UCL KD Research Newsletter

Below is the first newsletter from the UCL Kennedy's Disease Research Center. Many thanks to all who provide support as well as search for a treatment and a cure.

FYI - Kennedy’s Disease Clinic

This clinic is linked to the National Register for Kennedy’s Disease and is aimed at providing a central referring point for all patients in the UK. Kennedy’s disease (also known as Spinal Bulbar Muscular Atrophy) is a rare disorder and the Clinic will offer the multi-disciplinary approach available for MND and also provide screening for a number of non-neurological conditions that may associate with Kennedy’s Disease.

Coordinator for this clinic is Jan Clarke (jan.clarke1@nhs.net - Telephone: 020 3448 3517); general enquiries Marcia Forde (marcia.forde@nhs.net - Telephone: 020 3448 8251 - Fax: 020 3448 3633).

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UCL KD Research Newsletter

Hi and welcome to the inaugural research newsletter from the !

We always enjoy letting you know about exciting developments in KD research and care, and a few members of the KD community have asked to know more about the research happening at UCL, Oxford and further afield – so here we are!

We’re planning to update you with research news four times a year. We would really love to hear your feedback on what you like and what doesn’t work so well, so that we can improve what we are sending you. We really want it to be the most useful and interesting for you that it can be. Please do let us know at sbma@ucl.ac.uk.

KD Clinic

It has been wonderful to see so many faces coming through the KD clinic.

From the medical side we have a new consultant, Dr Carlo Rinaldi, who has many years’ experience in KD. Carlo runs a research group at Oxford University studying ways to develop new treatments for KD. Dr Helen Devine, a registrar, has returned from maternity leave and is joining the clinic alongside her PhD using stem cells to study KD.

KD research

There is plenty of ongoing research linked to the clinic, both in UCL and in Oxford. In some cases people with KD have been directly involved, for example: undergoing muscle MRI scans, or donating blood or skin samples that are currently being analysed in the lab. There are also numerous ongoing studies that use disease models to better understand KD and to find ways of changing its course.

We will include updates of these projects in upcoming newsletters.

Results from Japan using testosterone-lowering drug

Many of you have asked us about the results from a clinical trial recently published by colleagues in Japan.

Background: Our bodies naturally produce testosterone. In people with KD, this testosterone binds to faulty androgen receptors – and that causes damage to the nerves and muscles. Gen Sobue’s KD lab in Japan wanted to see if less testosterone would mean less activity of the androgen receptor – and therefore less damage. There is already a drug called Leuroprelin that makes men produce less testosterone. A team lead by the scientist Atsushi Hashizume ran a long-term trial giving Leuroprelin to some people with KD in order to reduce the levels of testosterone in their bodies, to see if they stayed healthier than others who were not given the drug. The scientists chose people who were similar in terms of age, length of disease and CAG repeat length. The first results were published in 2009 and actually showed that there was no clear benefit to people with KD after 18m of treatment.

Results from this study: Treatment was continued with Leuroprelin after the original study end and now the effect of the drug after up to 11.5 years in the longest-term patients has been published. Encouragingly, the researchers found that, over the observed time period, the people who were given Leuroprelin were less likely to develop pneumonia requiring hospitalisation, and they had a slower progression of disease.

Our view: The positive finding of this study is that reducing the action of testosterone can impact on the disease course of KD. On the cautionary side, however, the benefits are modest, and the drug, when taken chronically, has some side-effects.

In summary, although Leuprorelin may not prove to be clearly beneficial for people with KD, these results show that modifying testosterone can have an impact on disease, which brings optimism for future drug therapies.

Symptom management

We thought it would be useful to hear how you deal with KD’s most common and troublesome symptoms to create a resource for all of us to share, review and access.

So our first question is: what are the best strategies you have found to manage laryngospasm?  If you wish to contribute please e-mail Luca at: luca.zampedri@nhs.net

Best wishes,
Pietro, Carlo, Mike, Linda, Helen, Jan and Luca.

New Treatment for SBMA Approved in Japan

Since the initial announcement in mid-August, there has been a lot of buzz about this treatment. Mike Wilson posted the following translation on the KD-Downunder Facebook page. The comments posted from others living with KD is interesting.

The article he is referring to can be found at http://www.takeda.co.jp/news/2017/20170828_7818.html  When this trial was first introduced back in 2010, I posted an article on it. You can read it here. This month I posted the announcement about the long-term trial results. It can be found here.  

Interesting news - A new treatment for SBMA just approved in Japan:

Leuplin SR® Injection Kit 11.25 mg in Japan

About supplemental approval of indication of "suppression of progression of spinal and bulbar muscular atrophy"

We are pleased to announce that "Spinal and Bulbar Muscular (Spinal and Bulbar Muscular Disease)" from the Ministry of Health, Labor and Welfare for "Leuprin® SR Injection Kit 11.25 mg" (generic name: leuprorelin acetate, We are pleased to announce that we have received additional indication of the suppression of the progression of "Atrophy: SBMA").

Leuplin SR is a 12-week sustained-release sustained-release preparation of highly active LH-RH agonist (luteinizing hormone-releasing hormone derivative) synthesized by Sumitomo Chemical, which acts continuously on the pituitary gland, It inhibits the production of sex hormones by reducing reactivity. This drug is used as a therapeutic agent for hormone dependent diseases such as prostate cancer and premenopausal breast cancer in Japan.

The acquisition of additional indication for the indication was mainly evaluated based on the results of doctor-initiated trials that examined the effectiveness and safety of Leuplin SR for patients with SBMA, centering on Nagoya University neurology department. It is world's first approval as a therapeutic agent for the progression of SBMA.

Toshiro Taniya, director of the Company's Japan Development Center, said, "To date, no effective treatment for SBMA has been established domestically and internationally, and drugs that could contribute to the treatment of this disease were sought. , It will become the world's first medicine to be useful in treating patients of SBMA.We appreciate the patients and doctors who cooperated in developing this drug, and for the patient and medical staff We will strive to deliver medicines for diseases with high unmet medical needs. "

About indications / effects, dosage and dosage approved this time

Indications and effects: inhibition of progression of spinal and bulbar muscular atrophy

Dosage / administration: Usually, adults receive 11.25 mg subcutaneously as Leuprorelin acetate once every 12 weeks.

Upon administration, push the plunger rod with the injection needle facing upward, move the whole amount of the suspension liquid to the powder part, and carefully suspend and use it while taking care not to foam.

About SBMA

SBMA is characterized by muscle atrophy and is an X-linked lower motor neuron disease that develops in adult male. Due to abnormal accumulation of mutant androgen receptor (AR) with polyglutamine in the nucleus, an androgen hormone dependent neuronal damage occurs. It usually develops around 30 to 60 years old, it follows a slow progressive course, not only forced to live in bed chair or bedridden life at the end of the year, but also repeats aspiration pneumonia. In Japan, it is stipulated as a designated intractable disease, and it is reported that the number of persons with specific medical care recipient 's passengers is 1,223 (Research on Specific Diseases by Ministry of Health, Labor and Welfare in FY2006).

Long-term treatment with leuprorelin for spinal bulbar muscular atrophy

A gentleman living with Kennedy's Disease sent me the following email. I remember the initial trial years ago, but I wasn't aware researchers continued it. The link for the actual study is at the bottom of his message. I forwarded this to Dr. Fischbeck to see if he has any thoughts on the study.

In a conversation for Dr. Fischbeck several years ago, he mentioned the difficulty of measuring results in short term clinical studies because SBMA progresses slowly. This study is 84-months long and I assume is easier to quantify the results.


Long-term treatment with leuprorelin for spinal and bulbar muscular atrophy: natural history-controlled study
"Recently they published a new, interesting study about long term therapy of SBMA. It is an old candidate: leuprorelin. As you may know, there were two previous (phase 2 and 3) trials with leuprorelin, done in Japan, the second one is the JASMITT study. After continuing the treatment of 36 patients from the previous studies, the same researcher group have now new data with leuprorelin.

1. They have data from 84-months follow-up, with hard endpoints. 
2. They showed significant difference in several functional scores, compared to no-drug controll. 
3. Maybe most importantly, there was a significant difference in the event-free survival (death or pneumonia). The similar trend was in the risk of death, however it was not significant, they suppose because of the low statistical power (i.e. number of patients) of the study, and the slow progression of the SBMA. However, pneumonia is a very important event in SBMA since aspiration is one of the biggest, deadly threat in this disease. 
4. The final conclusion from the article: "In conclusion, this study showed that the continuous administration of leuprorelin acetate appears to slow the progression of motor deficits in subjects with SBMA. In addition, pneumonia-free survival in SBMA would be extended by long-term treatment with leuprorelin acetate, suggesting disease-modifying effects of androgen deprivation by leuprorelin acetate."

As far as I know, it is one of the longest, controlled trial in patients with SBMA. I think we may reconsider the therapeutic possibilities of antiandrogens, and I guess we will hear about in the near future. It would be nice to know Dr. Fischbeck's comments.

It is important to keep in mind that everyone have to talk his physician first.

Here is the abstract of the article: http://jnnp.bmj.com/content/early/2017/08/05/jnnp-2017-316015 , unfortunately the full-text version is not free-access."
Note:  The original post on the trial can be found here:  Leuprorelin

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.

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.