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).

Airway Obstruction after Robot-Assisted Laparoscopic Prostatectomy

This PubMed article was forwarded to me from another man with Kennedy's Disease. Read the entire article by following the title link.

It once again reiterates the need for extra caution when preparing for surgery. Discussions with the surgeon and the anesthesiologist are warranted.


Previously Undiagnosed Spinal and Bulbar Muscular Atrophy as a Cause of Airway Obstruction after Robot-Assisted Laparoscopic Prostatectomy

"... CONCLUSIONS: Vocal cord paralysis combined with postoperative laryngeal edema, the cause of which was presumed to be SBMA, likely caused airway obstruction after RALP. As neuromuscular symptoms progress gradually in patients with SBMA, muscle relaxants should be used carefully, even if patients with SBMA present no immobility of their extremities."

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

Muscle Tissue Changes with Aging

I caught a comment last night while watching TV that was interesting. The body loses an average of 5% of its muscle tissue with each decade after 30. It made me realize the double jeopardy those of us living with a progressive muscular disorder face.

I turned 70 this year. Over the last several years, I noticed my muscle mass appeared to decline more rapidly. Initially, I concluded this was more a perception and not reality. After reading this study, I now believe it is true. Interesting.

Today I did a little research and came across the following NIH study. Follow the link in the title to read the entire article.

__________________________

Muscle Tissue Changes With Aging

“Purpose of review
This review article focuses on the changes that occur in muscle with age, specifically the involuntary loss of muscle mass, strength and function, termed sarcopenia. Particular emphasis is given to the metabolic alterations that characterize sarcopenia, and to the potentially treatable causes of this condition, including age-related endocrine and nutritional changes, and inactivity.

Introduction

One of the most striking effects of age is the involuntary loss of muscle mass, strength, and function, termed sarcopenia. Muscle mass decreases approximately 3–8% per decade after the age of 30 and this rate of decline is even higher after the age of 60. This involuntary loss of muscle mass, strength, and function is a fundamental cause of and contributor to disability in older people. This is because sarcopenia increases the risks of falls and vulnerability to injury and, consequently, can lead to functional dependence and disability. A decrease in muscle mass is also accompanied by a progressive increase in fat mass and consequently changes in body composition, and is associated with an increased incidence of insulin resistance in the elderly. Furthermore, bone density decreases, joint stiffness increases, and there is a small reduction in stature (kyphosis). All these changes have probable implications for several conditions, including type 2 diabetes, obesity, heart disease, and osteoporosis.

Recent findings
Recent data reported include those regarding the potential role of insulin resistance in the development of sarcopenia, the potential role of androgens and growth hormone in the treatment of this condition, the usefulness of exercise including both resistance and aerobic training to improve muscle growth and function, and, finally, the possible use of nutritional manipulations to improve muscle mass.

Summary

Sarcopenia is likely a multifactorial condition that impairs physical function and predisposes to disability. It may be prevented or treated with lifestyle interventions and pharmacological treatment. Further long-term investigations are needed, however, to ascertain what type and combinations of interventions are the most efficacious in improving muscle mass and function in older people. …”

Image:  myheart.net

CRISPR - Gene Editing Explained

A man living with Kennedy's Disease posted this on Facebook. The short YouTube video (link below) does a good job of explaining what CRISPR is, how it works, and its potential. Those of us living with KD are very interested in the potential tools like CRISPR offer for future generations.

Biologist Explains One Concept in 5 Levels of Difficulty - CRISPR

Video published May 24, 2017

CRISPR is a new area of biomedical science that enables gene editing and could be the key to eventually curing diseases like autism or cancer. WIRED has challenged biologist Neville Sanjana to explain this concept to 5 different people; a 7 year-old, a 14 year-old, a college student, a grad student and a CRISPR expert.

Gene Editing Followup

A followup article in the New York Times by Pam Belluck dismisses some of the fears people have regarding Gene Editing. Since Huntington’s Disease is mentioned, that is a good sign for those of us with families living with Kennedy’s Disease. To read the entire article, follow the title link.

Gene Editing for ‘Designer Babies’? Highly Unlikely, Scientists Say

 “Now that science is a big step closer to being able to fiddle with the genes of a human embryo, is it time to panic? Could embryo editing spiral out of control, allowing parents to custom-order a baby with Lin-Manuel Miranda’s imagination or Usain Bolt’s speed?

News that an international team of scientists in Oregon had successfully modified the DNA of human embryos has renewed apprehensions that babies will one day be “designed.” But there are good reasons to think that these fears are closer to science fiction than they are to science.

Here is what the researchers did: repair a single gene mutation on a single gene, a defect known to cause — by its lonesome — a serious, sometimes fatal, heart disease. …”

“ … So are most physical diseases and psychiatric disorders. The genetic message is not carried in a 140-character tweet — it resembles a shelf full of books with chapters, subsections and footnotes.

So embryonic editing is unlikely to prevent most medical problems.

But about 10,000 medical conditions are linked to specific mutations, including Huntington’s disease, cancers caused by BRCA genes, Tay-Sachs disease, cystic fibrosis, sickle cell anemia, and some cases of early-onset Alzheimer’s. Repairing the responsible mutations in theory could eradicate these diseases from the so-called germline, the genetic material passed from one generation to the next. No future family members would inherit them.

But testing editing approaches on each mutation will require scientists to find the right genetic signpost, often an RNA molecule, to guide the gene-snipping tool.

In the study reported this week, it took 10 tries to find the right RNA, said Juan Carlos Izpisua Belmonte, a co-author and geneticist at the Salk Institute.

Dr. Greely noted that while scientists work to get human embryonic editing ready for clinical trials (currently illegal in the United States and many countries), alternate medical treatments for these diseases might be developed. They may be simpler and cheaper. …”

Photo:  https://rhapsodyinwords.com/2017/01/

The Last - I can only hope

A picture above my desk called, “The Last,” has a dual meaning for me. First off, I love the lithograph because it is so well done. To me it reflects the dying off of the American Indian culture. The second meaning is much more personal. I hope and pray I am the last male in my mother’s family with Kennedy’s Disease.

A NewYork Times article written by Pam Belluck reports on a recent study and potential milestone in genetic engineering. Nature,the International Weekly Journal of Science published the study this week. A portion of the article is shown below. Follow the links above to read the entire article and the study.

In Breakthrough, Scientists Edit a Dangerous Mutation From Genes in Human Embryos

“”Scientists for the first time have successfully edited genes in human embryos to repair a common and serious disease-causing mutation, producing apparently healthy embryos, according to a study published on Wednesday.

The research marks a major milestone and, while a long way from clinical use, it raises the prospect that gene editing may one day protect babies from a variety of hereditary conditions.

But the achievement is also an example of human genetic engineering, once feared and unthinkable, and is sure to renew ethical concerns that some might try to design babies with certain traits, like greater intelligence or athleticism.

Scientists have long feared the unforeseen medical consequences of making inherited changes to human DNA. The cultural implications may be just as disturbing: Some experts have warned that unregulated genetic engineering may lead to a new form of eugenics, in which people with means pay to have children with enhanced traits even as those with disabilities are devalued. …”

“… Scientists at Oregon Health and Science University, with colleagues in California, China and South Korea, reported that they repaired dozens of embryos, fixing a mutation that causes a common heart condition that can lead to sudden death later in life.

If embryos with the repaired mutation were allowed to develop into babies, they would not only be disease-free but also would not transmit the disease to descendants.

The researchers averted two important safety problems: They produced embryos in which all cells — not just some — were mutation-free, and they avoided creating unwanted extra mutations.

“It feels a bit like a ‘one small step for (hu)mans, one giant leap for (hu)mankind’ moment,” Jennifer Doudna, a biochemist who helped discover the gene-editing method used, called CRISPR-Cas9, said in an email. …”

"Desistance" is my current story I am in the final stages of editing. It is a Sci-Fi that takes place sixty years in the future. One of the storylines is the development of almost super-humans whose DNA has been edited to remove most of the known diseases. Perhaps it won’t be Sci-Fi after all.