Wednesday, September 11, 2019

Friday, September 6, 2019

MDA announces new research grants

Cision published a list of the newest MDA grant recipients today. Click on the link below to read the entire article.

Muscular Dystrophy Association Awards 25 Grants Totaling More Than $6.6 Million for Neuromuscular Disease Research

Critical funding provided by MDA will support studies to further understand disease mechanisms, optimize and build upon existing therapies, and advance drug target identification, especially toward gene-targeted therapies -- research that will have translational and clinical application across many neuromuscular diseases

Spinal-bulbar muscular atrophy (SBMA)

Alireza Mashaghi Tabari, PhD
Leiden University, The Netherlands
Research grant, $300,000
Single molecule folding studies on the mutant androgen receptor underlying SBMA

Friday, August 23, 2019


The UCL - London Research Team published their second newsletter. There are several updates on current research and projects. Click on the link below to read the PDF.

Wednesday, August 21, 2019

Autophagic and Proteasomal Mediated Removal of Mutant Androgen Receptor in Muscle Models of SBMA

This is way over my head. I need someone to simplify it. Follow the link below to the entire - very long - article in Frontiers in Endocrinology.

Autophagic and Proteasomal Mediated Removal of Mutant Androgen Receptor in Muscle Models of Spinal and Bulbar Muscular Atrophy

Spinal and bulbar muscular atrophy (SBMA) is an X-linked motoneuron disease (MND) caused by a mutant androgen receptor (AR) containing an elongated polyglutamine (polyQ) tract. ARpolyQ toxicity is triggered by androgenic AR ligands, which induce aberrant conformations (misfolding) of the ARpolyQ protein that aggregates. Misfolded proteins perturb the protein quality control (PQC) system leading to cell dysfunction and death. Spinal cord motoneurons, dorsal root ganglia neurons and skeletal muscle cells are affected by ARpolyQ toxicity. Here, we found that, in stabilized skeletal myoblasts (s-myoblasts), ARpolyQ formed testosterone-inducible aggregates resistant to NP-40 solubilization; these aggregates did not affect s-myoblasts survival or viability. Both wild type AR and ARpolyQ were processed via proteasome, but ARpolyQ triggered (and it was also cleared via) autophagy. ARpolyQ reduced two pro-autophagic proteins expression (BAG3 and VCP), leading to decreased autophagic response in ARpolyQ s-myoblasts. Overexpression of two components of the chaperone assisted selective autophagy (CASA) complex (BAG3 and HSPB8), enhanced ARpolyQ clearance, while the treatment with the mTOR independent autophagy activator trehalose induced complete ARpolyQ degradation. Thus, trehalose has beneficial effects in SBMA skeletal muscle models even when autophagy is impaired, possibly by stimulating CASA to assist the removal of ARpolyQ misfolded species/aggregates.

Friday, August 9, 2019

Researchers identify a possible therapeutic target for Kennedy's disease and prostate cancer


Researchers identify a possible therapeutic target for Kennedy's disease and prostate cancer


A study led by scientists at the Institute for Research in Biomedicine (IRB Barcelona) and published in Nature Communicationsproposes chaperone protein Hps70 as an attractive therapeutic target for the treatment of Kennedy's disease--a rare neuromuscular condition--and of castration-resistant prostate cancer.

Kennedy´s disease is caused by a mutation in the androgen receptor. This receptor serves as a sensor of testosterone, detecting the levels of this hormone and activating the genes responsible for male traits. But in patients with this disease, the mutated receptor shows an altered structure, as demonstrated by this lab in a previous study recently published in the same journal, and it forms aggregates that damage muscle cells and causes muscular atrophy or wasting.

Chaperone proteins are one of the mechanisms through which the formation of toxic protein aggregates is prevented. These chaperones bind to other proteins in order to facilitate their correct folding, assembly and transport, as well as regulating their degradation. "But we didn't know the role of these chaperones in the regulation of the activity, cell concentration and solubility of the androgen receptor," says ICREA researcher Xavier Salvatella, head of the Laboratory of Molecular Biophysics at IRB Barcelona.

Using a sophisticated biophysics approach, nuclear magnetic resonance (NMR), and experiments with human cell cultures, the scientists discovered that the chaperones Hsp40 and Hsp70 bind strongly to a region of the androgen receptor that is susceptible to forming toxic aggregates. This interaction between the chaperones and the receptor prevents the formation of these deposits and facilitates their clearance.

To confirm whether the increase in the activity of these chaperones decreases the formation of toxic aggregates and whether these proteins are therefore useful for the treatment of Kennedy`s disease, the scientists performed experiments in mouse models. These experiments were done in collaboration with the labs of Professors Jason E. Gestwicki and Andrew P. Lieberman from the University of California San Francisco and the University of Michigan, respectively.

"The results obtain in mice confirm that compounds that activate Hsp70 lead to a decrease in the formation of the aggregates," says Salvatella. "Therefore the chaperone Hsp70 emerges as a possible therapeutic target for Kennedy's disease," he goes on to say.

The results may also be useful in the search for a treatment for castration-resistant prostate cancer, the most advanced stage of this kind of cancer, which causes 30,000 deaths a year in Europe. In cells resistant to current treatments, the binding site of Hsp40 and Hsp70 in the androgen receptor is not altered, and therefore these chaperones may also serve as a therapeutic target in this disease.

Friday, August 2, 2019

Excessive Phlegm Buildup

It seems my Kennedy's Disease always finds new ways to intrude on my life. Excessive amounts of phlegm have become an almost daily ordeal for me. Here are two techniques to help clear your lungs plus an article on potential home remedies. 

How to Perform a Controlled Cough

Not all coughs are created equal though. Explosive, uncontrolled hacking does little to clear airways. In fact, a violent cough can cause the airways to collapse, making it even more difficult to clear them of mucus.

An effective cough is one that's controlled and that comes from deep within the lungs to loosen and mobilize mucus. It's something you can easily learn to do with practice. And once you've mastered the technique, you can call on it whenever you need it. 

  1. Sit upright in a chair or on the edge of a bed. Place your feet firmly on the ground, lean forward a bit, and take a few deep breaths to help your body to relax. 
  2. Fold both arms across your abdomen and breathe in fully through your nose.  
  3. As you exhale, lean forward a little more and press your arms against your abdomen. Open your mouth slightly and cough two or three times. Each cough should be short and sharp and you should feel your diaphragm move upward. 
  4. Breathe in slowly by gently sniffing throughout the entire inhalation. This will prevent mucus from being pushed back into the airways. 
  5. Rest and repeat if necessary. 

You may want to cough into a tissue and note the color, thickness, or overall appearance of what you bring up. If you notice any significant changes, let your doctor know.

To get the best from controlled coughing, incorporate these simple tips:

  1. Stay hydrated. Sticky mucus can be difficult to cough up. To help keep it thin and easy to expectorate, drink plenty of water throughout the day—at least six to eight glasses.
  2. Use a bronchodilator before you do controlled coughing. This will relax your airways to allow mucus to move more easily. ted, mucus clearance is more difficult.
  3. Slow down your breathing. After coughing, keep your breaths slow and shallow. If you inhale sharply and quickly it can interfere with the movement of mucus out of the lungs—precisely the effect you want to avoid.

Chest Percussion

An Airway Clearance Technique to Ease Mucous Blockage

Chest percussion is used frequently to help you clear your airways.

It literally involves "percussion" on your chest and/or back—in other words, your partner or a healthcare worker will clap you on your chest or back to help loosen the thick mucus in your lungs. Chest percussion also can be performed using electronic devices or other instruments that vibrate your chest.

When you loosen mucus using chest percussion, it will help you to cough it up.

Chest percussion is considered a part of chest physical therapy. The overall goal of chest physical therapy is to make it easier for you to expel mucus in your airways, which in turn should make it easier for you to breathe.

Performing Chest Percussion

Your doctor or respiratory therapist will give you specific instructions on how to perform chest percussion. You should always follow the instructions of your healthcare team, but here are some general guidelines on how the procedure normally is performed.

You'll likely be instructed to perform chest percussion at least once per day in several different positions: seated, on your back with a pillow under your chest so that your head tilts downward, and on your stomach, again with your head tilted downward.

If you're using a mechanical airway clearance device for your chest percussion, your doctor will show you how to use the device.

If you're doing the procedure manually, your partner (or a healthcare worker) will then clap you on the back or the chest (whichever is exposed) with their hand, quickly and repeatedly.

It's important to use the correct hand position to perform manual chest percussion: the person's hand should be in a cupped position, with fingers and thumb together. It's also important to clap on the sides of the chest and the back, not in the middle—your physician can show you exactly where.

Finally, you shouldn't perform the procedure on bare skin—make sure you're wearing a shirt, or use a towel to cover the area to be clapped upon.

When to Perform the Procedure

The best time to perform chest percussion is in the morning since it's likely that your lungs will have built up mucus during the night. If you have a problem with coughing overnight, you can consider performing it right before you go to bed, as well.

Of course, your doctor will advise you on the best times to perform the procedure. Chest percussion works best after a bronchodilator treatment, so you might want to keep that in mind.

It's not a good idea, though, to perform chest percussion right after you've eaten—banging on your chest or back following even a small meal could make you sick.

Another tidbit is that you should combine chest percussion with coughing or with other methods to bring up the mucus that is loosened by your efforts. 


Home remedies for mucus in the chest

A person can soothe symptoms and get rid of bothersome mucus using the following methods:

1. Warm fluids

Hot beverages can provide immediate and sustained relief from a mucus buildup in the chest.

Staying hydrated thins mucus, making it easier to expel by coughing.

According to a 2008 study, hot beverages provide "immediate and sustained relief" from congestion and accompanying symptoms, such as sneezing, a nagging cough, a sore throat, and chills.

A person can benefit from drinking:
  • broths
  • decaffeinated black or green tea
  • herbal teas
  • warm water

Some of these drinks are available for purchase online, including decaffeinated tea and herbal teas.

2. Steam

Keeping the air moist can loosen mucus and reduce congestion and coughing. The National Heart, Lung, and Blood Institute recommend using a cool-mist humidifier or steam vaporizer.

People with difficulty sleeping may wish to use a humidifier at night. To maximize the effects, keep windows and doors closed.

Humidifiers must be cleaned regularly to remove bacteria and other pathogens that can make symptoms worse and lead to infection.

Other ways to increase moisture in the air include:

Inhaling steam: Fill a large bowl with hot water. Lean over the bowl and drape a towel over the head to contain the stream. Gently inhale the steam to loosen mucus.
Having a hot shower or bath: The hot water will fill the room with steam and help to alleviate symptoms.

Breathe in the steam for as long as is comfortable, then drink a glass of water to prevent dehydration.

3. Saltwater

Gargling with a mixture of salt and warm water can remove phlegm and mucus from the back of the throat and ease symptoms.

Add half a teaspoon of salt to a cup of warm water. Stir until the salt dissolves.

Gargle with the mixture and allow it to sit in the back of the throat momentarily. Repeat several times a day as needed.

4. Honey

Honey is a popular home remedy, and research suggests that it has antiviral and antibacterial properties.

A person can consume 1 tablespoon of honey every 3 to 4 hours, until the symptoms ease. Honey is not suitable for infants under 12 months of age. 

5. Foods and herbs

Foods most commonly used to alleviate coughs, colds, and a buildup of mucus include:

Wednesday, July 31, 2019

Updated Swallowing Exercises

This last week I saw a Ear, Nose and Throat specialist. He scoped my throat and saw significant atrophy in the sphincter muscles and voice box. Below are a few updated Swallowing Exercises provided by a speech therapist.

Perform each of these exercises 10-20 times in a row.

1. Oral Control Exercises

    a. Using lips and tongue, move straw from left cheek to right cheek.

    b. Place straw at center of lips. Using lips and tongue, move in and out.

2. Pharyngeal Stripping Exercises

    a. Swallow hard, squeezing all your muscles. Pretend you are swallowing an egg.

3. Tongue Base Exercises

    a. Stick tongue out, bite tip with teeth or hold tip with a gauze pad. While doing this, swallow, keeping your tongue anchored.

    b. Pull the tongue into the back of the mouth, keeping tongue tip down. Hold for a slow count of 5.

4. Laryngeal Elevation Exercises

    a. Start to swallow normally. Hold your Adam’s apple up with your neck muscles when it gets to the top. Hold for a slow count of 5.

Here is a link to a video on throat exercises:

Thursday, July 25, 2019

What are SARMs?

I read this post from Tom Edward on the KD - Canada Facebook page: 
I heard back from Dr. Fischbeck last night. So SARMS are under active development for SBMA. We studied ASC- JM 17 and a lab in Tawain just received FDA approval to initiate a clinical trial. Paul Taylor's lab at St. Jude's did a study in mice and they were shown to be effective and at least 2 companies are interested in developing the drug. Diane Merry a researcher at Thomas Jefferson in Philadelphia is also working in the lab with other SARMS for SBMA. So it is having some positive results in the mice now let's hope it could translate into us humans.
So, I looked up SARMs and this is what I found...

Selective androgen receptor modulators or SARMs ...

are a novel class of androgen receptor ligands. They are intended to have the same kind of effects as androgenic drugs but be much more selective in their action, allowing them to be used for more uses than the relatively limited legitimate uses of anabolic steroids.

They are intended to have the same kind of effects as androgenic drugs but be much more selective in their action,[1] allowing them to be used for more uses than the relatively limited legitimate uses of anabolic steroids.
Ref:  Wikipedia

Current Uses: Hypogonadism; Osteopenia; Osteoporosis; Sarcopenia; Cachexia

SARMs are not approved by the Food and Drug Administration (FDA) for human use, They are illegally marketed and sold as dietary supplements, and they are banned in all professional and college sports. “SARMs are synthetic drugs that have negative effects similar to those of anabolic steroids, [Google Search of SARMs]

Thursday, June 13, 2019

Treatment of Prostate Cancers and Kennedy’s Disease

This is way above my understanding level, but might be of interest to some of you.

Treatment of Prostate Cancers and Kennedy’s Disease by PROTAC-Androgen Receptor Degradation


Prostate cancer (PCa) is the most common malignancy diagnosed among men in Western countries and the second leading cause of cancer-related deaths, with over three million men in the United States living with the disease. Positive predictor of prostate cancer risk and tumor stage involves the prostate-specific antigen (PSA)-related serine protease kallikrein-related peptidase 4 (KLK4), which is overexpressed in prostate cancer relative to benign tissue. In vitro, KLK4 has been found to promote prostate cancer cell migration, proliferation, and epithelial-to-mesenchymal transition. Despite improvements in external radiotherapy, brachytherapy, and radical prostatectomy treatment, up to 35% of patients with localized or locally advanced PCa may experience disease relapse.

Androgen deprivation therapies (ADTs) such as enzalutamide (an androgen receptor inhibitor) and abiraterone acetate (an inhibitor of androgen biogenesis) are considered to be frontline treatments and have shown benefit to patients with advanced PCa. However, castration-resistant prostate cancer (CRPC) invariably develops, leading to the lethal form known as metastatic castration-resistant PCa (mCRPC), which gives rise to high mortality rate, and no cure is currently available. Treatment targeting androgen receptor (AR) signaling becomes ineffective in advanced prostate cancer with AR gene mutation, amplification, and alternate splicing. Nonetheless, most patients who progress on enzalutamide and abiraterone have rising prostate-specific antigen (PSA) levels, which strongly suggests that these tumors are still dependent on the AR signaling.

Understanding the molecular mechanisms that drive the prostate cancer progression is essential to develop therapies that will attenuate the metastatic growth. As such, several mechanisms have been proposed to account for continued AR signaling such as point mutations in the AR ligand-binding domain (LBD) and expression of AR splice variants (ARVs) that have been shown to mediate resistance to abiraterone and enzalutamide. The ARVs are active even in the absence of ligands and are truncated AR isoforms that lack LBD but retain the DNA-binding domain (DBD) and N terminal domain (NTD). Several signaling pathways activate AR signaling in the absence of ligands in prostate cancer models like IL-6 and HER2. Interestingly, the majority of these pathways are thought to activate AR through its NTD, either by post-translational modifications or by direct interactions. Regardless of the mechanism at play, the continued expression of AR target genes is a major driver in the resistance found in PCa treatment, and new therapies are necessary to treat these cancers.

In the absence of androgens, AR is bound by Heat Shock Protein 90 (Hsp90) in the cytosol, which leads to conformational changes and the release of AR from Hsp90 that exposes the nuclear localization signal (NLS). Hsp90 is the most abundant intracellular protein in mammalian cells and is essential for a wide range of protein assembly, folding, trafficking, and degradation processes. Furthermore, Hsp90 is composed of an N-terminal adenosine triphosphate/adenosine diphosphate (ATP/ADP) binding domain, a middle domain involved in client protein binding, and a C-terminal dimerization domain. The N- and C-termini contain distinct binding sites for ATP and are associated with a specific functional activity. The binding of ATP at the N-terminus provides energy to modulate protein trafficking and folding, whereas nucleotide binding at the C-terminus is linked to allosteric regulation of ATP binding to the N-terminal site. Hsp90 inhibitors exhibit anticancer properties as proteins associated with malignant growth, including growth factors, kinases, and hormone receptors, which are dependent upon the Hsp90 protein folding machinery for their activation and maturation. Consequently, inhibitors of Hsp90 can disrupt multiple signaling cascades simultaneously, which may result in a combinatorial attack on numerous signaling pathways.

Thus, alternate therapeutic strategy, such as proteolysis targeting chimera (PROTAC) has gained momentum with its promise in the discovery and development of completely new types of small-molecule that induces targeted protein degradation. A PROTAC molecule is a heterobifunctional small molecule containing one ligand, which binds to the target protein of interest, and a second ligand for an E3 ligase system that is tethered together by a chemical linker. From the above discussion, AR protein plays a crucial role in CRPC, and AR degraders designed based upon the PROTAC concept could be potentially very effective for the treatment of CRPC. Compounds of this Patent Highlight comprise bifunctional small molecules that recruit endogenous proteins to an E3 ubiquitin ligase such as Von Hippel-Lindau (VHL) E3 ubiquitin ligase, for ubiquitination and subsequent degradation. Thus, these compounds (where ABM is an AR binding moiety, ULM is an E3 ligase binding moiety like VHL E3 ligase binding moiety (VLM), and L is a linker moiety) are modulators of targeted ubiquitination, degraders of androgen receptor (AR), and provide effective treatment or amelioration of a disease condition such as prostate cancer and Kennedy’s Disease. The first targeted protein degrader (Arv-110, an orally bioavailable small molecule AR PROTAC) has been cleared by the FDA for phase I clinical trial for the treatment of advanced prostate cancer (

The structural consequences of the mutation in Kennedy's Disease

The following was published in IRB Barcelona yesterday. It is further research on research performed a few years ago.

Researchers at IRB Barcelona discover the structural consequences of the mutation that causes Kennedy disease

The androgen receptor helix of polyglutamine becomes increasingly stable as the number (n) of glutamine amino acid residues increases.

The androgen receptor helix of polyglutamine becomes increasingly stable as the number (n) of glutamine amino acid residues increases.
12 JUN 2019

Kennedy’s disease is an untreatable neuromuscular disorder considered a rare disease

A study led by Xavier Salvatella may pave the way for new lines of treatment for Kennedy’s disease

Kennedy’s disease is a rare neuromuscular disease caused by a mutation in the androgen receptor protein. The Laboratory of Molecular Biophysics led by Xavier Salvatella at the Institute for Research in Biomedicine (IRB Barcelona) has recently discovered new key structural features of the androgen receptor induced by the mutation. This finding has been published in the journal Nature Communications and could open up new therapeutic avenues for a family of incurable rare conditions called polyglutamine (polyQ) expansion diseases.

Spinal and bulbar muscular atrophy (SBMA), also known as Kennedy’s disease, is an untreatable neuromuscular disorder that causes a dramatic decrease in patients’ quality of life. It is classified as a rare disease, meaning that it affects less than 5 in 10,000 people. The mutation in the androgen receptor protein causing the disease is an expansion of a repetitive amino acid sequence containing only glutamine residues, called a polyQ tract. Interestingly, the length of this tract determines whether a person develops Kennedy’s disease.

A similar mutation can also be found in other polyQ expansion diseases, the most known of which is Huntington’s disease. Why an expansion of the polyQ tract leads to the development of polyQ expansion diseases in not understood. In the case of Kennedy’s disease, researchers believe that androgen receptor proteins containing a very long polyQ tend to oligomerize. These oligomers then generate toxic protein aggregates inside the cell, thereby impeding its proper functioning.

For a protein to function properly, it must fold into an ordered three-dimensional structure. Up to now, the part of the androgen receptor protein holding the polyQ expansion was thought to be disordered and therefore unable to fold into such a structure. In 2016, Salvatella’s group found that the polyQ tract of the androgen receptor could adopt a helical structure. “This was a very interesting result, as so far these tracts were thought not to adopt any specific structure,” explains Salvatella.

In the current study, the team went one step further and visualized the polyQ tract protein helix via advanced biophysical and computational methods. They now report that this specific region can form well-ordered helices and, crucially, that the polyQ expansion greatly increases the degree of order and stability of these helices. This information furthers our understanding of androgen receptor function.

Wednesday, May 29, 2019

Joint Participation in Improving your Health and Relationships

Below is another great post from Richard Wright. Its focus is on senior citizens and their caregivers using mindfulness meditation and yoga to improve their mental and physical health while participating in an activity they are both involved in. 

I have practiced mindfulness meditation for several years now. Every day, after my morning exercises and stretches, I will meditate. I’ll often meditate again in the early afternoon. Stretching, along with daily exercise is beneficial for all of us living with Kennedy’s Disease (SBMA). 

Many senior centers and YMCAs offer programs in stretching, yoga, and mindfulness meditation. For the self-starters, Richard has included links to sources on the internet that offer podcasts on these topics. 

Let me reemphasize the important side benefit of “participating together.” Living with any debilitating disorder is difficult for the individual as well as the caregiver. It can also be a rewarding experience, especially when activities are done together. Thank you, Richard.

This Is How Yoga and Meditation Can Transform the Lives of Seniors (And Their Caregivers)

Without proper stimulation and health-boosting activities, the lives of seniors and their caregivers can quickly become monotonous. There’s nothing wrong with having a routine, but it should include activities to get your blood flowing, improve strength, expand your mind, and relieve stress. You might be wondering how you’ll have time to achieve all those goals, but the good news is that yoga and meditation provide all of those things and more. In addition, they are activities the two of you can enjoy together or alone, which can help foster a healthy bond.

Yoga Offers Senior-Specific Benefits

When done safely and properly, yoga provides many wonderful benefits for seniors and caregivers alike. For starters, it can help strengthen bones to minimize, prevent, or slow the progression of osteoporosis, as well as keep your weight in check to prevent it from interfering with your mobility and desire for a more active lifestyle. Yoga is a low-impact exercise with a focus on slow, fluid movements, which can help seniors build strength and balance.

There are benefits for the mind, as well. Most styles of yoga include focused breathing and meditation, which can help seniors and caregivers keep their mind clear and sharp. Additionally, this practice can spike the brain's production of GABA, the chemical that keeps you calm and relaxed. Yoga requires instruction and guidance to keep you safe, so classes at your local yoga studio are the best place to start. However, if you’re looking to get a group of seniors together with a shared interest in yoga, try a senior meetup group.

Meditation Can Stave Off Loneliness

Just like wrinkles and gray hair come with age, loneliness is common in seniors. Perhaps loved ones have passed away or children, family members, and friends no longer live close by. Loneliness has other impacts too. According to Psych Central, “loneliness is known to activate inflammatory genes which, in turn, are known to promote a variety of diseases” However, the study found that mindfulness meditation reduced feelings of loneliness in seniors via regular class attendance, and even reduced the genes that are markers for heart disease and inflammation. Meditation is an integral part of yoga, but it can be practiced on its own as well. There are several beginner podcasts online that will walk you through a meditation session.

Commit to the Practice

Yoga and meditation require dedication and consistent practice. There will be some days when getting to a class isn’t possible, or perhaps you’d just like to be able to practice at home once you learn the proper technique. To achieve this, you’ll need to clear out a room to give you enough space to safely and comfortably practice. It is best to create a dedicatedspace, as you’ll likely grow tired of having to move around furniture and items every time you want to practice. If need be, move some of your belongings into storage to free up space. Incorporate soothing sounds, scents, colors, and lighting for a truly zen experience.

Safety Comes First

Whether you are practicing yoga, meditation, or both, safety should always be your top priority. Yoga is appropriate for all ages, but seniors will benefit from gentle classes such as Iyengar, Viniyoga, and Kripalu. Most yoga studios offer gentle/beginner classes and can help you adapt the poses using chairs and props. As the caregiver, it is your job to communicate with the instructor about the needs and abilities of your senior loved one. This includes disclosing physical and mental ailments, as well as their mood for the day.

Life can be difficult at times for both seniors and caregivers. For this very reason, self-care is crucial. Yoga and meditation combine physical and mental health benefits for a relaxing activity the two of you can explore together.
Photo Credits:

Saturday, May 25, 2019

It's more than picnics and parades and a day off from work

The picnics and parades are fun and a paid holiday never hurts. As time marches on, it becomes easier to forget about the true meaning of Memorial Day.

It was originally called Decoration Day.

On May 5, 1868, General John A. Logan, leader of an organization for Northern Civil War veterans, called for a nationwide day of remembrance later that month. “The 30th of May, 1868, is designated for the purpose of strewing with flowers, or otherwise decorating the graves of comrades who died in defense of their country during the late rebellion, and whose bodies now lie in almost every city, village and hamlet churchyard in the land,” he proclaimed.

Memorial Day, as Decoration Day gradually came to be known, originally honored only those lost while fighting in the Civil War. But during World War I the United States found itself embroiled in another major conflict, and the holiday evolved to commemorate American military personnel who died in all wars.

Take a moment or two this weekend to remember and honor those who gave the ultimate sacrifice.

Wednesday, May 1, 2019

Study of High-intensity Training for SBMA Patients

SMA News Today published the following report on a recent "small" study. The number of participants and the duration of the study concerns me. I hope they follow up with more participants of various stages of progression, and for a longer period of time (six months or more).

High-intensity Training Improves Fitness While Being Safe for Patients with Kennedy’s Disease, Small Study Suggests

High-intensity training can improve fitness and may be performed safely by patients with spinal and bulbar muscular atrophy (SBMA), a small pilot study suggests.

According to patients, high-intensity training (HIT) did not increase their muscle fatigue and was preferred to other workouts. Although more studies are needed to understand the long-term benefits and compliance of patients to HIT, researchers recommend that the exercise be considered as part of rehabilitation therapy for SBMA.

The study, “High-intensity training in patients with spinal and bulbar muscular atrophy,” was published in the Journal of Neurology.

Exercise of low or moderate intensity does not seem to benefit patients with SBMA — a rare adult-onset form of spinal muscular atrophy (SMA) also known as Kennedy’s disease — which is characterized by muscle wasting and weakness in the arms and legs. In fact, low- and moderate-level exercise can produce muscular fatigue in these patients.

HIT is a form of cardiovascular exercise that alternates short periods of intense anaerobic exercise with less intense recovery periods. This type of workout has been shown to be time-saving and efficient for healthy individuals. HIT may also benefit SBMA patients because motor neurons — the nerve cells that control muscle activity and are damaged in SBMA — are only active for a small period of time.

To test this possibility, researchers at the University of Copenhagenand Aarhus University Hospital, in Denmark, conducted a small study to investigate if HIT is feasible and safe, and if it can improve the fitness in SBMA patients.

Patients were randomized to a supervised eight-week training, followed by optional self-training for another eight weeks, or they received no training (usual care) followed by an unsupervised, at-home eight-week training.

Training included eight minutes of warm-up followed by two five-minute cycles on a stationary bike, with three minutes of recovery in between. Each cycle was based on the 30–20–10 s concept, which consisted of low-, moderate-, and high-speed cycling for 30, 20, and 10 seconds, respectively, in five minutes.

Before training, the patients received a class and an audio file with a recorded training guide to use at home. During training, they wore a pulse-watch to record heart rate, intensity of training, and patient compliance.

Of the 10 male SBMA patients who participated, eight completed the study — half in the supervised and the other half in the unsupervised group.

Both maximal oxygen consumption (a measure of exercise capacity) and maximal workload were tested before and after the training program during an incremental exercise test — a test where participants have to perform exercise that increases in intensity over time.

Taken together, training improved both fitness and workload performance in all patients after eight weeks. This was evidenced by an 8% increase in maximal oxygen consumption and a 16% greater maximal workload, compared with the start of the study.

The training was safe, as judged by stable creatine kinase levels, a blood marker of muscle damage. Patient-rated muscle fatigue, muscle pain, and activity levels also remained the same over the training period.

Moreover, all patients preferred the high-intensity training compared with other workouts. In fact, three of the four patients who completed supervised training wished to continue the program for eight more weeks without supervision.

At the end of their entire training period (16 weeks), the participants maintained their improvements in maximal oxygen consumption and workload.

However, the training program did not change the patients’ walking capacity (as assessed by the 6-min walk test) and tended to reduce their walking distance slightly from a daily average of 3.1 to 2.4 km.

“In conclusion, HIT is well-tolerated and safe for patients with SBMA. It increases fitness and training does not decrease patient’s daily activity level, and should be considered as a rehabilitation strategy for patients affected by SBMA,” the researchers wrote.

Compared with other low- and moderate-level training modalities, HIT seems to work better to improve patients’ fitness and is favored by patients, they said.

“A likely explanation for the efficacy of HIT and inefficacy of lower intensity training in SBMA could relate to the longer period of restitution between training bouts, and the shorter period that the large motor units in SBMA need to be active vs. longer duration low-to-moderate-intensity training,” the researchers said.

Future studies should evaluate the long-term effects and compliance of high-intensity training for this patient population, they added..

Tuesday, April 30, 2019

ALS Disability Insurance Act

ALS Disability Insurance Act of 2019 (H.R. 1407, S.578)

ALS is a quickly progressing disease. People diagnosed with ALS can’t afford to wait to access the SSDI benefits they desperately need.

Currently, all people living with Amyotrophic Lateral Sclerosis (ALS) who qualify for Social Security Disability Insurance (SSDI) must wait five months before they can begin receiving these benefits.

To address this issue and provide relief for these individuals, Sen. Sheldon Whitehouse (D-RI), Sen. Tom Cotton (R-AR), Rep. Seth Moulton (D-MA), and Rep. Peter King (R-NY) introduced the ALS Disability Insurance Act in February 2019. The legislation would eliminate the five month waiting period for SSDI benefits for people living with ALS so that they can begin receiving these benefits immediately.

Because ALS can progress very quickly, it is essential that diagnosed individuals are able to access SSDI benefits as soon as possible. Congress has recognized the urgent need of the ALS community before when it voted in 2000 to waive the two year waiting period for Medicare eligibility for ALS patients.

The Muscular Dystrophy Association has led the way for innovations in ALS science and care for nearly 70 years. We have dedicated hundreds of millions of dollars to ALS research, and care for tens of thousands of people diagnosed with ALS and their families.

Wednesday, April 24, 2019

Mouse Study Explores Underlying Cause of Motor Neuron Degeneration in SBMA

CHMP7 has shown up twice recently in research on SBMA. The previous article can be found here:

Gene expression analysis reveals early dysregulation of disease pathways and links Chmp7 to pathogenesis of spinal and bulbar muscular atrophy

SMA News published a well written article and excerpts can be found below and the entire article can be read at this link" 

Mouse Study Explores Underlying Cause of Motor Neuron Degeneration in SBMA

"...Results showed that 178 genes were upregulated (overly active), while 287 were downregulated (under-activated) in motor neurons from SBMA mice compared to healthy animals, indicating that transcriptional dysregulation in SBMA starts at an early stage of development.

One of the genes that was donwregulated in motor neurons from animals with SBMA was Chmp7 (Charged Multivesicular Body Protein 7). Interestingly, the expression levels of this gene also were affected in motor neurons from the spinal cord and lower legs of adult SBMA mice before the onset of symptoms. (Of note, gene expression is the process by which information in a gene is synthesized to create a working product, like a protein.)

Similar alterations in the expression levels of CHMP7 (the equivalent gene of Chmp7 in humans) also were found in motor neurons’ precursors derived from SBMA patients’ induced pluripotent stem cells (iPSCs), suggesting that Chmp7 may play an important role in SBMA development. iPSCs are fully matured cells that are reprogrammed back to a stem cell state, where they are able to grow into any type of cell.

Moreover, the research team discovered that other genes involved in multiple signaling cascades essential for cellular function, such as the tumor suppressor (p53), DNA repair and energy metabolism, also were dysregulated in motor neurons from SBMA animals.

In addition, scientists observed that SBMA motor neurons showed signs of mitochondria (the cell compartments responsible for the production of energy) dysfunction and DNA damage, possibly caused by transcriptional dysregulation of genes involved in energy metabolism and/or DNA repair.

“Taken together, these findings indicate that an interplay of multiple pathways contribute to the disease pathogenesis [development] of SBMA. Significantly, the dysregulated genes and pathways, and in particular Chmp7/CHMP7 identified by our transcriptomic profiling may serve as candidate druggable molecular targets for therapy development in SBMA,” the researchers concluded."

Wednesday, April 17, 2019

CRISPR is Making News Again

Below is an excerpt of a good article on the National Public Radio website. Clink on the title below to read the entire article.

First U.S. Patients Treated With CRISPR As Human Gene-Editing Trials Get Underway

"...scientists have long hoped CRISPR — a technology that allows scientists to make very precise modifications to DNA — could eventually help cure many diseases. And now scientists are taking tangible first steps to make that dream a reality.

For example, NPR has learned that a U.S. CRISPR study that had been approved for cancer at the University of Pennsylvania in Philadelphia has finally started. A university spokesman on Monday confirmed for the first time that two patients had been treated using CRISPR.
The revelation comes as several other human trials of CRISPR are starting or are set to start in the U.S., Canada and Europe to test CRISPR's efficacy in treating various diseases.

"2019 is the year when the training wheels come off and the world gets to see what CRISPR can really do for the world in the most positive sense," says Fyodor Urnov, a gene-editing scientist at the Altius Institute for Biomedical Sciences in Seattle and the University of California, Berkeley.

Here are highlights of the year ahead in CRISPR research, and answers to common questions about the technology..."

So what's happening now with new or planned trials?

"We've finally reached the moment when CRISPR is moving out of the lab and into the clinic around the world..."

"...And yet another study, sponsored by Editas Medicine of Cambridge, Mass., will try to treat an inherited form of blindness known as Leber congenital amaurosis.

That study is noteworthy because it would be the first time scientists try using CRISPR to edit genes while they are inside the human body. The other studies involve removing cells from patients, editing the DNA in those cells in the lab and then infusing the modified cells back into patients' bodies.

Finally, several more U.S. cancer studies may also start this year in Texas, New York and elsewhere to try to treat tumors by genetically modifying immune system cells..."

When might we know whether any of these experimental CRISPR treatments are working?

"...All of these studies are very preliminary and are primarily aimed at first testing whether this is safe. That said, they are also looking for clues to whether they might be helping patients. So there could be at least a hint about that later this year. But it will be many years before any CRISPR treatment could become widely available..."

Friday, April 12, 2019

Have You or a Loved One Been Recently Diagnosed with a Rare Disorder?

Kennedy's Disease (SBMA) is considered a rare disorder.  Approximately 1 in 40,000 have this condition.

NORD's latest addition to its patient and caregiver resource center is this video providing tips for newly diagnosed patients and their families. 

The video includes further information on recommendations including giving yourself time to adjust, connecting with others and learning about your rare diseases. 

Click HERE or on the title below to watch the video.

10 Tips for Newly Diagnosed Rare Disease Patients and Families

For more resources and information, visit NORD's resource center here:

Tuesday, April 2, 2019

Gene expression analysis reveals early dysregulation of disease pathways in SBMA

Dr. Al La Spada at Duke University, who many of us know through the KDA, has published in Nature, Scientific Reports some research findings that could prove beneficial in future Kennedy's Disease research. 

Note:  You can read the entire report by clicking on the title (link) above.

Gene expression analysis reveals early dysregulation of disease pathways and links Chmp7 to pathogenesis of spinal and bulbar muscular atrophy

Published: 05 March 2019

Bilal Malik, Helen Devine, Rickie Patani, Albert R. La Spada, Michael G. Hanna & Linda Greensmith


Spinal and bulbar muscular atrophy (SBMA) results from a CAG repeat expansion within the androgen receptor gene (AR). It is unclear why motor neurons selectively degenerate and there are currently no treatments for this debilitating disease. To uncover the causative genes and pathways involved in motor neuron dysfunction, we undertook transcriptomic profiling of primary embryonic motor neurons from SBMA mice. We show that transcriptional dysregulation occurs early during development in SBMA motor neurons. One gene found to be dysregulated, Chmp7, was also altered in vivo in spinal cord before symptom onset in SBMA mice, and crucially in motor neuron precursor cells derived from SBMA patient stem cells, suggesting that Chmp7 may play a causal role in disease pathogenesis by disrupting the endosome-lysosome system. Furthermore, genes were enriched in SBMA motor neurons in several key pathways including p53, DNA repair, WNT and mitochondrial function. SBMA embryonic motor neurons also displayed dysfunctional mitochondria along with DNA damage, possibly resulting from DNA repair gene dysregulation and/or mitochondrial dysfunction. This indicates that a coordinated dysregulation of multiple pathways leads to development of SBMA. Importantly, our findings suggest that the identified pathways and genes, in particular Chmp7, may serve as potential therapeutic targets in SBMA.


Transcriptomic profiling of SBMA embryonic motor neurons

To characterise early transcriptional dysregulation and establish disease mechanisms in SBMA, we first performed a global transcriptomic screen of purified cultured spinal cord motor neurons from embryonic AR100 and wild-type (WT) mice treated with dihydrotestosterone (DHT), to reflect the ligand dependency of the disease. We found that 178 genes were upregulated, whilst 287 genes were significantly downregulated in AR100 motor neurons compared with WT cultures (Supplementary Information....

...Despite the ubiquitous expression of the causative AR gene and mutant protein, there is as yet no clear explanation for the selective loss of lower motor neurons in the anterior horn of the spinal cord and specific brainstem motor nuclei in SBMA, although high expression of AR within these cell types may be a possible contributory factor....

...Importantly, as no effective treatment or disease modifying therapies are available, the discovery of targets linked with early motor neuron dysfunction may provide promising therapeutic avenues in alleviating the development and course of the disease....

...There were also signs of DNA damage in spinal cord motor neurons of AR100 mice, which may result from downregulation of DNA repair genes and/or mitochondrial dysfunction. The identified pathways and genes, particularly Chmp7, may therefore represent attractive molecular targets for development of a therapeutic approach for SBMA....


...Although our results suggest that several pathways may be associated with SBMA pathogenesis, it is possible that mitochondrial and p53 dysfunction are the key, early drivers of disease (Fig. 5A,B). Mitochondrial deficits and p53 dysfunction may act independently and in parallel, but also synergistically to initiate the early features of disease....

...Finally, mitochondrial and p53 deficits may be early instigators of dysfunction possibly acting independently or also synergistically to initiate the early features of disease in motor neurons. Taken together, these findings indicate that an interplay of multiple pathways contribute to the disease pathogenesis of SBMA. Significantly, the dysregulated genes and pathways, and in particular Chmp7/CHMP7 identified by our transcriptomic profiling may serve as candidate druggable molecular targets for therapy development in SBMA....

Wednesday, March 20, 2019

SBMA Patients are More Likely to be Affected by Metabolic Disorders, Heart and Liver Disease

The following was reported in SMA News Today. The information is not new and from my perspective reflects mainly on the sedentary lifestyle after the progression has reached a point where the person can no longer perform aerobic physical exercise.

I believe it also reflects the need to continue to exercise (safely), change your diet, and be mindful of the possibility of these conditions in discussions with your doctor.

Heredity also plays an important factor in many of these conditions. 

SBMA Patients are More Likely to be Affected by Metabolic Disorders, Heart and Liver Disease

Patients with spinal-bulbar muscular atrophy (SBMA) are more likely to be affected by metabolic disorders, including insulin resistance and fatty liver disease, which can lead to heart disease and serious liver damage, a study says.

The study, “Prevalence of metabolic syndrome and non-alcoholic fatty liver disease in a cohort of Italian patients with spinal-bulbar muscular atrophy,” was published in Acta Myologica.

SBMA, also known as Kennedy’s disease, is a type of spinal muscular atrophy (SMA) that starts in adulthood and is characterized by widespread muscle weakness and wasting in the arms, legs, head, and neck (bulbar involvement).

The disorder is caused by mutations in the androgen receptor (AR) gene — located on the X chromosome — that lead to an abnormal expansion of a CAG nucleotide (the building blocks of DNA) repeat in the AR gene sequence and to the production of a much larger dysfunctional protein.

Besides neurologic symptoms, SBMA patients also tend to be affected by medical conditions associated with metabolic syndrome (a series of conditions that increase patients’ risk of developing heart disease, stroke or type 2 diabetes), such as insulin resistance, obesity, and glucose intolerance.

In the study, researchers at the University of Padua, in Italy, assessed the incidence of metabolic syndrome, insulin resistance, and non-alcoholic fatty liver disease (NAFLD) in a group of SBMA patients.

The study involved a total of 47 Italian patients with a confirmed diagnosis of SBMA who underwent a battery of biochemical tests to assess metabolic functions. A subset of 24 patients were examined by abdominal sonography (an imaging technique that allows physicians to visualize structures in the patients’ abdominal cavity).Results showed that 49% of the patients had abnormally high levels of fasting glucose (commonly used to diagnose diabetes), and 66% showed signs of insulin resistance.

In addition, 51% of the patients had high levels of total cholesterol, 38% had high LDL-cholesterol (“bad” cholesterol), and 38% had high triglycerides. Conversely, 77% had low levels of HDL-cholesterol(“good” cholesterol). More than half of the patients (55%) had three or more medical conditions associated with metabolic syndrome.

Researchers also found a positive relationship between insulin resistance and the length of CAG repeats in the AR gene sequence.

Biochemical tests showed high levels of two liver enzymes that, when elevated, may indicate liver inflammation or damage: aspartate transaminase (AST) levels were abnormally high in 62% of patients, and alanine transaminase (ALT) levels were high in 38% of patients.

Abdominal sonography revealed that 92% of the patients had liver steatosis (fatty liver disease) at different levels of severity, and one patient had liver cirrhosis (scarring of the liver).

“These alterations can be explained mainly by the reduction of testosterone activity because of (CAG repeats’) expansion in AR gene and must be considered as a main characteristic of Kennedy’s disease,” the researchers wrote.

“Metabolic alterations in SBMA are a suggestive model of androgen deprivation in male and require a multidisciplinary approach to disease. However, considering the conflicting data on the role of androgen stimulation in the metabolic involvement, further studies are needed to understand the pathogenesis of NAFLD and (insulin resistance) in SBMA patients and the possible detrimental consequences of anti-androgen approaches to disease,” they concluded.

Sunday, March 17, 2019

Report on the ENMC Conference

I wish to thank the Kennedy's Disease Association (KDA) for sharing this report from the recent European Neuro Muscular Centre Conference (ENMC). 

I feel this is a major step forward in finding a treatment for SBMA.  

Towards a European Unifying Lab for Kennedy's Disease

Twenty-four scientists working in academia, hospitals and industry from 8 different countries (Denmark, France, Germany, Israel, Italy, Spain, United Kingdom, USA) along with three patients’ representatives, (one who was also a representative of the USA patient group, The Kennedy’s Disease Association), met in the Netherlands on the weekend of the 15th- 17th of February 2019. They discussed the recent developments in research and shared the most recent clinical observations in spinal and bulbar muscular atrophy (SBMA). The workshop was conducted under the leadership of Maria Pennuto, Gianni Sorarù, Linda Greensmith and Pierre-Francois Pradat.

Background and Aims of the Workshop

SBMA, also known as Kennedy’s disease, is a rare, adult onset, neuromuscular disease caused by a mutation in the gene encoding for the protein which binds the male hormone androgen. This protein is called the Androgen Receptor (AR). The mutation is carried on the X chromosome and because the effects of the mutation are dependent on the presence of the male hormone androgen, the disease only affects males. However, females can be carriers of the mutation and if they do show symptoms, these tend to be mild.

The Androgen Receptor has an essential role in mediating the effects of the male hormone, androgen, and, when mutated, leads to muscle fatigue, weakness and atrophy of the arm and leg muscles, along with problems in speech, chewing and swallowing. Twitching or cramping of muscles can also occur.

Significant improvements have been made over the last few years in both our understanding of pathological mechanisms underlying the disease as well as in a greater recognition of the varied clinical manifestations of SBMA and in the development of clinical evaluation tools which together are essential to undertake effective therapeutic trials.

The aim of this workshop was to bring together leading clinical and basic scientists working in the field of SBMA to discuss the current understanding of basic disease mechanisms and to share and update the most recent developments in clinical evaluation of patients, with the objective of increasing the prospects of developing and testing new treatments that could effectively slow down disease progression in SBMA patients. ...

... Next Steps

In order to increase scientific and clinical collaborations between groups working in different countries, it was agreed that the First International Conference on SBMA will be organized, to be held in the spring 2020. The researchers and clinicians have underlined the need to collaborate with patients’ associations in the organization of the meeting with the aim of reinforcing the communication of scientific and clinical progress to SBMA patients and families, and providing the community with the possibility to directly collaborate in the research process.

Click here to read the entire report

Saturday, March 16, 2019

Leuprorelin Acetate May Reduce Swallowing Dysfunction

The following article was published in SMA News.  The study was 48 weeks long and included 283 patients with Kennedy' Disease.

Leuprorelin Acetate May Reduce Swallowing Dysfunction in SBMA Patients, Study Finds

By Joanna Carvalho

Leuprorelin acetate may be a promising therapy to minimize swallowing dysfunction in patients with spinal and bulbar muscular atrophy (SBMA), a study finds.

The study, “Efficacy and safety of leuprorelin acetate for subjects with spinal and bulbar muscular atrophy: pooled analyses of two randomized-controlled trials,” was published in the Journal of Neurology.

SBMA, also known as Kennedy’s disease, is a type of spinal muscular atrophy (SMA) that starts in adulthood and is characterized by widespread muscle weakness and wasting in the arms, legs, head, and neck (bulbar involvement). For this reason, besides having impaired mobility, SBMA patients may have difficulties swallowing and speaking.

The disorder is caused by mutations in the androgen receptor (AR) gene — located on the X chromosome — which provides instructions for the androgen receptor protein. Although this protein is present everywhere in the body, it is enriched in motor neurons, the nerve cells responsible for controlling voluntary movements that are gradually destroyed in patients with SMA.

Because the the AR gene affects the body’s response to androgens — the male hormones involved in sexual development, such as testosterone — patients may have other symptoms, including infertility and erectile dysfunction (male impotence).

After the discovery of the AR gene, studies in animal models of disease revealed SBMA is triggered by the interaction of androgens with the defective androgen receptors. For this reason, treatment for SBMA has centered on the development of therapies involving androgen deprivation.

“Successful treatment of SBMA in mouse models with castration or administration of leuprorelin acetate, a luteinizing hormone-releasing hormone (LH-RH) agonist that reduces testosterone release from testes, supported the idea that testosterone blockade therapy could be beneficial and enabled subsequent human clinical trials,” the study stated.

In the study, Japanese researchers performed a pooled analysis of two identical randomized, placebo-controlled, double-blind clinical trials — JASMITT-06DB and JASMITT-11DB — to evaluate in more detail the efficacy and safety of leuprorelin acetate in patients with SBMA.

In both trials, patients were randomly assigned to receive either leuprorelin acetate or a placebo (control), once every 12 weeks, for 48 weeks. The primary goal was to assess changes in the amount of barium residues (a contrast agent used to visualize structures in the body) in the pharynx (throat) when patients attempted to swallow. Secondary measures included blood tests to measure testosterone levels, scrotal skin biopsies, and quality of life assessments.

In total, 283 SBMA patients were enrolled, including 142 who were treated with leuprorelin acetate and 141 with placebo.

Patients treated with leuprorelin acetate and those treated with placebo had an average decrease of 4.12% in the amount of barium residues present in the pharynx after initial swallowing. Although differences between the two groups after initial swallowing suggested that leuprorelin acetate might be effective at each assessment point, the changes from the initial visit to the last were not statistically significant between both groups, and the primary objective was not reached.

In general, leuprorelin acetate treatment was well-tolerated. The incidence of side effects (81.7% taking leuprorelin and 80.1% in the placebo group) and drug-related side effects (62.7% taking leuprorelin and 53.9% in the placebo group) were similar between the two groups.

However, some of the side effects, including abnormal liver function, weight gain, skin reactions at the injection site, decreased libido, erectile dysfunction, and excessive sweating, were more severe in patients treated with leuprorelin acetate than in those treated with placebo.

“In conclusion, leuprorelin acetate may be safe and beneficial for improvement of swallowing dysfunction in the patients with SBMA, without increasing the number of serious side effects,” the researachers said. “Further investigations are needed to clarify the efficacy of this therapy for SBMA.”

Monday, March 4, 2019

New Gene Therapy Approach Able to Repair Mutations

Below is a small portion of the article in SMA News. Since the focus is on repairing triplet disorders, Kennedy's Disease (SBMA) could also benefit.

New Gene Therapy Approach Able to Repair Mutations Causing SMA, Other Inherited Diseases, Mouse Study Suggests

A new gene therapy approach using RNA molecules called transfer RNAs (tRNAs) was able to repair a subset of mutations causing spinal muscular atrophy (SMA) and other inherited diseases in living muscle tissue of mice, a study shows.

These genetic alterations, called nonsense mutations, alter the DNA sequence and introduce so-called stop codons — triplets of nucleotides, which are the building blocks for DNA — that prematurely stop gene expression and impair protein production. Besides SMA, these mutations also underlie diseases such as Duchenne muscular dystrophy, cystic fibrosis, and polycystic kidney disease.

The study, “Engineered transfer RNAs for suppression of premature termination codons,” was published in the journal Nature Communications.

Several lines of research have attempted to find compounds that are able to repair nonsense mutations. However, previous research has shown that certain small molecules can generate a different type of mutation that is able to disrupt protein function, but they can be toxic to the ears and kidneys. In addition, using the CRISPR/Cas9 gene editing technique — a potential treatment for diseases caused by nonsense mutations — has presented other challenges, such as off-target effects.

Aiming to find a suitable approach with the ability to repair nonsense mutations precisely, a team from the University of Iowa Carver College of Medicine, The Wistar Institute, the Cystic Fibrosis Foundation Therapeutics Lab and Integrated DNA Technologies investigated the potential of using tRNAs.

All genetic information contained within genes (DNA) is ultimately translated into proteins. However, the process is complex, with several steps: DNA is transformed into messenger RNA (mRNA), then a process called translation begins, which results in the production of proteins.

tRNA is a type of RNA molecule that helps decode a messenger mRNA sequence into a protein. Through specific sequences called anticodons, tRNA molecules match up with the corresponding mRNA and deliver the correct amino acid to build a protein in a cellular structure called ribosome.

Researchers engineered tRNAs to recognize and suppress three different stop codons — triplets of nucleotides that prematurely stop gene expression and impair protein production. (Gene expression is the process by which information in a gene is synthesized to create a working product, such as a protein). ...

To continue reading this article, click on this link

Tuesday, February 26, 2019

Muscle Biomarkers Correlate With Severity in SBMA

Neurofilament Light Chain [NfL]
Image: BestPractice

Wikipedia describes Neurofilaments this way: NF are intermediate filaments found in the cytoplasm of neurons. They are protein polymers measuring approximately 10 nm in diameter and many micrometers in length. Together with microtubules and microfilaments, they form the neuronal cytoskeleton. They are believed to function primarily to provide structural support for axons and to regulate axon diameter, which influences nerve conduction velocity. Neurofilaments are found in vertebrate neurons in especially high concentrations in axons, where they are all aligned in parallel along the long axis of the axon forming a continuously overlapping array. In addition to their structural role in axons, neurofilaments are also cargoes of axonal transport. Most of the neurofilament proteins in axons are synthesized in the nerve cell body, where they rapidly assemble into neurofilament polymers within about 30 minutes. These assembled neurofilament polymers are transported along the axon on microtubule tracks powered by microtubule motor proteins. 

Below is a portion of the abstract from a study published February 20th. You can read the entire study (PDF) at . 

Muscle and not neuronal biomarkers correlate with severity in spinal and bulbar muscular atrophy

Objective: To determine whether blood biomarkers of neuronal damage (neurofilament light chain [NfL]), muscle damage (creatine kinase [CK]), and muscle mass (creatinine) are altered in spinal bulbar muscular atrophy (SBMA aka Kennedy's Disease) and can be used as biomarkers for disease severity.

Methods: In this multicenter longitudinal prospective study, plasma and serum were collected from 2 cohorts of patients with SBMA in London, United Kingdom (n = 50), and Padova, Italy (n = 43), along with disease (amyotrophic lateral sclerosis [ALS]) and healthy controls, and levels of plasma and serum NfL, CK, and creatinine were measured. Disease severity was assessed by the SBMA Functional Rating Scale and the Adult Myopathy Assessment Tool at baseline and 12 and 24 months.

Results: Blood NfL concentrations were increased in ALS samples, but were unchanged in both SBMA cohorts, were stable after 12 and 24 months, and were not correlated with clinical severity. Normal NfL levels were also found in a well-established mouse model of SBMA. Conversely, CK concentrations were significantly raised in SBMA compared with ALS samples, and were not correlated to the clinical measures. Creatinine concentrations were significantly reduced in SBMA, and strongly and significantly correlated with disease severity.

Conclusions: While muscle damage and muscle mass biomarkers are abnormal in SBMA, axonal damage markers are unchanged, highlighting the relevant primary role of skeletal muscle in disease pathogenesis. Creatinine, but not CK, correlated with disease severity, confirming its role as a valuable biomarker in SBMA.

Note: The KDA just posted the research on their website. There was also a note from Pietro Fratta, who spoke about his biomarker research at last year's conference:

This work uses blood samples from 93 Kennedy’s patients, alongside controls and samples from models of disease, to look for traces of neuron and muscle damage in Kennedy’s disease. It finds that muscle damage is prominent, whilst neuron damage is below detection levels. This work highlights the role of muscle damage in Kennedy’s disease, which is extremely important for how therapies are designed. Further, this study supports the use of a specific biomarker, creatinine, for Kennedy’s disease clinical trials.

This study was possible only thanks to the incredibly strong participation to research of patients attending the Kennedy’s Clinic at the National Hospital in London and the University of Padova.