A Humbling Experience

Humility: A modest or low view of one's own importance; (or adjectival form: humble) is the quality of being modest, reverential, even politely submissive, and never being arrogant, contemptuous, rude or even self-abasing.

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I read a good article the other day in the Georgia Magazine. The ‘viewpoint’ by Paul Wood, President and CEO of Georgia Electric is titled, “Oh, Lord, it’s hard to be humble” and I encourage you to read it.

He mentions the Mac Davis lyrics, “Oh, Lord, it’s hard to be humble when you’re perfect in every way.” Mr. Wood goes on by saying the two best places to learn humility are on the golf course or at a favorite fishing hole. He cited a few examples of what he was referring to.

• You can be five strokes ahead in a golf tournament when that little round ball decides to take a bath in the nearest pond, play in the sand in a bunker, or hide behind a tree in the rough.
• You can be president of the United States and it still won’t matter to a striped bass or trout. President Hoover once said, “All men are equal before fish; fish make no distinction between presidents and garbage collectors.”

Paul Wood goes on to call these situations “teachable moments.” Humility is a tough row to hoe because it is natural for us to want to be recognized, admired and appreciated for the things we do. He also mentioned that Ben Franklin was quoted, “Even if I could completely overcome pride, I would probably be proud of my humility.”

The article concludes by Mr. Wood commenting on his relationship with golf. He said it if you want to know if a person is arrogant or humble; invite him to play a round of golf with you. Watch his reaction when he makes a bogey and when he makes a birdie. Does he ignore his success and talk about how he could improve his game or does he brag incessantly throughout the round? Golf will reveal his true character – and guarantee his humility.

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Being both a fisherman and golfer at one time in my life, I would agree. I could also add a few other sports because of several humbling personal experiences.

Yet, there has been nothing more humbling in my life than the progression of a non-treatable disease. The progression attacks you physically, mentally and emotionally.

• The impact on you physically is the most evident area. In the beginning there are only minor changes in your capabilities. You can always find some excuse that explains your inability to accomplish something. Over time, however, there are no more excuses and acceptance steps in.
• The progression attacks you mentally also. Most of us have played some competitive sport where you ‘played’ with an injury. You ‘gutted it out’ ... mind over matter. As you progress, however, you no longer can gut it out. When the muscles stop working, it doesn’t matter how strong your mind (determination) is.
• Finally, when it comes to emotions, the progression eats away at you almost everyday.
  • Initially, it shows itself as fear. “My God, what is happening to me?”
  • Later, it shows up as doubt. “What are we going to do if this gets any worse?” and “How long can I continue to work?”
  • Even later, resignation sneaks in. “Oh crap, I never thought it would be this bad?” and, “Will this never end?”

Where I was once self-sufficient and confident, I often find myself in need of something or someone to just get through the day. Now that is humbling!
 

Acceptance is what I am working on today.

For without it, I will never be able to take the next step forward.

Are All Stem Cells Created Equal?

The following is part two of a guest post from Ed Meyertholen.  For those who receive the KDA xPress Newsletter, you saw this article in the Fall edition.  Since the article is a little long for a blog, I broke  it up into two parts.
 

Part II: 

Are all stem cells created equal?

To begin stem cell therapy, obviously, one needs stem cells. Where do they come from? How does a researcher get them? There are, it turns out, several different sources for stem cells.

1. Embryonic Stem (ES) Cells: ES cells are the type that are the most controversial. ES cells are harvested from an early embryonic stage. They are capable of forming almost every possible cell type as these cells are the ‘authentic’ stem cells. In practice, these cells are acquired from embryos formed by in vitro fertilization (IVF). This is the same process by which infertile couples attempt to get pregnant using IVF.

The value of ES cells is that they truly can be differentiated into any cell type. In the case of KD, for example, they could be differentiated into motor neurons. These motor neurons could then be injected and hopefully, they will find the right area of the spinal cord, begin to mature and grow and make the correct neural connections to the muscle cells. In this way, they would replace the missing cells which should relieve the symptoms of KD.

2. Neural Progenitor Cells (NPC): These are a subtype of stem cells that essentially are partially differentiated into stem cells that can only become neural cells. These are found in more mature fetuses and in certain parts of adult brains. They can also be formed from ES. It is possible that these cells could be obtained from post-mortem brains or even collected from the brains of individuals undergoing neurosurgery.

It is believed that these cells can be induced to differentiate into almost any neuronal cell subtype, including motor neurons. Like ES, the NPC’s can be maintained and differentiated in a petri dish and then injected into patients.

3. Mesenchymal Stem Cells (MSC): These are stem cells isolated from bone marrow. These cells are primarily precursor cells for creating different types of bone and cartilage cells. There is evidence that it might be possible to ‘re-educate’ them to form nerve cells.

 
4. Induced Pluripotent Stem (iPS) Cells: These are cells that are  generated from adult tissues (often a cell known as a fibroblast) and are reprogramed to become stem cells. Ideally, this would be a great way to obtain stem cells, however, there are technical and safety issues that need to be worked out before this becomes a viable source of stem cells.

Great Potential, but ...

Stem cell technology has great potential especially in regard to the treatment of diseases such as KD. We are, alas, many years from the realization of this potential. There are still several major technical barriers that must be overcome before it will be a viable therapy. For example, if one forms motor neurons from either ES or NPC, these will not have been derived from the patient’s own cells, thus there is a good potential for tissue rejection. On the other hand, if the cells a derived from the patient’s own cells (as would be the case for MSC or iPC), the cells that are injected would contain the same genetic defect of the cell that has died.

Another issue is how do the injected cells know where to go? In KD, there is a loss of motor neurons in the lower parts of the brain and all along the spinal cord. One would need to inject cells into all these areas. It is not possible to simply inject the cells into the blood – they would not make it into the brain. A more complicated surgical procedure would have to be used to place the cells in the correct areas.

Even if this problem is solved, the transplanted neuron must now grow and make the physical connections to the muscle cells, not just any muscle cells, but the cells that lost their connections. Assuming that this could be done, it is estimated that the growth of the new connections would likely take a year to complete. Of course, there is also a problem of how the rest of your brain communicates with the new, transplanted cells.

Each of us has conscience control over our motor neurons and this control is mediated by neural connections from our brain. These connections must be recreated in all the transplanted cells. What I am trying to say is that while the use of stem cells, no matter what their origin, has unparalleled potential to treat diseases such as KD, the actual use of stem cells to treat neurodegenerative diseases in clinical practice is years away.

An Important Point

Let me add one more point. One can search the internet and find many sites that advertise stem cell therapy for many different disorders. Some are legitimate and, sorry to say, many are not. At the present time, there are no proven clinical procedures using stem cells that will successfully treat KD. If you see a web page claiming otherwise, you should be very suspicious. Please, talk it over with your physician before you risk your money or your life on such treatments.

What are stem cells and what good are they?

The following is a guest post from Ed Meyertholen.  For those who receive the KDA xPress Newsletter, you saw this article in the Fall edition.  Since the article is a little long for a blog, I am breaking it up into two parts.
 

Part I: 

What are stem cells and what good are they?

One does not have to go very far to find articles dealing with stem cells. A 0.1-second Google search for “stem cell” returns over 31 million hits. These hits includes not only articles describing what stem cells are but also the possible use in helping treat a myriad of different maladies, from cancer and liver disease to spinal cord injuries and ALS. Also included are over 3.7 million hits dealing with the ethical issues of using stem cells. No matter what feelings you have about stem cell research, there is no doubt that that many believe that stem cells have the potential to revolutionize medical procedures – especially for those with neurological diseases.

In this essay, I will not venture into the ethical dilemma associated with stem cells but will restrict myself to the world of science. I will try to describe what are stem cells, how might they be employed to treat KD and what is the current state of the clinical use of stem cells for the treatment of neurodisorders. Since this is a fluid field and this is being written for a lay audience, some may find my simplifications too simple as I may have omitted some information. So please beware!
 

What are stem cells and what good are they?

Stem cells are undifferentiated cells that have the potential to become almost any cell type. What does this mean? I expect that most of you know that the human body is composed of lots of individual structures called cells. It is estimated that there are between 50-100 trillion cells in a typical human. The ancestry of all of these cells in one person can be traced back to one fertilized egg. This egg cell undergoes many cycles of cell division that will ultimately produce all the cells in one’s body.

It is important to understand, however, that not all cells are the same. We have liver cells, kidney cells, brain cells and even big toe cells. While each of these different cell types originated from the same fertilized egg, the properties and functions of these cells are quite different from each other. A kidney cell cannot, for example, do the work of a nerve cell; different cell types have different structures and different proteins that are specific for their respective functions. If one was to follow the process by which an egg cell becomes a liver cell, one would discover that there are chemical mechanisms by which a nonspecific cell ‘becomes’ a liver cell. This is a highly studied area of cell biology and you can imagine a complex one as well.

This same argument can be made for any cell type in your body. The process by which a specific cell type is formed from a general cell is known as differentiation and the changed cell is said to be differentiated. Once a cell becomes differentiated (that is, once it becomes a specific cell type), it is very difficult to go back and become undifferentiated. Essentially, it is tough to teach a differentiated cell a new trick. An undifferentiated cell that has the ability to become a differentiated cell (of any type) is a stem cell.

  What makes this process more interesting and important is that some types of differentiated cells lose the ability to reproduce. Nerve cells are well known for this. In addition, for most nerve cell types (yes, there a many different types of nerve cells), there is no way in an adult to use new stem cells to make new neurons. This is because neuronal stem cells do not exist in most areas of the brain. Thus, once an adult loses a nerve cell, it is likely that there is no way to replace it and it and its function is gone for good.

In KD, for example, the key cause of symptoms is due to the death of motor neurons, a particular type of nerve cells that controls the contraction of muscle cells. There are no known mechanisms that are capable of naturally replacing a dead or missing motor neuron. Thus once it is gone, one loses the ability to use the muscle cells that it controlled and this ultimately is the cause of the symptoms suffered by KD patients.

What this all means is that in order to treat KD, one must be able to either discover a technique to keep the motor neurons from dying or to discover a process to replace those that have died. The more traditional attempts to treat KD have concentrated on the former approach. Researchers have been hunting for a ‘pill’ that will keep the motor neurons alive and well.

This was the goal of the dutasteride and leuprorelin clinical trials. To replace a dead motor neuron requires the development of new techniques by which stem cells are directed to become motor neurons, and then these new motor neurons are injected into the spinal cord. It is hoped that the new motor neuron can then be induced to make the same connections to the same muscles as did the old, dead motor neuron. As you may imagine, this is a very difficult set of procedures and it presents researchers with a formidable set of problems that they must overcome before stem cell treatment will be SOP.

Garbage In = Garbage out

From the comments and emails I received, Terry Waite’s story of anxiety and depression moved a lot of people. It reminded each of us how fragile we are ... no matter what our façade. I have written countless times about ‘being the man’ and ‘manning up’, but we still have emotions and we all handle situations differently.

Over the last few months several spouses and significant others have contacted me. They were frustrated or hurt that the recently diagnosed men in their lives wouldn’t talk about how they are feeling. Each could see that their man was not handling it well. They all wanted to help, but felt shut out and unable to ‘be there’ for the person they love. It must be a terrible feeling watching a loved one go through something a traumatic as this and yet be unable to help.

Having someone to share your feelings with is an important part of the healing and acceptance process. I use the term ‘healing’ because the news often scars us mentally and emotionally. Before we can accept our situation, we must first heal our emotional wounds. The healing process is not easy and is often a painful experience. It is even more difficult when there is no one to share your thoughts and concerns with.

So, why do we push away the person we love the most? Do we really believe we can protect them by not talking? Or, do we believe that opening up will somehow change their impression of who we are?

Whatever the reason, it is wrong. At a time like this, our loved ones need more than ever to be let into our private world. They cannot help if we don’t allow them to know what is happening and what we are thinking. And, we need to come to terms with the fact that going down this path alone will cause more harm than good.


What happens if you do not have a spouse or significant other? Then seek out a good friend or family member that you trust. You’ll know who that is.
Further, if the situation remains problematic even after sharing then seek help from a professional. That doesn’t always mean a psychologist. It could mean your doctor, pastor, rabbi, or cleric.

The idea is to change your perspective because when something  like this happens we tend to see the worst. It becomes difficult to focus on anything positive because we are feeding ourselves a bunch of ‘worst case’ scenarios. I will use an old programmers saying, “Garbage in = garbage out.” Our thoughts often become our worst enemy. And, that is why we must have someone to share your thoughts with.

The right person can help us work through our erroneous thoughts and be there for us as we move forward with out lives.
 

Enough said!

A Tale of Depression and Anxiety

Today’s article is a guest post from Terry Waite, the co-founder of the Kennedy’s Disease Association.  He wrote the article for the KDA’s fall newsletter, but I felt it needed a greater distribution because of its message.

Many of us with Kennedy’s Disease (aka Spinal Bulbar Muscular Atrophy) occasionally become a little down.  These feeling can lead to frustration and even depression if we are not careful. 

We often feel isolated.  And, we occasionally wear the mantle of guilt (not wanting to be an anchor to our loved ones).  Getting beyond those feelings is difficult.  And, there are times when no matter how hard we try, we just can’t break out of this negative thought cycle. 

Terry’s story is a powerful message and a reminder to all of us that occasionally we need to reach out for help.

Just do it!

Many of us with Kennedy’s Disease will suffer with depression and anxiety at some point as the disease progresses. I had always told myself that I could handle any feelings in my head that come along without help; I was wrong and almost DEAD wrong.

Over the past 6 months, I started on a downhill slide in my progression that seemed to have no end. About 5 months ago something very strange started happening to me. Most mornings, just as I awoke, I would be overtaken by anxiety and a deep emotional overflow that would have me in tears and I could not control it.
Along with this was the feeling that I wish I had died in my sleep. This would happen most mornings and seemed to get somewhat better as the day went on. However, at anytime during the day no matter where I was I would sometimes just breakdown into tears. I did some research online and found some interesting information.

One of the worst times for those with anxiety and/or depression is waking up in the mornings. When you come out of your sleep that is when your problems start. In the morning all the things that you have been suppressing come to the top of your awareness.

Morning anxiety is caused by debating with yourself … 

• Can I handle this?
• How am I going to get things done?
• Is this ever going to change?
• How many more days like this before something changes for the better?

I found out that in the morning you get back in touch with your subconscious mind upon awakening.

Some people with anxiety oversleep to avoid life because it is horrible. At some stage when you are asleep you become detached from all your problems and your soul merges with pure consciousness and deep silence. You take a deep rest and feel at peace. At that stage, your problems have disappeared completely. When you are asleep, you have no problems. As you are waking up, you are aware that you are coming out of peace and your worries or concerns return.

This had gotten to the point that I was avoiding going places and even trying to do things because I had already set myself up for failure before I even started. My wife Susanne suggested that I should speak with my doctor and perhaps try a medication to help uplift my mood for a while because I was no longer able to control these thoughts.

I drove to the doctor's office and spoke with him for about an hour and a half about what was going on and he suggested I try Cymbalta to see if would help. I went home and took my first dose and the next day I started to feel improvement. Each day forward, I felt better. Within 3-4 days, I was waking up without the anxiety and depressive attacks. It also changed my outlook on trying to get out and do things and quit being ruled by the “what ifs” and the “I can't's”.

I had a 50^th Birthday coming up and Susanne had been trying for the past few months to get me to pick something special to do. I looked up tandem hang gliding on the Internet because I had always wanted to do that, but I found that all of them had a requirement that I be able to run 20 steps at a fast pace. That shot down that idea but I was determined to keep looking. A friend suggested that I do a Tandem Skydive. I had always said I would like to do it, but I started to get those “what ifs” and I can't's” again but this time my mind was more balanced and I was ready for it, and I said, “YES! I will do it!” I pushed those bad thoughts aside and was not going to let them ruin my life.

A couple other friends decided to join in – the three of us were going to sky dive, while Susanne, her mother and another friend were our ‘ground crew - pit party’. We caravanned 3 hours to the Lodi Parachute Center in Central California.

The jump facility was fantastic! I explained to them about Kennedy’s Disease and they thought that it was great that I came out to do this. They assigned extra help to assist me getting up into the plane (5 guys lifted me up), ordered a larger chute for a slower/softer landing and then my tandem instructor hooked me up to his rigging while en route to our jump spot. My instructor told me that the week prior, he had a man with no legs jump with him and he had a great time as well.



I was perfectly calm (more than the other first time jumpers).  People said afterwards that they could see it in my face even seconds before the jump and I was to be the first one out of the plane. It was awesome and the landing was perfect even with my bad legs. My tandem professional jumper held my legs up and used his to plant the soft landing.

I am sharing a very personal story of mine because I know that many of you that will read this can relate. Some of you may be a little too close and if this story helps just one of you, I will be happy. If you feel the way I felt, see your doctor about the possibility of some extra help (even if just temporary) with perhaps some medication.

My next adventure is to find a place where I can do a tandem hang glide where there is enough updraft that I do not need to run to launch. I know they are out there because I have seen videos of it.

Therefore, for those of you who have stopped enjoying life because you are stopping your dreams before you even give them a try …

JUST DO IT

... or at least try. We can still do many things!

What is the Placebo Effect?

The following is another guest post from Ed Meyertholen.  I have written of the placebo effect a few times in my articles, but Ed has done a fine job of explaining how it happens and why it is important for researchers to be able to isolate it from their trials.  This article was also included in the fall KDA xPress newsletter.


Even though it is a little long for a blog post, I could not find a good place to break it into two parts. 

What is the Placebo Effect?

One of the difficult things in setting up any clinical trial for KD is determining what factors should be measured to assess the effectiveness of the treatment. This seems like a no-brainer – but to a researcher it is critical to the success of the study.

For those of you who were in the dutasteride clinical trial, you surely remember that different types of measurements were employed to assess the progression of the disease. The researchers were not sure what measurements were best and so hedged their bets by employing a myriad of different functional tests. Most of the tests dealt with objective measurements of muscle function (strength, for example, or how far one could walk in 2 minutes), but they also used some subjective tests, tests that tried to measure the quality of life. These latter tests were essentially questionnaires surveying how the patients felt about their physical condition and how well they felt they coped with the problems of KD.

An Actual Example

Dr. Gen Sobue’s research group just published a paper in which the compared two groups of patients with Kennedy’s Disease. This was not a report from a new clinical trial and it really offers no new insights on how to treat KD. Despite this apparent lack of relevance, I found the paper to be quite compelling. The data reported compared the rate of progression of KD in two groups of individuals, a group of men with KD that served as a placebo control in Dr. Sobue’s previous study of the effect of leuprorelin on the progression of KD (we will label these PG) and a second group of men with KD who were not part of any clinical trial, we will label them NTG.

So that it is clear, the PG group took a pill that had no therapeutic value for KD – simply, it was a sugar pill. However, they thought it was leuprorelin, a substance they were told would reduce the progression of their symptoms of KD. Since neither of these two groups received any real medicine, we would expect these two groups to show a similar disease progression over the time period of the study, 48 weeks. We will see that this is not exactly what happened.

In Dr. Sobue’s paper that served as the catalyst for this article, the progression of the patients’ KD symptoms was also measured by both objective and subjective tests. Specifically, they compared how certain clinical ‘outcomes’ from these two groups changed in a span of 48 weeks. One of the tests they performed was the distance that a patient could walk in 6 minutes – a measurement known as the 6 min walk distance (6MWD). They found that this distance decreased in both groups at about the same rate. This is not surprising as both groups had KD and were essentially untreated groups.

They also measured something known as the ALSFRS-R. This is a self-assessment questionnaire (thus subjective) that attempts to measures how a patient feels they perform normal activities. The patient would be asked, for example, how are you doing at walking (or climbing stairs or swallowing). The patient then scores their answer on a 5 point scale, the higher the number, the better they felt they were doing. The researchers found that the ALSFRS-R scores fell for both groups, but it fell significantly more slowly for the PG than it did for the NTG. So essentially, the PG, who thought they were receiving a drug that would lessen their symptoms, reported that they could function better than the NTG, the group that did not take any drug or treatment and had no preconceived expectations. This was despite the fact that both groups received nothing that would actually help them! Remember, there were no differences in an objective measurement (the 6MWD).  Apparently, the idea that they expected to be helped by a drug was enough to make them feel that they were being helped.

Now this result is not groundbreaking research but I do think that it does have an important lesson for those of us with KD as well as those who are trying to cure KD. The results published by Sobue suggest that we need to be cautious when interpreting the results of a subjective test. The biases of the patients and the researchers can come into play in the form of a placebo effect.

Sobue defined the placebo effect as “the improvement resulting from psycho physiological effects such as a positive expectation for a new treatment by patients and raters or a subconscious desire to meet the attending doctor’s expectations.” In other words, the patients feel like they are getting better because they want to get better and not because they are getting better. It is common, I think, for people to underestimate the power of the placebo effect – it is real!

The Power of the Placebo Effect

As patients who have a disease that has no treatments, we need to be aware of the power of the placebo effect when we hear of possible therapies, especially if they are not from a reliable source. Let me give an example. Until recently, a company in Germany (they were able to do this in Germany due to a legal loop hole, no other EU country, not the US or Canada would let them do what amounted to experimental surgery) advertised a safe and effective treatment for KD (as well as a host of many other neurological diseases) using stem cells.

At this time, this is no effective standard stem cell therapy for KD or the other diseases they claimed to cure. The website for this company referenced patient surveys to indicate efficacy of their treatment – I had not seen any reference to any objective data and they have not published any clinical trials. To no one’s surprise, they claim that something like 50% of the patients reported that they thought that the stem cells made them better.

Now if you think of these results in light of the Sobue paper, we have a group of individuals who desperately want to get better, so much that they spent tens of thousands of dollars to go to Germany and get this ‘treatment’. Just as in the PG group described above, this group felt like they were getting better when you asked them. But did they really get better? We cannot know for sure as there were no objective tests employed to verify that the disease progression had really been slowed.

Using patients from a similar clinic in China, a group of researchers did find that despite the reports from patients that they were better, objective criteria showed this was not the case. The stem cell treatment was not effective. This appears to be a classic case of the placebo effect. As an aside, the company in Germany has been closed by the German government after at least one patient died due to the stem cell treatment.

The ‘take home’ message from this is that we have to be alert and be able to differentiate viable treatments from scams and hearsay. Before embarking on any exotic treatment, look for objective evidence that it really works and always make such decisions in concert with your doctor.

Eight Month Update on Dutasteride

It has been another good month. My ‘every-other-day’ exercise program averaged 112 minutes. My short program (the light days) averaged 18 minutes. I find myself having to cut back on the number of reps I am doing because they have become so easy that I could go on for another 20-30 minutes without a problem. I am sure muscle memory plays a part in this factor.

I keep on wondering if this is the placebo effect, but the longer I feel this way the more I tend to discount it because it has lasted eight months.

I continue to keep my dutasteride journal and hope to review it with my doctor in December. He is most interested in how things are going.

When I woke up last Thursday morning I noticed a weakness (more than normal) in my right arm. All day the weakness was evident. Fortunately, when I woke up Friday morning the arm was back to normal. Also, I noticed during my long exercise routine that the right arm was actually stronger than normal. Go figure!

The neck weakness I wrote about back in May has not reappeared. The week of the weakness had me concerned, but fortunately it was just another Kennedy’s Disease anomaly.
And, still no apparent side effects.


Fall is in the air and my next challenge will be how I hold up this winter. The cold is tough on me ... especially my four walks a day with Fred, my beagle. I already have the ‘hand warmers’ out because morning temperatures will be in the high 30s by Wednesday. I’ll take it “one day at a time” and hope that things continue to go well.

KDA Awards $65,000 in Research Grants

 
Thanks to the generosity of its supporters, the Board of Directors of the Kennedy’s Disease Association announced today that they awarded three research grants.  The three recipients and a brief explanation of their research are shown below.

_________________________________

1.  Masahisa Katsuno, M.D. – Ph.D.,  Department of Neurology, Nagoya University Graduate School of Medicine


Amount Awarded:  $25,000


Proposal:  Elucidation of neuronal death signaling pathways and development of disease-modifying therapies for Kennedy’s disease

Brief Explanation: Their lab has evidence that the synthesis of two proteins are affected by the defective androgen receptor in KD. They wish to determine if neuronal cell death is caused by the alteration in the levels of these proteins and if cell death can be prevented by the addition of drugs that target the activity of these proteins.


2.  Elise Kikis, Ph. D., Northwestern University

Amount Awarded:  $20,000 


Proposal:  Modeling SBMA: from understanding proteotoxicity to identifying therapeutics


Brief Explanation: They believe that the specific cell death is due to the
accumulation of misfolded proteins (the androgen receptor) and the inability of cells to handle this accumulation. They propose to use a new model organism (a little worm called C. elegans – a very common and important model system in biology) to examine how different cell types handle the misfolded proteins and genetically look for other proteins that may help the cell get rid of the messed up proteins.


3.  Sara Parodi, Ph.D., Department of Neuroscience and Brain Technologies, Genoa, Italy

Amount Awarded:  $20,000 


Proposal:  Identification of PKA signaling as a new therapeutic approach for SBMA


Brief Explanation:  There is evidence that the cell death may involve changes to the androgen receptor (specifically changes in which phosphate is added to the protein, a process called phosphorylation). They hope to determine whether this cell death can be stopped due to the activation of another protein, known as PKA.

Good News for the Rare Disease Community

This morning I received a news release from NORD.  This is good news for those of us living with Kennedy’s Disease.  When a treatment is discovered, we would hate to see something that works tied up in ‘red-tape’ (a long approval process).

The last two paragraphs of this news release summarize the findings and reason for the study.

  

LANDMARK NORD STUDY CONCLUDES FDA IS FLEXIBLE IN REVIEWING THERAPIES FOR RARE DISEASES

Study Catalogues Flexibility in Orphan Drugs Approved Since 1983

Washington DC, October 11, 2011 - “The National Organization for Rare Disorders (NORD) today released a landmark report documenting flexibility in the Food and Drug Administration (FDA) review of potential treatments for patients with rare diseases.

Released at the U.S. Conference on Rare Diseases and Orphan Products, the report examined the basis for FDA’s approval of 135 non-cancer “orphan drugs” … those for rare diseases since the Orphan Drug Act was enacted in 1983 to provide incentives to encourage development of treatments for rare diseases.
This is the first study of its kind ever conducted and the first time that there has been a systematic

examination of the basis for approval for any category of drug products extending over such a long period of time.  The study demonstrates a decades-long pattern of flexibility in FDA review of orphan drugs.

Frank J. Sasinowski, chairman of the NORD board of directors and author of the report, said: “We wanted to determine whether FDA requires that orphan drug applications provide the conventional effectiveness data that are ordinarily expected for most drugs for more prevalent diseases, or whether the agency has over the years exercised flexibility in approving drugs for patients with rare diseases.  This issue is critical to the patients and families NORD serves because the patient population available for testing of orphan drugs is, by definition, more limited than for drugs for more prevalent diseases.”

NORD President and CEO Peter L. Saltonstall said: “We are gratified that this extensive study, spearheaded by NORD on behalf of the entire rare disease community, found that there is supportable evidence to document flexibility by FDA medical reviewers.  This study should provide an extra level of confidence for investigators, companies and investors who are considering developing new drugs for rare diseases.”

While any disease affecting fewer than 200,000 Americans is defined by law as “rare,” many rare diseases affect only a few hundred or a few dozen people.  Conducting the clinical studies required to develop treatments for these diseases poses special challenges to medical researchers, the report pointed out.

The NORD study looked at all drugs for diseases other than cancer approved as orphans since 1983 to identify when flexibility was employed in the review process.  The evaluation process distinguishes between flexibility applied as a result of a previously described FDA system, such as the accelerated approval program, or on a case-by-case basis.

For each of the non-cancer drugs approved as orphans since 1983, NORD sought to access the FDA approval letter, the labeling at the time of approval, the decision memoranda of the FDA officials who approved the products, and the reviews of the medical and statistical officers.  While such documents were retrievable in most cases, only subsets of those documents were recoverable for some drugs, especially for some of the earliest approved orphan therapies.

The drugs were then divided into three categories: those that, in NORD’s judgment, would have met the traditional data requirements for effectiveness; those whose approval was based on flexibility applied as a result of some documented FDA system for flexibility; and those whose approval appeared to reflect case-by-case flexibility.

Of the 135 drug approvals studied, NORD concluded that 45 would have met traditional data requirements, 32 reflected “administrative flexibility” based on a previously documented FDA system, and 58 reflected flexibility applied on a case-by-case basis.

“This review of FDA actions concludes that two of every three orphan drugs approved show FDA’s historic flexibility in its review of effectiveness data on orphan drug therapies, ” Sasinowski said.  “Therefore, FDA has demonstrated in its actions on orphan products that it recognizes the importance of therapies for persons with rare disorders.  It would be helpful for such flexibility and importance to be recognized in a formal FDA policy, and for FDA officials to incorporate and recognize that flexibility in a systematic way in their evaluations of each new therapy in development and under FDA review for Americans with any rare disease.”

Saltonstall added that NORD undertook this study because, of the nearly 7,000 known rare diseases, only about 200 have FDA-approved treatments. “Better understanding the regulatory process and the pathways most likely to lead to increased study of rare diseases and safe, effective treatments for patients is very important to us,” he said.

An All-Terrain Wheelchair – Alright!

I have been an outdoors person (a nature lover) since I was a kid. Hiking in the woods or mountains were my favorite pastimes. I miss not being able to just go without thinking about capabilities, getting stuck, or worrying about the weather.

Well, Mike Goynes called me yesterday to discuss the ultimate ‘power’ wheelchair. He found it online and wanted to share his ‘dream-chair’. There is an old saying, “The only difference between men and boys is the cost of their toys.” This chair proves it is true!

It is the Viking 4x4 All Terrain Wheelchair. The six videos of what this baby can do are amazing. I not saying that I would want to try everything they demonstrated, but it is something else to watch.

This bad-boy appears to handle it all without much trouble. It has four-wheel drive and over 4” of ground clearance that allows it to climb stairs or curbs, go up and down steep hills (up to 36 degrees) and comfortably cross beaches of loose sand or mud while still turning on a dime, if necessary. And, after watching the videos I can also see why you might want the four-point seatbelt option.

Even more fascinating is the seating system. “The Viking 4 X 4 has an automatic digitally programmed vertical seating system that maintains a vertical position at all times. Weather climbing a hill or going down a hill the driver will always be able to maintain a vertical position.”

The chair even comes has two sets of tires available (standard and ‘all-terrain’). Even with all these capabilities, it can still travel at 4 mph and run for up to 19 miles without needing a charge.

I had no idea how much this baby would cost ... $15-20,000 was my best guess. I was shocked to see a sticker price of <$10,000 with free shipping. There is even a promotional coupon that takes another $800 off the price.

Yup, that is still a lot of money, but boy would it be fun. 
A man’s gotta dream, right!

Acceptance is an on-going process

I read a good article the other day in the “Balance in Me” blog on Natural Spirituality. Ms. Goers provided several practical steps to help uncover your natural spirituality. While reading the article I realized that several of her points were very appropriate for those of use learning to live (accept) Kennedy’s Disease.

1. Stop being in control: “... you need to let go of several beliefs, and the myth of control is the first one to go.” If you are anything like me, having confidence in your abilities was important. I was good at many things and trusted that I could learn what I did not know. As my disease progressed, however, the confidence in my body’s ability to hold me upright or perform certain normal tasks eroded. Too often my body has let me down. Since there is little I can do about it and because it is going to get worse, letting go (stop trying to be in control) becomes an important part of the acceptance process.

2. Spend more time in nature: “Open up your eyes to this world right now and stop spending so much time behind the screen of your computer or your smart phone.” This always works for me. I spend about two hours every day outdoors. Nature never seems boring. There is always something happening with birds, animals, insects as well as the flora. By just sitting, listening and watching another world unfold right in front of me helps  to take my mind off most of the negativity associated with Kennedy’s Disease.

Miracles exist. They happen every day in our world. Just being an observer makes me a participant in these miracles. Just being an observer causes my mind to refocus itself on the beauty and magnificence of the world I live in.

3. Keep asking yourself, “What is the meaning of all this?”: The “why me” and “this can’t be happening to me” questions have to end at some point. By asking “what is the meaning of this” regularly, I am forced to come to terms with my inability to control many things in my life including some health issues. I did not cause this to happen. I am not to blame nor is anyone else. It just happened. Once I believe that, I need to ask some other personal questions:

• What can I learn from this situation?
• How can I make it better for everyone involved (family, friends, etc.)?
• How does this change me and my situation?

4. Start enjoying life ...: “Your life is not just about you, it is also about people around you. We are all connected in one way or another and our actions and words can influence the lives of people around us. Start living for others the same as you live for yourself by being generous and grateful.” Getting beyond the grieving, fear and anger is important. Until I do, it is almost impossible to enjoy life (this beautiful world that I live in). Once I can begin living again, I can become a more ‘beneficial presence’ in my world.

 

One more important point

Being that we are learning to live with a progressive disorder, the “one and done” solution no longer applies.

Acceptance is an ongoing process. Accepting that we have the disease is one thing. However, learning to live with the disease as it progresses becomes a challenge.  The steps above will help us “live” a life that is both loving and beneficial.

Rules to Live By

This weekend my wife showed me an article in the Chattanooga Sunday paper titled, “Four Rules for Living” by Dr. Nell Mohney. She interviewed a fifty year old woman with multiple sclerosis (MS) in 1999 who had been introduced to her by a friend. Zoe Koplowitz had lived a normal life until she was diagnosed with MS at the age of 25. Multiple Sclerosis is a chronic, progressive and disabling disease of the central nervous system that eventually leads to paralysis and blindness.

When Dr. Mohney interviewed her, Zoe had just finished her eleventh New York City Marathon, finishing the 26 miles in 30 hours.  Can you imagine … 30 straight hours?  That is amazing.

Ms. Koplowitz went through some of the same shock, why me and denial that most of us do when something like this happens. Over time, however, she accepted her situation and developed four rules to live by. As a result of her marathons, she wrote “Winning Spirit – Life’s Lessons Learned in Last Place.”
 
Zoe Koplowitz’s Four Rules to Live By:

1. If you don’t like what you see, change the channel. She believes God gives each of us a TV set with 100 channels. Only one channel has static ... reflecting on our disease, problems and difficulties. You can sit in front of the one channel with static, or you can change the channel. (It is your choice and she obviously changed the channel)

2. Have a mission or purpose in life. Zoe’s mission is to help children trapped in inner-city ghettos to develop confidence and self-esteem. She accomplishes this by visiting inner-city schools with other disabled athletes and telling them what it means to win. She also leads Marathon Strides for MS to raise funds for research.

3. Decide to be a winner. You can either pursue your dreams or fall by the wayside. The choice is yours.

4. Live your life with courage, faith and laughter.

Dr. Mohney said that there is no doubt Zoe Koplowitz lives by these rules. After a ten minute conversation with her, you will be motivated to change the channel if you are still on the station with static.

Learning to live with any disease is difficult.  However, we are all born with free-will … the ability to choose how we will respond to adversity and what our purpose in life will be. 

After reading the article I came up with four questions that I need to ask myself regularly.

• Will I recognize that the only disability in life is a bad attitude?
• Will I be a beneficial presence in this world? 
• Will I inspire others by my words and actions? 
• Will I look for opportunities to help another person or creature today?

The choice is mine to make.

Testosterone Treatment Fails to Accelerate Disease

Ed Meyertholen came across this research paper on Kennedy’s Disease and  the effect of testosterone on the disease.  Previously it was assumed that since testosterone appears to be the instigator of the onset of Kennedy’s Disease as well as the failure of a testosterone trial in 1999, that testosterone injections would be more harmful. 

This research report indicates that there appears to be no harm to mouse models when given additional testosterone.  As Ed indicated in his email to me, however, this testing was done on mice and not on humans. 

Testosterone Treatment Fails to Accelerate Disease in Mouse Models

  Doctors Erica S. Chevalier-Larsen and Diane E. Merry reported in Disease Models & Mechanisms:


Transgenic AR112Q and non-transgenic mice were implanted with timed-release pellets designed to deliver 4-6 ng/ml of testosterone for 90 days. Over the course of the experiment, implantation of testosterone pellets increased circulating testosterone an average of threefold, from 0.40±0.23 ng/ml; this is a significant elevation of testosterone levels in treated animals over those implanted with placebo pellets. Although 90-day testosterone pellets were used, we observed a decline in potency of the pellets by the end of the 90-day period (months three and six).


Implantation of new pellets at the end of 90 days restored circulating testosterone levels. Although circulating testosterone was elevated in treated mice, motor function assays did not reveal any effect of testosterone treatment on phenotype. Motor function assays were performed monthly for 6 months; results were consistent for all 6 months of treatment. Beginning at 3 months of age (1 month following treatment), AR112Q males showed decreased rotarod performance, regardless of T-treatment, when compared with non-transgenic T-treated males.


The entire report can be read by following this link to download the paper:  Research Report (PDF)