX001 based on the dose-dependence observed at week 24.

About Hereditary Inclusion Body Myopathy
Hereditary inclusion body myopathy (HIBM) is also known as GNE myopathy,
Quadriceps Sparing Myopathy (QSM), Inclusion Body Myopathy type 2, Distal Myopathy
with Rimmed Vacuoles (DMRV) and Nonaka myopathy. HIBM is a severe, adult-onset,
progressive, genetic neuromuscular disease caused by a defect in the biosynthetic
pathway for sialic acid (SA). Patients with HIBM typically begin to have weakness and
abnormal walking at 18 to 30 years of age. The body’s failure to produce enough sialic
acid causes muscles to slowly waste away and can lead to very severe disability within
10 to 20 years of diagnosis, with patients often ending up wheelchair-bound within that
time. There is currently no approved therapy.
About Ultragenyx
Ultragenyx is a privately held, clinical-stage biotechnology company committed to
bringing to market life-transforming therapeutics for patients with rare and ultra-rare
metabolic genetic diseases. The company, founded in 2010, is rapidly building a diverse
portfolio of products addressing diseases for which the unmet medical need is high, the
biology for treatment is clear, and for which there are no effective treatments.
Ultragenyx has two products in Phase 2 clinical trials, UX001 for the treatment of
hereditary inclusion body myopathy (HIBM), and UX007 for the treatment of fatty acid
oxidation disorders (FAOD). A third compound, UX003 for MPS 7 (Sly Syndrome), will
begin Phase 1/2 clinical trials later this year. The company is led by a management team
experienced in the development and commercialization of rare disease therapeutics.
Ultragenyx’ strategy is predicated upon time and cost-efficient drug development, with
the goal of delivering safe and effective therapies to patients with the utmost urgency.

For more information on Ultragenyx, please visit the company’s website at
www.ultragenyx.com.
http://www.ultragenyx.com/index.php?ht=a/GetDocumentAction/i/12770

Muscular Dystrophy Association is Partnering with French Muscle Disease Association to Advance Gene Therapy

This is a very interesting article on gene therapy for neuromuscular diseases.  It discusses the progress, limitations and  new development strategies.

Of importance to me, as most of you are aware that I am enrolled in a clinical trial for HIBM; I recently completed one year  on this trial.

Moving Toward 'Next-Generation' Gene Therapy

MDA partnered with a French muscle disease association to host a symposium on advancing gene therapy for neuromuscular diseases

Article Highlights:

• Planning for the next generation of gene and stem cell therapies for muscle diseases is on the minds of scientists seeking to overcome challenges inherent in current “first-generation” approaches.
• MDA partnered with the Association Française Contre Les Myopathies (French Association Against Myopathies) to host a May 16, 2013, symposium at which experts came together to share ideas about how to keep the field moving forward.
• The symposium was held in Salt Lake City in conjunction with the 16th annual meeting of the American Society of Gene & Cell Therapy.

by Amy Madsen on May 23, 2013 - 5:00am

Planning for the next generation of gene and stem cell therapies for muscular dystrophies — even as the first generation is still under development — was the theme of a joint symposium sponsored by MDA and the Association Française Contre les Myopathies (French Association Against Myopathies, or AFM) at the 16th annual meeting of the American Society of Gene & Cell Therapy (ASGCT).
The MDA/AFM symposium was held May 16, 2013, in Salt Lake City, in conjunction with the May 15-18 ASGCT meeting. It was co-chaired by Charles A. Gersbach, an assistant professor at Duke University in Durham, N.C., and Kathryn Wagner a neurologist and neurogeneticist at the Kennedy Krieger Institute in Baltimore. Gersbach’s research includes gene therapy, biomolecular and cellular engineering, regenerative medicine and synthetic biology; Wagner, a longtime and current MDA research grantee, studies muscle regeneration.

Limitations to current muscle gene therapy approaches

Finding effective methods of gene delivery to muscle tissue is one of the main challenges facing the field, noted symposium speaker Jeffrey Chamberlain, professor of neurology, medicine and biochemistry at the University of Washington, Seattle, and a longtime MDA grantee and member of MDA's Scientific Advisory Committee.
He explained that current approaches to gene therapy aim to deliver therapeutic genes directly to muscle fibers using the emptied-out shells of adeno-associated viruses (AAV) as delivery vehicles. (This is the approach being used to deliver micro- and mini-dystrophin genes in gene therapy strategies under development for Duchenne muscular dystrophy, or DMD.)
Two problems with AAV delivery are:

• it's unable to accommodate very large genes (like dystrophin); and
• it's not an efficient method for delivering genes to muscle satellite cells, which are muscle-specific stem cells.

New strategies in development

Symposium speakers discussed ideas specific to their own research, as well as more general concepts, including overcoming the delivery challenge.
Chamberlain reviewed recent developments in an alternative delivery approach involving a different type virus — a lentivirus — that may prove more effective at delivering genes to satellite cells, which are stem cells that are on their way to becoming muscle.
He noted that satellite cells can be obtained from patients, corrected using genes delivered in a lentiviral vehicle, and then introduced back into the body, where they may serve to permanently repair and replenish abnormal muscle with healthy muscle. Unfortunately, the efficiency of this method, which has been tested in mice, is low, but Chamberlain's lab and other labs are working to improve that.
Molecular geneticist Xiao Xiao, at the University of North Carolina at Chapel Hill, reviewed his lab's recent efforts at overcoming an important hurdle in gene therapy efforts: delivering sufficient numbers of therapeutic genes to all of the muscles that need them.
His lab currently is working on delivering genes to individual limbs by isolating the limb from the rest of the body with a tourniquet, while pumping therapeutic genes (encased in delivery vehicles) into a vein in the isolated limb. Xiao noted that the method has been demonstrated to be safe (using only a saline solution) in humans, and highly effective at gene delivery in large animal models.
At Généthon, a not-for-profit biotherapy lab funded by AFM in Evry, France, research scientist Anna Buj-Bello currently heads a translational program focused on investigating the potential for gene therapy to treat myotubular myopathy (MTM).
Buj-Bello presented updates about a collaboration with Martin Childers on an MDA-AFM-funded project to investigate gene therapy for MTM, in which the team is using a dog research model that has a naturally occurring form of the disease. (The dogs have a mutation in the myotubularin gene.)
Buj-Bello reported that therapeutic myotubularin genes encased in AAV delivery vehicles were delivered to the limbs of MTM dogs. The limbs had been isolated from the rest of the body via the use of a tourniquet. However, in at least one of the dogs, the tourniquet leaked and a systemic therapeutic effect was observed, including dramatically increased life span, and vastly improved muscle and respiratory function.

Fulvio Mavilio, an expert on gene therapy for rare diseases and director of Généthon, presented information about two gene therapy efforts under development for DMD, focusing in particular on an exon-skipping approach that has the potential to persist much longer in the body than exon-skipping strategies currently in testing.

Several current exon-skipping strategies would involve periodic and repeated injections of biological components called U7 splice site modulators. With the new method, genes that carry the instructions for building the modulators are injected (encased in AAV delivery vehicles) instead. Cells are able to use those instructions to synthesize the U7 splice site modulators. Because the replacement genes persist in the body over time, it’s unlikely that repeat treatments would be needed. A clinical trial to test the new method is expected to begin in late 2013 or early 2014.

For more information

To learn more about gene therapy advances, read:

• DMD, BMD: Combining Gene Therapy and Stem Cell Transplantation, Quest News Online, March 21, 2013;
• SMA Research Briefs: Gene Therapy, New SMA Mouse, Quest News Online, March 14, 2013;
• DMD: Dystrophin-Deficient Dogs Benefit from Gene Therapy, Quest News Online, Jan. 15, 2013; and
• Podcast Describes Results of LGMD2C Gene Therapy Trial, March 14, 2012.

Online Career Fair for People With Disabilities

Having trouble viewing this email? Click here

Stay Connected   Forward to a Friend  Like MDA  Follow MDA  Watch MDA  +1 Us   Learn More  Advocacy News  Diseases Research  Clinics/Services  Spokespeople  Publications  Donate Ways to Help Quest Magazine  MDA.org   To: MDA Community From: MDA ---- Advocacy Date: May 15, 2013 A great opportunity for all job seekers within the MDA community! Whether you are about to graduate, currently unemployed or seeking different career options, or if you're an individual with a disability, this online career fair may be for you. Register for the next Think Beyond the Label Online Career Fair. There are four events this year and the next one is a week away ---- Tuesday, May 21 from 1-4 p.m. Eastern time! Employers are registering now for this one-of-a-kind online career fair to recruit job seekers with disabilities nationwide. This year's Think Beyond the Label Online Career Fairs, powered by Brazen Careerist, will connect you with businesses like Aetna, United Therapeutics, NextEra Energy, Grundfos Pumps, University of Southern California, University of North Carolina and Eastern Michigan University are actively recruiting qualified job candidates with disabilities ---- all without leaving your computer. It's a great event to meet and chat with businesses who are committed to building a diverse workforce. What type of job seekers should attend this event? People with disabilities who want to meet employers nationwide who are actively recruiting them. People with disabilities of all skills level across the United States. Participation is free but space is limited, so register today to be sure you don't miss this great opportunity! See you May 21 at the Think Beyond the Label Online Career Fair!  mda.org/advocacy Annie Kennedy MDA Senior Vice President ----  Advocacy  https://www.brazenconnect.com/event/thinkbeyondthelabel_may_21

ARM/HRG Newsletter. Article on my Family's Journey in Getting Diagnosed with HIBM

Dear fellow patients and friends:

Here is a current newsletter from Advancement for Research Myopathies (ARM/HRG). There is an article on my family's journey towards getting a diagnosis.  There are other news in this edition and my hope and I am sure of all HIBM patients  is for us to be able to get a cure on the market as soon as possible.
Please refer to this link for the complete newsletter; the article on my family is on page 3.  

http://www.hibm.org/arm/_media/about_arm:armnewsletter_may2013.pdf

MDA Conference in Washington D.C. to Focus on Neuro-muscular Therapy Development

Please refer to the link at the bottom of this page for the complete article.  It seems like they will address most neuromusclar disease except HIBM.  How can we influence them to include HIBM in their focus?

MDA is bringing together professionals from academia, industry, government and the nonprofit sector to discuss development of therapies for neuromuscular disorders.

Article Highlights:

• MDA will host a scientific conference April 21-24, 2013, in Washington, D.C.
• The conference will emphasize specific therapy development for neuromuscular disorders in a way that would not have been possible as recently as five years ago.
• The conference, which is not open to the general public, brings together experts from different disease areas and with different types of expertise.
• Blogs and other reports will be posted on the MDA website during and after the meeting.

by Margaret Wahl on April 18, 2013 - 10:03am

^-A ⁺A

The Muscular Dystrophy Association’s annual conference being held in Washington, D.C., on April 21-24, 2013, is centered on the theme Therapy Development for Neuromuscular Diseases: Translating Hope into Promise.
"Five years ago, this meeting couldn’t have happened," said Jane Larkindale, MDA's vice president of research. "We couldn’t have filled two-and-a-half days with the kinds of presentations we have now. The agenda is packed with important talks discussing everything from early-stage therapeutic targets through to clinical trial results, along with sessions discussing the development of new tools that will allow us to conduct trials more effectively."
The conference is aimed at professionals and is not open to the public. However, blogs and reports will be available to all on the meeting website, both during and after the proceedings.
Nearly 500 attendees from academic laboratories, clinics and industry are expected, with more than 60 platform presentations and more than 200 poster presentations planned.
The goal, said Larkindale, is to “identify barriers to therapeutic development and how to overcome those barriers.”
Conference co-chairs are C. Frank Bennett, CEO of the biomedical company Isis Pharmaceuticals, and Eric Hoffman, director of the Research Center for Genetic Medicine at Children's National Medical Center in Washington, D.C.

From targets to trials

Conference presentations have been organized into broad themes relating to therapy development.
Targets: These presentations will focus on identifying molecular targets at which to aim therapies in different disorders, such as amyotrophic lateral sclerosis (ALS), Charcot-Marie-Tooth disease (CMT), facioscapulohumeral muscular dystrophy (FSHD), myotonic muscular dystrophy (MMD) and spinal muscular atrophy (SMA).
Genetic modifiers: Presentations will explore naturally occurring gene variations that modify the course of diseases and can help explain an individual's disease course, as well as provide targets for therapeutic development, in disorders such as ALS, Becker muscular dystrophy (BMD), Duchenne muscular dystrophy (DMD), SMA and MMD.
Therapeutic modalities: Presentations will focus on different types of compounds that have the potential to be developed into therapies, such as stem cells, proteins, small molecules and antisense, with particular application to ALS, one form of congenital muscular dystrophy (CMD), DMD and FSHD.
Biomarkers: Presentations will discuss the identification and use of biological indicators, including imaging studies, which may reflect the progress of a disease or its response to treatment, with particular application to ALS and DMD.
Animal models: Discussions will center on research animals that replicate the characteristics of various human neuromuscular diseases and how they can be used to study these diseases, with particular application to ALS, centronuclear myopathy (CNM), DMD, Emery-Dreifuss muscular dystrophy (EDMD) and SMA.
Use of animal models in drug development: Presenters will explore how well animal models of human disorders can be used to develop drugs, with particular application to ALS, DMD FSHD, myotubular myopathy (MTM) and SMA.
Preclinical work for trial design and regulation: Designing laboratory studies that can serve as the foundation for human trials of investigational drugs will be focus of these talks.
Clinical trials: These presentations will include updates on trials of tirasemtiv in ALS; drisapersen and eteplirsen in DMD; cardiac treatments for DMD; RG2833 for Friedreich's ataxia (FA); and ISIS-SMNRx for SMA.
The latest and greatest: Discussions will include late-breaking research reports, with particular application to CNM, DMD, FA and mitochondrial myopathies.
Resources for drug development: Topics to be covered include working with the National Institutes of Health's National Center for Advancing Translational Sciences (NCATS), tissue banks, stem cells, databases, and computer chips, with particular application to ALS.

http://quest.mda.org/news/mda-scientific-conference-emphasize-therapy-development?utm_source=Research+Update+-+MDA+Scientific+Conference+-+All+Fam+-+4+18+13&utm_campaign=SC+-+All+Fam+4+18+13&utm_medium=email

Extension Study for Phase 2 of Sialic Acid Tablet Announced Not Yet Recruiting

It's official that Ultragenyx will do  an extended study using Sialic Acid Extended Realease starting in June 2013 for the next 3 years. They plan to accept 45 patients.  Please refer to the link below.  Also, the National Institutes are still doing study on Natural History of patients with HIBM and they anre in Phase 1 trial of ManNac.  I would urge patients with HIBM to contact them.

 is not yet open for participant recruitment.

Verified April 2013 by Ultragenyx Pharmaceutical Inc

Sponsor:

Ultragenyx Pharmaceutical Inc

Information provided by (Responsible Party):

Ultragenyx Pharmaceutical Inc

ClinicalTrials.gov Identifier:

NCT01830972

First received: April 10, 2013

Last updated: NA

Last verified: April 2013

History: No changes posted

• Full Text View
• Tabular View
• No Study Results Posted
• Disclaimer
• How to Read a Study Record

  Purpose

GNE myopathy or hereditary inclusion body myopathy (HIBM) is a severe progressive metabolic myopathy caused by a defect in the biosynthetic pathway for sialic acid(SA). The purpose of the study is to measure long term safety and the effects of Sialic Acid-Extended Release (SA-ER) pills.

Condition	Intervention	Phase
GNE Myopathy HIBM	Drug: SA-ER tablets	Phase 2

Study Type:	Interventional
Study Design:	Endpoint Classification: Safety/Efficacy Study Intervention Model: Single Group Assignment Masking: Open Label Primary Purpose: Treatment
Official Title:	An Open-label Phase 2 Extension Study to Evaluate the Long Term Safety and Efficacy of Sialic Acid-Extended Release (SA-ER) Tablets in Patients With GNE Myopathy or Hereditary Inclusion Body Myopathy

Resource links provided by NLM:

Genetics Home Reference related topics: inclusion body myopathy 2

MedlinePlus related topics: Muscle Disorders

U.S. FDA Resources 

Further study details as provided by Ultragenyx Pharmaceutical Inc:

Primary Outcome Measures:

• Assess long-term safety of 6000 mg/day SA-ER in HIBM subjects [ Time Frame: approximately 3 years ] [ Designated as safety issue: Yes ]

Estimated Enrollment:	45
Study Start Date:	June 2013
Estimated Primary Completion Date:	June 2016 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Experimental: open label, 6000 mg/day	Drug: SA-ER tablets

http://clinicaltrials.gov/ct2/show/NCT01830972?term=hibm&rank=5