Pat Furlong's Journal

« December 2004 | Main | February 2005 »

January 31, 2005

Making SENSE of ANTISENSE OLIGONUCLEOTIDE (Exon Skipping) THERAPY

Workshop: Antisense Oligonucleotide Therapy
1/31/2005, Washington, DC

PPMD is interested in accelerating promising therapies into clinical trial. In the last several years, we have been hearing about technology that could potentially repair the gene – ‘snip’ it back together utilizing chemistries that ‘skip’ over a certain exon or several exons and in the ‘skipping’ produce a shortened, but functional version of dystrophin. While it sounds a little like ‘Star Wars,’ antisense oligonucleotides (AON) are not new and have been used in a number of other conditions. Two outstanding investigators – Steve Wilton and Judith van Deutekom have been working on applying this technology to Duchenne for the last several years and believe this approach has the potential to alter the Duchenne phenotype into a Becker phenotype. AND it’s not just ‘belief’; they have animal data to back this up!

This idea came about because all boys have revertent fibers - random muscle fibers that contain dystrophin. These 'revertent fibers' apparently happen because of 'natural' exon skipping, a genetic mistake on the cellular level that causes the cell to naturally skip over the missing part (exons) and produce a shortened version of dystrophin. While researchers believe that all boys have revertent fibers, this 'natural skipping' does not occur often enough to provide benefit to muscle.

What if there was a way to increase the number of revertent fibers? What if there was a way to tip that balance, to trick the cell into 'skipping' over the missing exons (deletions) in such a way that would substantially increase the quantity of muscle fibers making the shortened protein? Would this help?

We know that individuals diagnosed with Becker muscular dystrophy have slower progression, some significantly slower and some who have very few symptoms at all. We know that persons diagnosed with Becker produce a modified (shortened) version of dystrophin. Researchers have evaluated the type of dystrophin found in many individuals diagnosed with Becker and have ‘examples’ of shortened versions of dystrophin. Symptoms or manifestations are referred to as ‘pheontype’ and, in some cases, we now have a very good correlation between genotype (what’s wrong with the gene) and phenotype (symptoms). This information provides substantial insight into the question of AON therapy or exon skipping and what might occur in Duchenne patients IF the AON therapy was used.

For this reason, AON directed exon skipping is certainly an exciting possibility. PPMD and our professional consultants in Washington, DC organized a workshop in an effort to understand the state of the art, understand what hurdles need to be addressed and issues that need to be considered in order to accelerate the development of clinical trials.

The workshop was limited to a small number of individuals and work is ongoing. I thought it might be helpful to outline some of the discussion points. In addition, we are developing a report and, when available, it will be posted on-line.

Here are the basic issues:
1. What chemistry is best? What will be most effective? This is not yet known and there are several teams of researchers evaluating different chemistries. In other words, there is not a ‘one size fits’ sort of AON (oligo). There are different formulations, each of which will need to be tested.
2. What sequences? In other words, we need to understand the effectiveness of each shortened version of dystrophin, recognizing that some may provide more benefit than others. Human clinical trials will be the only way to determine the effectiveness in terms of functional improvement and slowing muscle turnover. The effectiveness of the treatment will vary with specific deletions. Some may have the potential to produce effective normalization, while other mutations may not be treatable or may be less effective.
3. Delivery. Systemic delivery remains a hurdle. AON’s have already been delivered intravenously, but what is not clear is how much AON is required, how often and/or how easy to direct the AON to go into muscle.
4. Duration of effect. AON is not a permanent ‘fix’ rather a treatment that would need to be applied at intervals that may be in terms of weeks or months. We will have to understand if there are toxicity problems with repeated treatments.
5. Regulatory hurdles. In the United States, the FDA’s first concern is safety and the first experiments in humans will be evaluating toxicity. The first trials will involve injecting a single muscle, followed by biopsy of the muscle, studies for toxicity and dystrophin expression. Systemic delivery toxicity studies will need to answer questions about toxicity as well, especially repeated delivery of AON and potential toxic effects to major organs – liver, kidney, etc. For this reason, large animal data will be required before systemic delivery can be tested.
6. Cardiac. At this time, there is no delivery to cardiac muscle. We will need to consider the effectiveness of AON as a therapy and understand the potential of added burden to the cardiac muscle.

You may already be aware: the first human (single muscle) trials are scheduled for 4th quarter 2005 in the Netherlands.

Posted by ppmd at 02:46 PM | Comments (1)

Burden of Care Workshop

On Jan. 26 and 27, NIH held a Burden of Care workshop. This workshop is the result of your advocacy efforts. Last year Congressional language directed NIH to conduct a workshop to understand and measure the ‘burden of care’ for muscular dystrophy. This is important information and necessary in order to develop Standards or Guidelines for Optimal Care, to assist and encourage companies to invest in developing treatments for DMD, for insurers (private and Medicaid) and for policies related to services.

It is certainly not a simple task and there are many questions and considerations that need to be taken into account: what perspective or who’s burden? In order to understand the ‘burden’ for the individual, for the family, for the clinician and for society, are we talking to families with boys of all ages and across all levels of severity, all levels of income, all levels of education and outspokenness? Are we sampling families that do not speak English? Are we overburdening patients and families with multiple questionnaires asking for the same or similar information? Is one particular method of measure is better than another? Is it is necessary to compare burden with specific mutations? We need to make sure we are asking appropriate questions that will help us develop Standards of Care and interventions that reduce burden.

It is easy to say the goal of the workshop is to identify both the financial burden for families as well as the intangible costs, but difficult to accomplish. Financial burden (referred to as Direct Cost) is fairly easy to understand beginning with the odyssey of diagnosis, the visits to any number of physicians and specialists and following diagnosis, equipment, home modifications, education needs, etc. These are concrete costs and easy to quantify.

It is far more difficult to figure out the intangible (Indirect and Relative – relative to income) costs to the family. I am sure we could all agree that it is very difficult to attach an exact number to the anxiety of diagnosis, the physical and emotional cost to the child, siblings, parents and extended family.

How one goes about collecting information is directly related to the question you need to answer. We were presented with an overwhelming ways to collect data and another overwhelming amount of acronyms used to describe these data sets. It is quite amazing to be able to develop a ‘picture’ of a given condition from any number of views and the basic ‘take home’ is that different tools/instruments are utilized in different ways to gather specific data. Often these data sets are then compared one to another, which provides another view.

One huge problem in trying to assess this data is the fact that there is no specific billing code, called an ICD 9 for Duchenne muscular dystrophy. The ICD 9 code for neuromuscular disease is 359.1 and this includes a number of neuromuscular conditions. As a result, it is difficult for health economists and data experts to capture specific information related to Duchenne. This general ICD 9 code is confusing for insurers as well and because there are no Standards of Care for muscular dystrophy, securing equipment and services from insurance companies is often a frustrating and lengthy process.

The meeting was a comprehensive approach to identify costs across the spectrum of life with Duchenne/Becker, trying to quantify lost work hours, family’s out-of-pocket expensive, work /school days lost, and the amount of time a family caregiver spends providing care.

Several presenters discussed comparative costs - that is comparing costs to that of raising a child without illness. It was estimated that the expenses related to care for an individual with a neuromuscular condition are 10-25 times greater than for an individual without a neuromuscular condition. The group recommended that in order to really understand the consequences of the diagnosis of Duchenne muscular dystrophy, it is important to measure at each stage of the disorder because an overall cost does not adequately describe what happens over time. Specifically in Duchenne, families have to make different accommodation at different stages and it may be important to use different (or more adequate) tools in order to adequately understand the ‘burden’ (financial, emotional, psychological and social) in Duchenne muscular dystrophy.

We continue to insist that there is a critical need to develop standards or guidelines for care AND insure that all physicians/clinics providing care for Duchenne muscular dystrophy patients are knowledgeable about such care and agree to provide this care to all patients.

It was noted that individuals with disability are less likely to be employed and those that are employed typically are paid less and often, work less hours. One of the participants in the meeting described a conversation with a young man with Duchenne. His family worried that he was depressed. The reality was that his opinion was strikingly different than that of his family. He wanted four things:

1. to go to college
2. to live independently
3. to have counseling
4. to have sex

Thankfully, we need to plan for our sons to grow up and become adults and develop systems to encourage their independence and productivity.

I hope you are familiar with the CDC’s Duchenne/Becker muscular dystrophy program. After all, it is thanks to your advocacy efforts that it exists! One of the components of the MD CARE Act, was the mandate for CDC to being to collect surveillance data. The program has been in expanding since its initiation in 2001. Four states are now collecting data (Iowa, Colorado, Arizona and Upstate NY) and Georgia will soon be added. This is a population-based survey, collecting records not only from the MDA clinics but State Health records. This is an important study and will cover a range of issues from incidence and prevalence to quality of life.

www.cdc.gov/ncbddd/duchenne/default.htm

I’m sure you may have already received a number of surveys and several more are either on the way or will be in the upcoming months. I also realize you have few moments (none probably) to spare and at the end of the day, rest seems much more important that filling out forms. The reality is that this information is really essential if we are going to understand how many children have Duchenne muscular dystrophy, the difficulty of accessing optimal care, the need for Standards of Care, the need to reduce care-giver burden, the need to reduce social isolation and the need to develop systems that promote independence and improve the health of the family. We are now mailing a survey for the ‘Dystrophinopathy Network’ of Dr. Kevin Flanigan. Dr. Flanigan is collecting information related to genotype (specific genetic mutation) phenotype (progression). If you do not receive a survey, please let us know and we will make sure you receive a copy.

Please understand the importance of your advocacy. Telling your story and working together is critical if we are to change the face of DMD. On a State level, it is an idea to connect with Family Voices (www.familyvoices.org). Advocating to your local representative will give you the ability to understand what services are offered and what services need to be provided. Our Washington DC efforts are broad – about increasing the investment in research, about accelerating the development of treatments, about Standards of Care and about access for all families. If you keep in mind, individual needs for families are linked to the State level and to increase investment in research, accelerate the development of therapies – come to Washington and if that is impossible, please call your congressman and Senator. Please access our website to understand the ‘ask’; call your Congressional/Senate office; tell your story. One very important thing is to be consistent and deliver a consistent message. If we are all asking for different things, you might imagine, the message is confusing and will not be heard. Follow-up is important as well and one call won’t be enough. Keep in mind the squeaky wheel approach: calling, thanking and calling again.

One of our advocacy agenda items is to see that Congress continues to provide money for the CDC’s surveillance program in DMD and further advises CDC to add additional full-time CDC employees dedicated to the Duchenne muscular dystrophy project – a critical step if we are to expand the program.

We are making progress.

Posted by ppmd at 08:14 AM | Comments (1)

January 18, 2005

The meeting in Monaco, like the previous three meetings, was a complete success.

The meeting in Monaco, like the previous three meetings, was a complete success. The subject of this meeting was centered around Insulin Growth Factor (IGF), Myostatin inhibition, Bowman-Birk (protease) Inhibitor (BBIC), and Calpain inhibitor, Myodur.

IGF
Gill Butler-Browne chaired the first session and Nadia Rosenthal was the first presenter. Dr. Rosenthal opened with the statement "Isomers Matter" referring to IGF. The somatomedins, or insulin-like growth factors (IGFs), comprise a family of peptides that play important roles in growth and development. IGF mediates many of the growth-promoting effects of growth hormones. Imagine the role of IGF and Myostatin as the balancing mechanisms in muscle. IGF promotes muscle growth and regeneration, and Myostatin limits growth and regeneration.

In the body, IGF is produced in different forms and utilized for specific purposes related to growth. Part of the discussion centered around the existence of circulating and localized that were localized and specific to muscle. Based on increasing knowledge of IGF isoforms, IGF is an interesting therapeutic possibility in DMD.

Researchers cautioned against internet or health food store purchases containing IGF, suggesting that the form contained in such products is not the muscle specific form and could be potentially harmful.

Myostatin

Myostatin is a negative regulator of muscle. In other words, Myostatin limits the size of muscle. Work in the mdx mice suggest that inhibiting Myostatin would improve strength by increasing satellite cell repair/regeneration. Wyeth has completed Phase I (healthy volunteers) trials and will soon initiate Phase II trials involving individuals diagnosed with Becker muscular dystrophy, FSHD and Limb-Girdle muscular dystrophy. These trials are in development and anticipated to begin early this year. Individuals participating in the trial will receive an IV injection of the Myostatin antibody once every two weeks for a period of six months. Wyeth is also involved in high throughput screens to identify a small molecule (oral drug) with the capacity to inhibit the signaling of the Myostatin protein.

Dr. Marcus Schulke identified the ‘superbaby,’ the little boy in Germany with the mutation in his Myostatin gene. The little boy is remarkably strong for his age. This identification of this child provides us with some proof that inhibiting Myostatin increases strength in healthy individuals and may provide a therapeutic possibility for DMD. There is some concern that inhibiting Myostatin may ‘wear out’ the regenerative capacity of muscle. However, Dr. Kathryn Wagner presented evidence that, at least in rodents, prolonged inhibition of myostatin continues to yield benefits for muscle regeneration. Myostatin inhibition would not be considered a ‘cure’ but certainly has the potential to improve muscle strength and slow degeneration.

BBIC

Bowman-Birk Inhibitor (BBIC) is a protease inhibitor. The Sweeney lab has been investigating BBIC in the mdx mouse. Protease inhibitors limit protein degradation by improving calcium handling in muscle. BBIC is not a ‘cure;’ rather the mdx mouse looks to have a similar effect as steroids. BBIC is an excellent candidate for clinical trial because it has no side effects and improves the stability of the muscle cell. Dr. Kurt Fischbeck and Glen Nuckolls are planning clinical trials at the National Institutes of Health (NIH). A meeting with the Food and Drug Administration (FDA) is scheduled on Feb. 2. This trial is expected in second quarter 2005.

MYODUR

MYODUR includes a carnitine as the carrier molecule synthesized (combined) with leupeptin, a known calpain inhibitor. Calpain is the primary protease that degrades skeletal muscle. The absence of Dystrophin causes an insufficiency of dystrophin leading to poor muscle cell membrane integrity, which allows for abnormal calpain up regulation due to extracellular calcium ion activation. Data suggests that the calpain inhibiting effect leupeptin, along with the muscle cell targeting effect of carnitine, will provide a promising therapeutic candidate for Duchenne muscular dystrophy. Terry Michelle from the Ceptor Corporation has a scheduled meeting with FDA on Feb. 7. We anticipate Myodur in clinical trial before the end of 2005.

Feels like progress.

Posted by ppmd at 09:19 PM | Comments (2)

January 13, 2005

Therapeutics for DMD

I leave today to attend a meeting to discuss Therapeutics for DMD - specifically concentrating on Protease Inhibitors and Myostatin inhibition. This meeting is organized by Duchenne Parent Project France and in coordination with UPPMD (our international group). You are probably well aware that Phase I trials involving the Myostatin antibody (to inhibit myostatin) are complete. Phase II trials involving adult Becker muscular dystrophy patients (as well as other muscular dystrophies) are moving forward.

In addition, NIH is preparing a trial involving a protease inhibitor, the soybean-derived Bowman-Birk inhibitor (BBI) that has been particularly effective in the ability to suppress the carcinogenic process (currently in Phase III trials). BBI has been extensively studied, both as purified BBI (PBBI) and as an extract of soybeans enriched in BBI, called BBI Concentrate (BBIC). MDX mouse data suggests that BBIC improves downstream pathology (what happens in the muscle cell because of the absence of dystrophin – loss of stability of muscle cell membrane, influx of calcium). BBIC is an oral compound with a mild side effect profile and when compared with corticosteroids (in mdx mice) looks equal in terms of benefit but without side effects.

Many of you may recall discussions or presentations about Leupeptin, the calpain inhibitor. Leupeptin has been synthesized with Carnitine to increase muscle cell targeting and can be found by ‘googling’ Myodur. Calpain is the primary protease that degrades skeletal muscle. The loss of stability of the muscle cell membrane allows for abnormal calpain up regulation. The company (XECHEM) has filed an application with FDA.

Consider this a ‘base hits’, possibilities to slow muscle degeneration. Keep in mind, a few base hits can make a home run. I’ll take notes…

Posted by ppmd at 02:51 PM | Comments (1)

January 10, 2005

More Disney Marathon

It’s hard to describe the Disney Marathon. There is something magical about Disney, everywhere you look and everyone you see. It was PPMD’s first year to participate. Fireworks and 86 runners strong, the run was amazing, mind-boggling actually. Most importantly, the Disney Marathon was a success – for the runners who trained so long and so hard to qualify and participate in the run, for the families and friends who cheered them on and for the boys. We raised approximately $150,000 for research. This DMD community is strong, alive, committed and brilliant. They work together, play together and fight to change the face of DMD. The strength of this group is incredible and it becomes crystal clear when you see them together.

Posted by ppmd at 12:31 PM | Comments (0)

January 06, 2005

Disney Marathon

I’m on my way to Florida to participate in the Disney marathon. It’s strange how things happen. Kimberly mentioned the opportunity to participate in the Disney Marathon, a fundraiser where runners (those who are really running) sign on to run the 26 mile marathon at Disneyworld in Florida. There are also spirit runners (people who participate in their heart and mind). Participants are sponsored by friends, relatives, colleagues and sometimes people they don’t even know with the purpose of raising money for a charity. Our discussion centered on "who do we know that could run 26 miles", recognizing that Kim and I have no entry into the world of marathon runners. We were guessing, oh maybe 10 runners. Okay, 15 tops, but worth a try. Now, 86 runners strong and a remarkable fundraising effort from the runners, we are headed to the Magic Kingdom. I was reluctant to go because Mush and I were in an auto accident on 12/28; hit head-on while driving the ‘Jesus” car (my father’s car before he died - with a picture of Jesus on the dash). The other driver lost control, crossed the median and you can imagine the rest of the story. Seatbelts on, airbags deployed, Mush was bruised, banged up and terrified. I thought it was the end, the next shoe dropping. The Jesus car is totaled and fortunately, Mush and I survived. I was holding my laptop, which ended up smashed into my sternum and face. Teeth shoved into my jaw, upper jaw fractured, mouth a mess and a lovely shiner on the left eye. I was feeling pretty sorry for myself and then I heard that strange little whisper that happens now and again. ‘Get over yourself mom, you and Mush are just fine. Those runners are running for me and for so many boys like me, who need and deserve investments in research. Go, you could use a little magic’.

Posted by ppmd at 02:06 PM | Comments (0)