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]

I found the link to this article on the Kennedy’s Disease DownUnder Facebook page. You can read the entire article by clicking on the Title below. The ability to reproduce motor neurons that are the age of the patients could be helpful in studying the progression as well as potential treatments.

Scientists create new motor neurons out of skin cells

“… Scientists have converted human skin cells from adults directly into motor neurons without going through a stem cell state.

Motor neurons drive muscle contractions, and their damage underlies devastating diseases such as amyotrophic lateral sclerosis and spinal muscular atrophy, both of which ultimately lead to paralysis and early death. Scientists working to develop new treatments for neurodegenerative diseases have been stymied by the inability to grow human motor neurons in the lab.” …

“… The new technique makes it possible to study motor neurons of the human central nervous system in the lab. Unlike commonly studied mouse motor neurons, human motor neurons growing in the lab would be a new tool since researchers can’t take samples of these neurons from living people but can easily take skin samples.

Avoiding the stem cell phase eliminates ethical concerns raised when producing what are called pluripotent stem cells, which are similar to embryonic stem cells in their ability to become all adult cell types.” …

Importantly, avoiding a stem cell state also allows the resulting motor neurons to retain the age of the original skin cells and, therefore, the age of the patient. Maintaining the chronological age of these cells is vital when studying neurodegenerative diseases that develop in people at different ages and worsen over decades.

“… In this study, we only used skin cells from healthy adults ranging in age from early 20s to late 60s,” says senior author Andrew S. Yoo, an assistant professor of developmental biology at Washington University School of Medicine in St. Louis. “Our research revealed how small RNA molecules can work with other cell signals called transcription factors to generate specific types of neurons, in this case motor neurons. In the future, we would like to study skin cells from patients with disorders of motor neurons. Our conversion process should model late-onset aspects of the disease using neurons derived from patients with the condition.” …

“…The ability of scientists to convert human skin cells into other cell types, such as neurons, has the potential to enhance understanding of disease and lead to finding new ways to heal damaged tissues and organs, a field called regenerative medicine. …”

Neuromuscular junctions are pathological but not

This abstract was published in PubMed ahead of the printed version of the study. No additional information is available at this time, but it sounds interesting.

Neuromuscular junctions are pathological but not denervated in two mouse models of spinal bulbar muscular atrophy

Poort JE1, Rheuben MB1, Marc Breedlove S1, Jordan CL2.

Abstract

Spinal bulbar muscular atrophy (SBMA) is a progressive, late onset neuromuscular disease causing motor dysfunction in men. While the morphology of the neuromuscular junction (NMJ) is typically affected in neuromuscular disease, whether the NMJs in SBMA are similarly affected by disease is not known.”

Follow this link to read the rest of the abstract.  NeuromuscularJunctions

SMA Drug Trial Goes So Well It Ends Early

This Los Angeles Times article on a new treatment for SMA Type 1. This is very promising news and I believe it will lead to additional breakthroughs for Type 2,3 and 4. SMA is different then SBMA (Kennedy's Disease), but antisense technology is being used in other progressive disorders and could be the bridge to a treatment.

Below is an excerpt from the Times article. You can read the entire article by following this link: Ionis shares leap 30% after a drug trial goes so well, it ends early

"The only option

Spinal muscular atrophy occurs in about 1 out of 6,000 to 10,000 births. It's caused by mutations in a gene that reduce production of a protein needed for survival of movement-controlling spinal neurons.

Nusinersen increases production of the protein from a closely related gene by altering how RNA made from the gene is translated into protein. This is done with antisense technology, a field pioneered by Ionis.

Drugs based on antisense technology are meant to block or change how targeted genetic instructions delivered through RNA affect the making of proteins, which are the building blocks of life. For instance, they could block certain mutations from resulting in protein synthesis that causes an unwanted medical condition.

Nusinersen has been granted orphan drug status in both the U.S. and the European Union — indicating it shows promise in treating a rare disease or condition — and it’s designated for fast-track review in the United States."

Image:  http://www.slideshare.net/pooranachithraflowry/antisense-therapy-48602109

2017 annual budget process reflects support for research

Medical research is important for those of us living with a chronic or progressive disorder. The MDA Advocacy Newsletter included the following piece of positive news regarding funding of research.

Increase Funding for Research

One of MDA’s policy priorities is ensuring that maximum funding is available for biomedical research. To that end, thank you to all MDA Advocates who have taken action to encourage Congress to make increased research funding a priority.


Both chambers of Congress have included increased research funding in their spending proposals for next year by increasing support for the National Institutes of Health (NIH). The Senate plan includes a $2 billion increase while the House calls for a smaller, but still substantial increase of $1.25 billion. While these figures are not final, and no agreement has yet been reached in terms of final funding levels for fiscal year 2017, it is promising to see Congress making research funding a priority, and we are grateful to each member who has made sustained and robust research funding a priority. We will follow up with additional information when Congress resumes the budget process in September. 

More on CRISPR

A friend sent me this seven minute CBS video that does a good job of reporting what CRISPR is, and what are its potential benefits and concerns on its use. Genes and Dreams

CRISPR, gene editing technology, is light years ahead of other technology in this one area. Its potential uses are almost unbelievable. Yet, it is still in its infancy, and therefore needs strong parenting and further guidance to insure the technology is not abused.

Yet, for me, the hope grows stronger that a treatment, and potentially a cure, for Kennedy's Disease, SBMA, will become available in the not to distant future. It might not be available for my generation, but it sure appears it will be there for my children, and their children.

Photo: MIT News

Diane Merry - SBMA Researher

The MDA published the following article on a Kennedy's Disease researcher many of us know.

Five Questions with SBMA Researcher Diane Merry

Diane Merry, associate professor at Thomas Jefferson University in Philadelphia, is working to identify therapeutic opportunities to promote normal androgen receptor function while preventing the toxic effects of polyglutamine expansion in spinal-bulbar muscular atrophy (SBMA). With GlaxoSmithKline, Merry will test small molecule compounds that activate an enzyme called SIRT1 in cell and mouse models of SBMA to determine their therapeutic potential.

Please describe your current research in SBMA.
Many neurodegenerative diseases result from protein misfolding and accumulation due to genetic or environmental causes. SBMA is one such disease; it is an inherited, adult-onset, neuromuscular disease that is caused by the expansion of a polyglutamine tract within the androgen receptor (AR) and is related mechanistically to other neurodegenerative diseases caused by polyglutamine expansion.

An important feature of SBMA is that its onset and progression are dependent on the binding of androgenic hormones to the mutant receptor. Our studies of mouse and cell models of SBMA that reproduce the androgen- and polyglutamine-dependent nuclear AR aggregation seen in patients, as well as its toxicity, revealed that the mutant AR must be modified by the addition of acetyl groups for its aggregation and toxicity. Moreover, the deacetylase SIRT1 is strongly neuroprotective in cell models of SBMA and this neuroprotection largely depends upon its ability to remove acetyl groups from the mutant AR.

We are investigating the therapeutic potential of activating this acetyl group-removing enzyme, SIRT1, with small molecule activators. We will test these compounds in cell models, and ultimately in mouse models, of SBMA.  We anticipate that these studies will reveal new and powerful opportunities for therapeutic development in SBMA.

Is this your first MDA grant?
No, I was funded previously (as a post-doctoral fellow and then when I started my lab) by MDA.  It means a tremendous amount to me to be funded once again by this organization that is so committed to finding a cure for neuromuscular diseases.

What inspired you to study SBMA?
I come from a strong background of training in molecular genetics and molecular pathophysiology. I began to study the molecular basis of this disease in 1993, just a short time after the genetic cause of the disease was identified.  I have been studying SBMA ever since that time — for the past 22 years.

What is your focus within the SBMA field, and why is it important?
My focus is on the mutant androgen receptor protein itself and the effect of the polyglutamine expansion on androgen receptor metabolism (structure, trafficking, protein interactions, turnover), in order to identify therapeutic opportunities to promote normal androgen receptor function while preventing the toxic effects of the polyglutamine expansion. The work funded by this grant is designed to do just that.

There is currently no effective therapy or cure for SBMA and thus an effective therapy is a primary goal of our work. The work funded here is likely to bring us closer to that goal.

What do you feel people impacted by SBMA can have the most hope about with respect to research right now?
We know so much more about the disease process at this point in time, and we and others have identified disease targets for therapeutic development. I do think that a therapy or therapies are within sight for SBMA in the foreseeable future.

Does your work have any potential implications for other disease fields?
Our work has implications for other diseases in which the enzyme SIRT1 is neuroprotective.  Although the SIRT1 target proteins may be distinct, the identification of small molecule activators of SIRT1 is likely to open up possibilities for using these activators to treat other diseases.

Latest Research of SBMA (Kennedy's Disease)

Both EurrekAlert and News Medical published the following article on misfolding diseases including Kennedy’s Disease (SBMA). It is good to see more attention focused on this condition.

Future Science OA explores current research into protein misfolding diseases

“Future Science Group (FSG) today announced the publication of a special issue in Future Science OA, covering the rapidly evolving field of protein misfolding diseases.

Protein misfolding diseases, such as Alzheimer's and Parkinson's Disease, are rising in incidence and seeing increasing financial and healthcare burden. Treatments and accurate diagnostics for these diseases are lacking.

This issue of Future Science OA, featuring Guest Editor Salvador Ventura (Universitat Autònoma de Barcelona, Spain), highlights recent advances in the understanding of these disorders, and provides fresh ideas for their future therapy. In a series of articles written by experts at the cutting edge of the field, the issue begins by looking at recent inroads into our expanding knowledge of protein misfolding disorders and their protein targets. It then goes on to look at amyloid aggregation in specific disease areas, including the neurodegenerative: Alzheimer's, Parkinson's and Huntingdon's disease; glioblastoma; cystic fibrosis; spinal and bulbar muscular atrophy; and malaria. …”

__________

Also, eLife published the abstract of a recent study of Kennedy’s Disease. I understood some of the article, but am hoping Ed Meyertholen will provide some needed clarification on this research.  

Nemo-like kinase is a novel regulator of spinal and bulbar muscular atrophy

Abstract

“Spinal and Bulbar Muscular Atrophy (SBMA) is a progressive neuromuscular disease caused by polyglutamine expansion in the Androgen Receptor (AR) protein. Despite extensive research, the exact pathogenic mechanisms underlying SBMA remain elusive. Here we present evidence that Nemo-Like Kinase (NLK) promotes disease pathogenesis across multiple SBMA model systems. Most remarkably, loss of one copy of Nlk rescues SBMA phenotypes in mice, including extending lifespan. We also investigated the molecular mechanisms by which NLK exerts its effects in SBMA. Specifically, we have found that NLK can phosphorylate the mutant polyglutamine-expanded AR, enhance its aggregation, and promote AR-dependent gene transcription by regulating AR-cofactor interactions. Furthermore, NLK modulates the toxicity of a mutant AR fragment via a mechanism that is independent of AR-mediated gene transcription. Our findings uncover a crucial role for NLK in controlling SBMA toxicity and reveal a novel avenue for therapy development in SBMA.”

Note: You can download the PDF of the abstract near the top of the linked page.

Will CRISPR be the answer we have been hoping for?

I was reading the KDA Forum this afternoon and ran across this article in GIZMODO about CRISPR. It appears the possibilities are almost endless in regards to what you can use this for in the area of editing genomes. When I say endless, I mean finding a cure for Kennedy's Disease (SBMA). 

Excerpts from the article are shown below. Click on the title below to read the entire article.

Everything You Need to Know About CRISPR, the New Tool that Edits DNA

“CRISPR, a new genome editing tool, could transform the field of biology—and a recent study on genetically-engineered human embryos has converted this promise into media hype. But scientists have been tinkering with genomes for decades. Why is CRISPR suddenly such a big deal?

The short answer is that CRISPR allows scientists to edit genomes with unprecedented precision, efficiency, and flexibility. The past few years have seen a flurry of “firsts” with CRISPR, from creating monkeys with targeted mutations to preventing HIV infection in human cells. Earlier this month, Chinese scientists announced they applied the technique to nonviable human embryos, hinting at CRISPR’s potential to cure any genetic disease. And yes, it might even lead to designer babies. (Though, as the results of that study show, it’s still far from ready for the doctor’s office.)

In short, CRISPR is far better than older techniques for gene splicing and editing. ..."

Then, later in the article it mentioned the snipping of DNA sequences and the light bulb clicked on:  

"It is a more precise way of editing the genome...

As this point, you can start connecting the dots: Cas9 is an enzyme that snips DNA, and CRISPR is a collection of DNA sequences that tells Cas9 exactly where to snip. All biologists have to do is feed Cas9 the right sequence, called a guide RNA, and boom, you can cut and paste bits of DNA sequence into the genome wherever you want.”

This caught my attention near the end of the article. “… with CRISPR/Cas9, it’s theoretically possible to modify the genomes of any animal under the sun. That includes humans. CRISPR could one day hold the cure to any number of genetic diseases, but of course human genetic manipulation is ethically fraught and still far from becoming routine.”

Stem Cell Derived Motor Neurons from SBMA Patients

The following research paper was published in Science Direct this month. Some of the report is a little beyond my level of comprehension, so I will try to have it dumbed down. The highlights, abstract and conclusion are shown below. You can read the entire article by following the link above.  My dumbed-down conclusion is that it is interesting, but more study is needed.

_______________________________

Stem cell-derived motor neurons from spinal and bulbar muscular atrophy patients

Christopher Grunseich^{a, ,}  Kristen Zukosky^{a, 1,} , Ilona R. Kats^{a, 1,} , Laboni Ghosh^a, , George G. Harmison^a, , Laura C. Bott^{a, b,} , Carlo Rinaldi^a, , Ke-lian Chen^a, , Guibin Chen^c, , Manfred Boehm^c, , Kenneth H. Fischbeck^a,

---

Highlights

•  We characterized stem cells and motor neuron derivatives from patients with SBMA.

•  Variation in the repeat expansion mutation was observed in the cultured cells.

•  Reduced HDAC6 levels were found in the derived motor neurons.

•  Motor neurons from 2 patients with long repeats had increased acetylated α-tubulin.

---

Abstract

Spinal and bulbar muscular atrophy (SBMA, Kennedy's disease) is a motor neuron disease caused by polyglutamine repeat expansion in the androgen receptor. Although degeneration occurs in the spinal cord and muscle, the exact mechanism is not clear. Induced pluripotent stem cells from spinal and bulbar muscular atrophy patients provide a useful model for understanding the disease mechanism and designing effective therapy. Stem cells were generated from six patients and compared to control lines from three healthy individuals. Motor neurons from four patients were differentiated from stem cells and characterized to understand disease-relevant phenotypes. Stem cells created from patient fibroblasts express less androgen receptor than control cells, but show androgen-dependent stabilization and nuclear translocation. The expanded repeat in several stem cell clones was unstable, with either expansion or contraction. Patient stem cell clones produced a similar number of motor neurons compared to controls, with or without androgen treatment. The stem cell-derived motor neurons had immunoreactivity for HB9, Isl1, ChAT, and SMI-32, and those with the largest repeat expansions were found to have increased acetylated α-tubulin and reduced HDAC6. Reduced HDAC6 was also found in motor neuron cultures from two other patients with shorter repeats. Evaluation of stably transfected mouse cells and SBMA spinal cord showed similar changes in acetylated α-tubulin and HDAC6. Perinuclear lysosomal enrichment, an HDAC6 dependent process, was disrupted in motor neurons from two patients with the longest repeats. SBMA stem cells present new insights into the disease, and the observations of reduced androgen receptor levels, repeat instability, and reduced HDAC6 provide avenues for further investigation of the disease mechanism and development of effective therapy.

Abbreviations

• AR, androgen receptor;
• DHT, dihydrotestosterone;
• EtOH, ethanol;
• iPSC, induced pluripotent stem cell;
• SBMA, spinal and bulbar muscular atrophy

Keywords

·         Spinal and bulbar muscular atrophy;

• Induced pluripotent stem cells;
• Motor neuron disease;
• Androgen receptor

___________________

Conclusions

Our study demonstrates several findings in the SBMA iPSCs that warrant additional investigation. The finding that CAG repeat length is unstable in specific iPSC lines allows additional study of factors that may be involved in the expansion or contraction of the repeat. It is possible that genetic factors in some lines make them more susceptible to instability, or that factors intrinsic to the reprogramming strategy modify the instability. SBMA iPSCs appear to have motor neuron differentiation capacity equivalent to controls, and although no changes in cell survival could be appreciated it is possible that treatment with additional stressors would induce a selective vulnerability. Although increased acetylated α-tubulin was observed predominantly in cells from two patients with particularly long repeats, the HDAC6 decrease was also observed in motor neurons cultured from several others. Decreased HDAC6 and increased acetylated α-tubulin levels were also seen in an MN1 cell model of SBMA, and in the spinal cord of an SBMA patient. Since HDAC6 has been shown to be important for trafficking misfolded protein to the aggresome, a deficiency in HDAC6 may produce a reduction in autophagic flux, with changes in mitochondrial activity, protein trafficking, and lysosomal function. Changes in lysosomal localization were observed in the SBMA motor neurons, and the lysosomal marker LAMP1 was found to have increased glycosylation. The significance of this glycosylation is not clear at this time, but it appears to indicate abnormal function of the lysosomal compartment. Further studies may help to determine how HDAC6 levels are reduced in SBMA and to characterize the consequence of these changes in the disease mechanism.