Archived Research Updates
2012 - 2011 Research
GOOD NEWS on the Research Front
MDA’s Quest Magazine just published an update on IGF-1. Maria Pennuto, a previous recipient of a KDA Research Grant and MDA funding, provided an update to reporter Amy Madsen.
The Living with Kennedy's Disease blog has several articles about IGF-1 because of its potential. We hope to hear more promising news at the upcoming KDA Conference and Educational Symposium the second week of October in New Orleans.
Neurological Review Article, April 2012 - Molecular Pathophysiology and Disease-Modifying Therapies for Spinal and Bulbar Muscular Atrophy
A BBC News article by James Gallagher reports that: Stem cells, which can become any other specialist type of cell from brain to bone, are thought to have huge promise in a range of treatments. Many trials are taking place, such as in stroke patients or specific forms of blindness.
An alternative method has been to take skin cells and reprogram them into "induced" stem cells. These could be made from a patient's own cells and then turned into the cell type required.
This study created "neural precursor" cells, which can develop into three types of brain cell: neurons, astrocytes and oligodendrocytes. These precursor cells have the advantage that, once created, they can be grown in a laboratory into very large numbers. This could be critical if the cells were to be used in any therapy.
Ed Meyertholen comments: “As is always the case with stem cell research, one needs to understand that while this is an important piece of work, we are still years (and years) away from therapy. In any case, I have attached the actual paper. This is also interesting as several of the attendees at the 2010 KDA conference donated skin cells for just such a project (and I believe that NIH has something similar going on).”
The article can also be found in the Living with Kennedy's Disease blog:
We take it for granted, but the fact that our muscles grow when we work them makes them rather unique. Now, researchers have identified a key ingredient needed for that bulking up to take place. A factor produced in working muscle fibers apparently tells surrounding muscle stem cell "higher ups" that it's time to multiply and join in, according to a study in the January Cell Metabolism, a Cell Press journal.
In other words, that so-called serum response factor (Srf) translates the mechanical signal of work into a chemical one. "This signal from the muscle fiber controls stem cell behavior and participation in muscle growth," says Athanassia Sotiropoulos of Inserm in France. "It is unexpected and quite interesting." It might also lead to new ways to combat muscle atrophy.
Sotiropoulos' team became interested in Srf's role in muscle in part because their earlier studies in mice and humans showed that Srf concentrations decline with age. That led them to think Srf might be a culprit in the muscle atrophy so common in aging. The new findings support that view, but Srf doesn't work in the way the researchers had anticipated. Srf was known to control many other genes within muscle fibers. That Srf also influences the activities of the satellite stem cells came as a surprise.
Mice with muscle fibers lacking Srf are no longer able to grow when they are experimentally overloaded, the new research shows. That's because satellite cells don't get the message to proliferate and fuse with those pre-existing myofibers. Srf works through a network of genes, including one known as Cox2. That raises the intriguing possibility that commonly used Cox2 inhibitors - think ibuprofen - might work against muscle growth or recovery, Sotiropoulos notes.
Treatments designed to tweak this network of factors might be used to wake muscle stem cells up and enhance muscle growth in circumstances such as aging or following long periods of bed rest, she says. Most likely, such therapies would be more successfully directed not at Srf itself, which has varied roles, but at its targets.
"It may be difficult to find a beneficial amount of Srf," she says. "Its targets, interleukins and prostaglandins, may be easier to manipulate."
2011 Research Updates-
December 09, 2011 - SIRT1 Modulates Aggregation and Toxicity through Deacetylation of the Androgen Receptor in Cell Models of SBMA. To access the article, click here.
Montie HL, Pestell RG, Merry DE.
Published in Journal of Neurosciece - 2011 Nov 30;31(48):17425-36.
Departments of Biochemistry and Molecular Biology, and Cancer Biology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107.
Posttranslational protein modifications can play a major role in disease pathogenesis; phosphorylation, sumoylation, and acetylation modulate the toxicity of a variety of proteotoxic proteins. The androgen receptor (AR) is substantially modified, in response to hormone binding, by phosphorylation, sumoylation, and acetylation; these modifications might thus contribute to DHT-dependent polyglutamine (polyQ)-expanded AR proteotoxicity in spinal and bulbar muscular atrophy (SBMA). SIRT1, a nuclear protein and deacetylase of the AR, is neuroprotective in many neurodegenerative disease models. Our studies reveal that SIRT1 also offers protection against polyQ-expanded AR by deacetylating the AR at lysines 630/632/633. This finding suggested that nuclear AR acetylation plays a role in the aberrant metabolism and toxicity of polyQ-expanded AR. Subsequent studies revealed that the polyQ-expanded AR is hyperacetylated and that pharmacologic reduction of acetylation reduces mutant AR aggregation. Moreover, genetic mutation to inhibit polyQ-expanded AR acetylation of lysines 630/632/633 substantially decreased its aggregation and completely abrogated its toxicity in cell lines and motor neurons. Our studies also reveal one means by which the AR acetylation state likely modifies polyQ-expanded AR metabolism and toxicity, through its effect on DHT-dependent AR stabilization. Overall, our findings reveal a neuroprotective function of SIRT1 that operates through its deacetylation of polyQ-expanded AR and highlight the potential of both SIRT1 and AR acetylation as powerful therapeutic targets in SBMA.
Below is an explanation from Ed Meyertholen of what the researchers found and what this means for those of us living with Kennedy’s Disease.
What did they find?
This paper was an investigation related the effect of modifying the androgen receptor (AR) on the toxicity of mutant AR on cells. As a brief introduction, Kennedy’s Disease (aka KD or SBMA) is due to a mutation in the gene that tells the cell how to make a protein called the androgen receptor. It is generally believe that this mutation results in the formation of a toxic by-product when the cell is removing old AR. This toxic fragment results in the death of certain nerve cells known as motor neurons. It is the death of these cells that is thought to be ultimately responsible for the formation of symptoms of Kennedy’s Disease. Many studies on Kennedy’s Disease involve attempts at reducing the toxicity of this fragment.
Cells often modify proteins and in doing so, can alter their activity. One such alteration of the AR is the addition of a small molecule called an acetyl group to the protein. The addition of this group has a special name, acetylation. Removing the acetyl group is deacetylation. This study primarily found that if you reduce the amount of acetylation on mutant AR, cells do not die even though they have the mutant form of AR.
What does this mean to Kennedy’s Disease patients?
One of difficult aspects of Kennedy’s Disease is that scientists do not know enough about all the normal factors that affect the working of the AR and that makes it more difficult to determine why it kills cells. This study could open up a new pathway for discovering drugs/chemicals that may reduce Kennedy’s Disease symptoms. If one could find a drug that stimulates the deacetylation of the AR, it could be therapeutic.
December 02, 2011 - Molecular Mechanisms of Androgen Action – A Historical Perspective
By Albert O. Brinkmann
Androgens and the androgen receptor (AR) are indispensable for expression of the male phenotype. The two most important androgens are testosterone and 5-dihydrotestosterone. The elucidation of the mechanism of androgen action has a long history starting in the 19th century with the classical experiments by Brown-Séquard. In the 1960s the steroid hormone receptor concept was established and the AR was identified as a protein entity with a high affinity and specificity for testosterone and 5-dihydrotestosterone. In addition, the enzyme 5-reductase type 2 was discovered and found to catalyze the conversion of testosterone to the more active metabolite 5-dihydrotestosterone. In the second half of the 1980s, the cDNA cloning of all steroid hormone receptors, including that of the AR, has been another milestone in the whole field of steroid hormone action. Despite two different lig-ands (testosterone and 5-dihydrotestosterone), only one AR cDNA has been identified and cloned. The AR (NR3C4) is a ligand-dependent transcription factor and belongs to the family of nuclear hor-mone receptors which has 48 members in human. The current model for androgen action involves a multistep mechanism. Studies have provided insight into AR association with co-regulators involved in transcription initiation and on intramolecular interactions of the AR protein during activation. Knowl-edge about androgen action in the normal physiology and in disease states has increased tremendously after cloning of the AR cDNA. Several diseases, such as androgen insensitivity syndrome (AIS), prostate cancer and spinal bulbar muscular atrophy (SBMA), have been shown to be associated with alterations in AR function due to mutations in the AR gene or dysregulation of androgen signalling. A historical overview of androgen action and salient features of AR function in normal and disease states are provided herein.
To download the entire report in a pdf format, CLICK HERE
November 28, 2011 - Videos of presentations at the 2011 KDA Annual Conference
The 2011 Kennedy’s Disease annual conference and educational symposium was held this month. Over twenty researchers were involved in the conference and many gave updates on their current research.
Jack Durning recorded some of the presentations and released them to YouTube this week.
Ed Meyertholen, the KDA’s guru in explaining Kennedy’s Disease, was one of the presenters. From the attendees after-conference survey, most everyone rated Ed’s discussion as one of the most interesting. Ed’s presentation is five 15 minute videos and one six minute video. Ed explains Kennedy’s Disease, DNA, bindings, folding, the ‘wood-chipper’, cytoplasm, clinical trials, placebos and much more.
Ed, unfortunately, did not use a mike. There were many times he was not facing the recorder’s mike so he is more difficult to hear.
Below is a link to Dr. Lenore Bietel's presentation. Lenore is a Kennedy's Disease researcher located in Canada. She gives a thirteen minute presentation on her lab’s research project including discussing whether the PolyQ AR clogs up Proteosomes as well as a study of the androgen receptor and the protein interaction connection.
And, the following link is for Dr. Masahisa Katsuno's presentation of his research including an explanation of neuro-degeneration and the leuprorelin clinical trial. This recording starts a few minutes late into the presentation.
If you have any questions, please let us know and we will try to have them answered.
November 01, 2011 - Macroautophagy Is Regulated by the UPR–Mediator CHOP and Accentuates the Phenotype of SBMA Mice
Zhigang Yu,#1 Adrienne M. Wang,#1,2 Hiroaki Adachi,3 Masahisa Katsuno,3 Gen Sobue,3 Zhenyu Yue,4 Diane M. Robins,5 and Andrew P. Lieberman1,2*
Altered protein homeostasis underlies degenerative diseases triggered by misfolded proteins, including spinal and bulbar muscular atrophy (SBMA), a neuromuscular disorder caused by a CAG/glutamine expansion in the androgen receptor. Here we show that the unfolded protein response (UPR), an ER protein quality control pathway, is induced in skeletal muscle from SBMA patients, AR113Q knock-in male mice, and surgically denervated wild-type mice. To probe the consequence of UPR induction, we deleted CHOP (C/EBP homologous protein), a transcription factor induced following ER stress. CHOP deficiency accentuated atrophy in both AR113Q and surgically denervated muscle through activation of macroautophagy, a lysosomal protein quality control pathway. Conversely, impaired autophagy due to Beclin-1 haploinsufficiency decreased muscle wasting and extended lifespan of AR113Q males, producing a significant and unexpected amelioration of the disease phenotype. Our findings highlight critical cross-talk between the UPR and macroautophagy, and they indicate that autophagy activation accentuates aspects of the SBMA phenotype.
The entire report can be read by following this link: Macroautophagy
October 01, 2011 - Testosterone Treatment Fails to Accelerate Disease in Mouse Models
Doctors Erica S. Chevalier-Larsen1 and Diane E. Merry reported in Disease Models & Mechanisms:
Transgenic AR112Q and non-transgenic mice were implanted with timed-release pellets designed to deliver 4-6 ng/ml of testosterone for 90 days. Over the course of the experiment, implantation of testosterone pellets increased circulating testosterone an average of threefold, from 0.40±0.23 ng/ml; this is a significant elevation of testosterone levels in treated animals (ntg T-treated and tg T-treated) over those implanted with placebo pellets. Although 90-day testosterone pellets were used, we observed a decline in potency of the pellets by the end of the 90-day period (months three and six).
Implantation of new pellets at the end of 90 days restored circulating testosterone levels. Although circulating testosterone was elevated in treated mice, motor function assays did not reveal any effect of testosterone treatment on phenotype. Motor function assays were performed monthly for 6 months; results were consistent for all 6 months of treatment. Beginning at 3 months of age (1 month following treatment), AR112Q males showed decreased rotarod performance, regardless of T-treatment, when compared with non-transgenic T-treated males.
The entire report can be read by following this link to download the paper: Research Report (PDF)
-September 29, 2011 - NIH TO MAKE A MIGHTIER MOUSE RESOURCE FOR UNDERSTANDING DISEAS
U.S. Department of Health and Human Services
NATIONAL INSTITUTES OF HEALTH NIH News
National Human Genome Research Institute (NHGRI)
For Immediate Release: Thursday, September 29, 2011
Over the next five years, National Institutes of Health (NIH)-funded researchers will extensively test and generate data about mice with disrupted genes to gain clues about human diseases. NIH today awarded a set of cooperative agreements totaling more than $110 million to begin the second phase of the Knockout Mouse Project (KOMP).
The results of the next stage, called the Knockout Mouse Phenotyping Project, or KOMP2, will be placed in a public database. Researchers make knockout mice by disrupting the function of individual genes across the animal's genome.
KOMP2 is a trans-NIH and NIH Common Fund project that will work with other members of the International Knockout Mouse Phenotyping Consortium (IMPC) to generate about 5,000 strains of knockout mice that will undergo a large battery of clinical phenotype tests. A phenotype includes biological information about appearance, behavior and other measurable physical and biochemical characteristics. Such information will help reveal how all traits are affected by deleting a given gene in an individual mouse.
In the long term, the project aims to enable the research community to establish the traits associated with the function of every protein-coding gene in the mammalian genome. Such information will be valuable for the discovery of the genetic causes of human diseases and will aid efforts to identify new drug targets.
"The generation of detailed phenotypic information for each knockout mouse strain will be a boon to disease researchers who want to determine the function of genes and to improve mouse models of human disease," said NIH Director Francis S. Collins, M.D., Ph.D. "I am grateful to all of the people and programs across NIH who are supporting this effort and to our international partners who have joined us in this scientific endeavor."
In partnership with several international programs, the initial five-year phase of KOMP will reach its goal of creating knockout mouse embryonic stem cell lines for each of the approximately 21,000 protein-coding genes in the mouse genome this year. The International Knockout Mouse Consortium (IKMC) includes the Knockout Mouse Project (KOMP), U.S.A.; the European Conditional Mouse Mutagenesis Program (EUCOMM) funded by the European
Commission: the Texas A&M Institute for Genomic Medicine (TIGM); and the North American Conditional Mouse Mutagenesis Project (NorCOMM) funded by Genome Canada.
"NIH is committed to making knockout mouse models more widely accessible to the biomedical research community," said James Battey, M.D., Ph.D., director of the National Institute on Deafness and Other Communication Disorders (NIDCD), who is also a co-chairman of the Trans-NIH Mouse Initiative. "Getting these valuable models into the hands of a wide range of researchers will serve to accelerate our efforts to develop new strategies for understanding and treating human disease."
During the next five years, KOMP2 will transform the knockout mouse embryonic stem (ES) cells into adult mice for 2,500 lines of well-characterized knockout mice strains, and IMPC will create about 2,500 additional knockout mouse strains. Each mouse will undergo the same standard analysis so that the results can be compared for all of the mice tested. NIH has awarded six cooperative agreements to three groups to establish production and phenotype centers for the project.
"It is going to take a great deal of scientific teamwork to assimilate phenotypic information about this knockout mouse resource, but we are confident in the team that has been assembled to accomplish the task," said National Human Genome Research Institute (NHGRI) Director Eric D. Green, M.D., Ph.D. NHGRI is involved in the planning and administration of KOMP2.
The National Center for Research Resources (NCRR) will administer the awards for the production centers, and NHGRI will administer the awards for the phenotyping centers. NCRR and NHGRI are components of the NIH.
The funded groups will all receive a total of approximately $34 million and are expected to produce and phenotype 833 strains of knockout mice each for a total of about 2,500 knockout mouse lines. Recipients of the awards are:
- Baylor College of Medicine, Houston. This center will collaborate with the Wellcome Trust Sanger Institute in Hinxton, England and the Medical Research Council (MRC) Harwell in Oxfordshire, England.
- University of California, Davis. This center will collaborate with the Toronto Center for Phenogenomics in Canada, Children's Hospital Oakland Research Institute in California, and Charles River Laboratories in Wilmington, Mass.
- The Jackson Laboratory in Bar Harbor, Maine.
"This resource will enable many more researchers to tap into the power of knockout mice for exploring gene function, which in turn will speed our efforts to improve human health," said Louise E. Ramm, Ph.D., acting director, National Center for Research Resources.
In addition to the production and phenotype centers, NIH awarded a five-year, cooperative agreement totaling $10 million to the European Bioinformatics Institute in Hinxton, England, which will collaborate with MRC Harwell and Wellcome Trust Sanger Institute to set up a data coordination center and database to track progress of the project and to coordinate efforts between KOMP2 and IMPC researchers. In addition, this center will build an integrated Web portal that will provide researchers access to the phenotype data.
The mouse is a key mammalian system in which to produce a genomics resource because of the long history and depth of understanding of mouse genetics and the availability of the mouse genome sequence. What's more, researchers have made advances over the last several years in improving the efficiency and decreasing the cost of generating knockout mice.
Historically, researchers have generated their own lines of knockout mice to serve as models for human disease, such as heart disease or cancer. However, rather than generating a detailed and comprehensive phenotype of the mouse, they often are only interested in a handful of phenotypes. For example, a researcher interested in cardiovascular disease may only want to examine the effect of a disrupted gene on blood pressure.
This single-lab approach can be expensive and inefficient. A researcher with access to a low-cost knockout mouse that has been extensively phenotyped can focus his or her time and research budget on more in-depth research questions rather than spending it on producing a knockout mouse about which the researcher has limited information.
KOMP2 and IMPC researchers will begin by creating lines of knockout mice from embryonic stem cells produced by KOMP. The 5,000 genes that will be knocked out will be selected from nominations already submitted by the research community. Many of the selected genes will be used to study disease processes and underlying mechanisms. Others will be selected based on the genetic variations associated with the human diseases that have been uncovered by genome-wide association studies.
Statistically, about 25 percent of the mouse pups will inherit both copies of the knocked out gene, while their littermates will have only one copy and be heterozygous, or normal. The knockout mice and the healthy littermates will both undergo a battery of more than 400 phenotype measurements at multiple times during their lives. Tests will include X-ray imaging, magnetic resonance imaging (MRI), blood exams, balance tests, and urine and fecal analysis, to name a few. Both the knockout and normal phenotype data will be made available through the KOMP2 data coordination center so that researchers who acquire and study the knockout mice can compare various phenotypes.
"We want to characterize each line of mice broadly with no assumptions about what the gene is or is not doing," said IMPC Executive Director Mark Moore, Ph.D. "If you think of the function of a gene as a needle in a haystack, we're removing the haystack so you can see what the needle does."
At the end of the initial five years of the effort, the NIH and IMPC will evaluate the usefulness of the resource to the research community. If the evaluation is a positive one, both efforts may scale up to create and phenotype a total of 12,000 more knockout mice.
Once each knockout mouse is phenotyped, researchers can obtain information on what knockout mouse lines are available and how to order them from the University of California Davis KOMP Repository.
To access the IKMC Web portal, please go to <www.knockoutmouse.org>.
The 18 NIH institutes, centers and offices contributing to the Knockout Mouse Project are: the NIH Office of Strategic Coordination/Common Fund; NCRR; the National Eye Institute; NHGRI; the National Heart, Lung and Blood Institute; the National Institute on Aging; the National Institute of Alcohol Abuse and Alcoholism; the National Institute of Arthritis and usculoskeletal and Skin Diseases; the Eunice Kennedy Shriver National Institute of Child Health and Human Development; NIDCD; the National Institute of Dental and Craniofacial Research; the National Institute of Environmental Health Sciences; the National Institute of General Medical Sciences; the National Institute of Mental Health; the National Institute of Neurological Disorders and Stroke; the National Institute of Diabetes and Digestive and Kidney Diseases; the National Cancer Institute; and the Office of AIDS Research.
For several months now we knew a clinical study was coming. This week NIH posted the following information on their website. (If you are interested in participating in this study, the contact information is near the bottom of this page)
Effect of Functional Exercise in Patients
with Spinal and Bulbar Muscular AtrophyNumber: 11-N-0171
- A. Summary: Background:
- -Spinal and bulbar muscular atrophy (SBMA) is an inherited disorder that affects men. People with SBMA often have weakness throughout the body, including the muscles they use for swallowing, breathing, and speaking. We do not know if exercise helps or harms people with SBMA.
-To see if a 12-week program of either strength exercise or stretching exercises will improve strength, function, or quality of life in people with SBMA
-Participants will be men 18 years of age or older who have genetic confirmation of SBMA.
-They must be able to walk at least 50 feet with or without an assistive device such as a cane or a walker and stand for 10 minutes without using an assistive device.
-They must have access to a computer with an Internet connection.
-At the first visit to NIH (2 days), participants will have a medical history taken and undergo a physical exam. They will also have blood tests and an EKG, and complete questionnaires about mood, health, and exercise. Tests of muscle strength, balance, and endurance will also be done.
-Participants who qualify for the study will receive instruction about either strengthening or stretching exercises. They will do these exercises at home one to three times a week for 12 weeks.
-They will wear a small activity monitor while they exercise and record their exercise in a diary.
-At the end of 12 weeks, participants will return to the NIH for 2 days. They will undergo the same tests as they had on the first visit.
-Participants will receive follow-up phone calls and e-mails during the study and for 4 weeks after the last visit.
E. Sponsoring Institute:
- National Institute of Neurological Disorders and Stroke (NINDS)
- F. Recruitment Detail
- Type: Participants currently recruited/enrolled
- Gender: Male
- G. Eligibility Criteria:
1. Genetically confirmed SBMA.
2. Ambulatory and walk a distance of at least 50 feet with or without a walker.
3. Able to stand for 10 minutes without the use of any assistive devices.
4. Willing to travel to the NIH at the beginning and end of the study.
5. Willing to participate in telephone monitoring.
6. AMAT score of less than 41, but greater than 14.
8. Willing to participate in all aspects of trial design and follow-up.
9. Access to a computer with an internet connection
10. Able to do all of the exercises according to the standards of the study examiners at the beginning and end of the study
11. Willing to forgo starting an additional exercise plan for the 12 week duration of the study
12. Age greater than 18 years
- EXCLUSION CRITERIA:
1. Medical condition which would preclude exercise such as COPD, congestive heart failure, and cardiac arrhythmias.
2. Presence of an additional comorbid condition such as stroke, myopathy, or radiculopathy which also results in weakness.
3. Beginning a separate exercise program involving at least two weekly sessions of 20 minutes of exercise each within two months of the start of the trial.
- Patient Recruitment and Public Liaison Office
10 Cloister Court
Bethesda, Maryland 20892-4754
Toll Free: 1-800-411-1222
TTY: 301-594-9774 (local),1-866-411-1010 (toll free)
AndroScience Corporation Awarded a $3.8 Million, 3-Year Milestone-Driven, Cooperative Translational Research Grant from the NIH to Develop an Oral Treatment for Spinal Bulbar Muscular Atrophy (Kennedy's Disease)
SAN DIEGO, Jan. 25, 2011 /PRNewswire/ -- AndroScience Corp. (ASC), based in San Diego, California, announced receiving a $3.8 Million, 3-year milestone-driven, cooperative translational research grant from the National Institute of Neurological Disorders and Stroke (NINDS) of the National Institutes of Health (NIH). Through a joint research effort with the Neurogenetics Branch of the NINDS, ASC will use the funding to pursue development of an oral drug treatment for spinal and bulbar muscular atrophy (SBMA) or Kennedy's Disease, a rare hereditary neurodegenerative disease, which currently has no approved drug available to patients. Key pathological features of SBMA include progressive motor neuropathy and androgen insensitivity syndrome caused by a distinctive mutation within the androgen receptor (AR) gene. ASC has developed a unique platform of therapeutic small molecule drugs, which selectively and potently enhance degradation of the AR protein, termed AR degradation enhancers (ARD enhancers).
"Given encouraging pre-clinical results and the clear need for a new therapeutic option for SBMA patients, ASC is excited to continue advancing preclinical development of this promising novel drug candidate," said ASC President Charles Shih, Ph.D. "The funding provided by the NINDS/NIH will significantly propel our efforts in validating ARD enhancers as a disease-modifying therapeutic intervention against such a rare and devastating neurodegenerative illness."
This $3.8 Million cooperative translational research grant will leverage expertise from the NINDS and draw upon ASC's innovative approach to targeting the mutant androgen receptor (AR). The goals of the grant will be to first validate an orally administered ARD enhancer drug is efficacious in the SBMA transgenic animal model, and further, to complete preclinical toxicology, safety pharmacology, and ADME studies necessary in supporting of an IND filing to commence human clinical studies. To date, ASC has provided robust proof of concept data using an ARD enhancer compound; demonstrating treatment ameliorates cardinal features of SBMA neuromuscular pathology, restores functional activity, and improves survival in a SBMA transgenic mouse model.
About Spinal Bulbar Muscular Atrophy (SBMA) – Kennedy's Disease
Spinal and bulbar muscular atrophy (SBMA or Kennedy's Disease) is a rare hereditary neurodegenerative disease that affects lower motor neurons, with progressive muscle atrophy and weakness of the bulbar, facial, and limb muscles. The disease results in progressive dysphasia, motor dysfunction, and typically affects men in the fourth or fifth decade of life. SBMA is caused by a mutation in the X-chromosome linked androgen receptor (AR) gene that results in excessive repeats of the amino acid glutamine (polyQ) within AR protein. A molecular genetic test is clinically available which has a 100% mutation detection rate to definitively diagnose SBMA. Neurotoxicity caused by these expanded polyQ AR aggregates is believed to play a pivotal role in the pathogenesis of SBMA. SBMA is considered an orphan drug indication and no approved therapy exists. Furthermore, very few drug candidates are being evaluated in clinical trials.
About AndroScience Corporation
AndroScience (ASC) is a privately held San Diego, California based pharmaceutical company applying expertise in natural product chemistry to develop proprietary small molecule drug compounds targeting disease dependent intracellular signaling events related to the Androgen Receptor (AR) and selective Signal Transducer and Activation of Transcription (STAT) pathways. The company is focused on therapeutic indications of significant medical and commercial importance, including androgen-dependent diseases in both topical and systemic treatment settings and novel approaches to the treatment of cancer. Active ARD enhancer therapeutic programs include topical indications: acne (in Phase 2b clinical trail), alopecia (male pattern baldness) and wound healing; and systemic indications: SBMA, prostate cancer, HBV-induced HCC, and bladder cancer. Currently, the newly discovered STAT inhibitor compounds demonstrate potent anti-tumor properties across a wide range of solid and hematological tumors. ASC is actively seeking licensing partners for multiple products at various stages of program development with both domestic and international based pharmaceutical companies.
About National Institute of Neurological Disorders and Stroke (NINDS), NIH
The Intramural Research Program of the National Institute of Neurological Disorders and Stroke (NINDS) is one of the largest neuroscience research centers in the world. Investigators in the NINDS intramural program conduct research in the basic, translational, and clinical neurosciences. Their specific interests cover a broad range of neuroscience research including molecular biophysics, synapses and circuits, neuronal development, integrative neuroscience, brain imaging and neurological disorders. Through collaboration, pre- and postdoctoral training programs, jointly sponsored seminar series and special interest groups, NINDS investigators and investigators in other intramural programs (NIMH, NEI, NIDCD and NICHD) contribute to a vital and growing neuroscience research community at the National Institutes of Health. www.ninds.nih.gov
Bilal Malik, Niranjanan Nirmalananthan, Lynsey G. Bilsland2, Albert R. La Spada, Michael G. Hanna, Giampietro Schiavo, Jean-Marc Gallo and
February 7, 2011 - Spinal and bulbar muscular atrophy (SBMA), or Kennedy’s disease, is a late onset motor neuron disease (MND) caused by an abnormal expansion of the CAG repeat in the androgen receptor (AR) gene on the X-chromosome, encoding a polyglutamine sequence (poly-Q) in the protein product. Mutant poly-Q expanded AR protein is widely expressed but leads to selective lower motoneuron death. Although the mechanisms that underlie SBMA remain unclear, defective axonal transport has been implicated in MND and other forms of poly-Q disease. Transcriptional dysregulation may also be involved in poly-Q repeat pathology. We therefore examined axonal transport in a mouse model of SBMA recapitulating many aspects of the human disease. We found no difference in the expression levels of motor and the microtubule associated protein tau, in spinal cord and sciatic nerve of wild-type (WT) and SBMA mice at various stages of disease progression. Furthermore, we found no alteration in binding properties of motor proteins and tau to microtubules. Moreover, analysis of axonal transport rates both in cultured primary motoneurons in vitro and in vivo in the sciatic nerve of adult WT and mutant SBMA mice, demonstrated no overt axonal transport deficits in these systems. Our results therefore indicate that unlike other motoneuron and poly-Q diseases, axonal transport deficits do not play a significant role in the pathogenesis of SBMA.
Explanation by Ed Meyertholen: There has been speculation that the reason that the motor neurons die in KD is that the transport of materials to the end of the axon is blocked. The motor neurons are the cells that tell muscle to contract. They have a cell body (main part of cell with all the usual cell parts) is in the spinal cord. Each cell also has a long tubelike process called an axon that connects to the muscle cell. Thus, the axon is a long continuation of the motor neuron - it is very long and thin (can be over 2-3 feet long in some instances). Since the cell body is where the cell machinery exists, the cell must be able to transport needed chemicals to the end of the axon - this is axonal transport. If this transport were to be blocked, then the axon, and thus the cell, would no longer function. This paper apparently has evidence that this axonal transport is NOT defective in KD.