Research Progress on Charcot-Marie-Tooth Disease


CMT shark logo

As some of you know, I have CMT, a hereditary disease that I’ve traced back at least five generations in my father’s maternal line. There’s a lot of research being conducted into the 80+ genetic causes of this neuromuscular disorder, much of it sponsored by the CMT Association’s STAR program (Strategy to Accelerate Research.) The various research projects are funded largely by donations from individuals and families who know firsthand what it’s like to live with the debilitating effects of CMT. I recently received an update about research progress, which I’d like to share with you all today.

First, here are some enlightening statistics taken from Wikipedia.

“Charcot–Marie–Tooth disease (CMT), also known as Charcot–Marie–Tooth neuropathy, hereditary motor and sensory neuropathy (HMSN) and peroneal muscular atrophy (PMA), is a genetically and clinically heterogeneous group of inherited disorders of the peripheral nervous system characterized by progressive loss of muscle tissue and touch sensation across various parts of the body. Currently incurable, this disease is the most commonly inherited neurological disorder, and affects approximately 1 in 2,500 people[1][2] equating to approximately 26,000 people in the United Kingdom and 128,000 people in the United States. CMT was previously classified as a subtype of muscular dystrophy.“

More from the Mayo Clinic:

Charcot-Marie-Tooth disease is a group of related conditions all caused by inherited mutations in genes involved with the structure and function of the nerves that serve your feet, legs, hands and arms.

In some cases, these genetic mutations result in damage to the nerve itself. Other mutations damage the myelin sheath, the protective coating that surrounds the nerve. The end result, however, is the same — weaker messages traveling between your extremities and your brain.

Now here is the 3rd Quarter Research Update through September 31, 2015 from CMTA’s CEO, Patrick Livney. (technical but enlightening)

CMT1A (most common form, believed to be the culprit in about 60% of CMT cases)

· Sanofi-Genzyme completed 1.9 million compound screen early in the year. Further work distilled the results down to 742 active compounds. Continuous triage will bring this number down even further over the next quarter. Pilot sets of compounds are being tested using stem cell-derived human Schwann cells (G. Lee, Johns Hopkins), myelination assays in culture (L. Feltri, Univ. of Buffalo), and in primary Schwann cells.

· We initiated a collaborative development of serum biomarkers for CMT1A together with Genzyme. Serum samples are being collected at the University of Iowa. Joint meeting with Genzyme is being planned for November.

· An Addex compound that regulates a target implicated in Schwann cell myelination is being evaluated in studies in CMT1A rodent models.

· An agreement with licensing rights was completed with Affectis Pharmaceuticals to work on a compound that regulates P2X7, a cell surface target on Schwann cells that may regulate myelin formation. This has entered testing in CMT1A rodent models.

· Signed an MTA (Material Transfer Agreement) with AbbVie for use and data on their P2X7-directed compounds.

· The Amgen proteasome inhibitor is currently in testing in rodent models of CMT1A.

· On-going discussion with ISIS to use their custom molecules in an in vivo study. Study has been initiated in a rodent model of CMT1A and samples are being analyzed.

· NCATS (National Center for Advancing Translational Science) has completed a 400,000 compound screen. Svaren laboratory finished a new assay to establish specificity for PMP22 lowering (intended goal) vs. MPZ or Myelin Protein Zero lowering (which would be a negative side effect). Trish Dranchak at NIH has tested and validated this assay. This assay has been used on approximately 10,000 cherry- picked compounds from NCATS screen to identify specific inhibitors of PMP22 expression that do not affect the vital MPZ myelin component. The secondary screen is now completed and under analysis.

· Pfizer provided an additional ~250 compounds from their chemogenomics library that had shown promise of reducing PMP22. These compounds were tested in both PMP22 and MPZ assays listed above. Screen was completed, and we are awaiting Pfizer’s “decoding” of the results.

CMT 2A:

· Creation of a CMT2A target discovery and drug screening assay has been completed and validated by Brittany Wright (NCATS). It is now ready for pilot screening.

· The next phase of CMT2A projects is being developed:

o Characterization of two mutant rats (H361Y and R364W) by behavioral, electrophysiological and pathological studies, to be done by PsychoGenics and Dr. Steve Scherer in collaboration with Renovo.

CMT 2E

· Dr. Liem has demonstrated under a microscope that there are neurofilament clumps evident in the CMT2E mutated mouse that are not evident in the normal or wild-type mouse. He has also shown this in neurons derived from the mouse embryonic stem cells from this model, which has enabled at least limited testing of small compound libraries at Columbia University.

· Mouse colony for CMT2E has been established at PsychoGenics, and phenotyping results (observable traits or characteristics) indicate measurable deficits. Dr. Steve Scherer has also written a proposal to characterize when the mutant mice develop neuropathy, by electrophysiological and pathological studies.

· A number of investigators with experience in disorders related to CMT2E gathered in Chicago for a one-day meeting. A number of relevant results were presented and several initiatives for future efforts for CMT2E were proposed.

CMT 1X (the type that runs in my family)

· Dr. Martini, in collaboration with Plexxikon Pharmaceuticals, has completed a study with an anti-inflammatory compound on a CMT X animal model. His published studies indicate that this approach has positive results in both CMT1X and CMT1B.

· Dr. Scherer has put forth a proposal from Dr. Brett Morrison, which is being reviewed by the STAR Advisory Board (both Science Experts Board and Translational Experts Board)

CMT 1B

· Dr. Brittany Wright, in collaboration w/ Dr. Shy’s lab, has built three cell lines associated with the activation of UPR (Unfolded Protein Response), which is believed to be the cause of this disease state. Assays being worked on currently to detect such activation.

· Dr. Wrabetz on track in building CMT1B mutated mouse model.

CMT 4

· Dr. Scheideler and STAR team have considered several presentations made by investigators across the various type 4s. Looking for commonalities and proposals on translational projects to fund. Working on putting together CMT Type 4 STAR team.

· Dr. Kleopa has put together a proposal for CMT4, which is being reviewed by the STAR Advisory Board (both Science Experts Board and Translational Experts Board).

STEM CELL Effort

· Dr. Shy sent 18 fibroblast-derived cell lines to the New York Stem Cell Foundation (NYSCF), which were used to produce iPSCs (adult stem cells). These cell lines have been mostly completed by the beginning of September. Once created, the STAR team will work to differentiate these cells into Schwann cells (1A) and neuronal cells (Type 2). Dr. Baloh has begun a project for 2A and Dr. Gabsang Lee has begun project for 1A. Goal is to create a human assay suitable for evaluating potential targets of therapeutic intervention.

If you have questions pertaining to this STAR update, please contact Patrick Livney: pal@cmtausa.org or 1-312-750-9800.

CreateSpace, Step-by-Step


**Although I have permission from Createspace to use these images, this article is in no way sponsored or endorsed by CreateSpace and its affiliates.

Signing up with CreateSpace is easy. Go to their website https://www.createspace.com/ and open an account. You’ll receive a member ID number and dashboard.

1. Your Member Dashboard will look something like this, minus my blacked out information.

1.Member Dashboard

Click the blue Add New Title button. This takes you to the:

2.  Start Your New Project page. Fill in the name of your book, the type of project and choose a setup method. There are two choices:

2.Start Your New Project

A. Guided: A step-by-step process with directions along the way. (I always choose this because I’d never remember the steps.)

B. Expert: A streamlined single-page experience for those familiar with the process.

Click the Get Started button by your choice and move on to the next step.

3. Title Information page: Fill in your book title, subtitle (if applicable), author name, contributors, series name and number (if applicable) and other details.

3.Title Information

Note: If you leave “Publication Date” blank, the date your book publishes on CS will be added. If you published the book previously such as on Kindle or with a traditional publisher, you can fill in the original pub date if you wish.

Click Save & Continue.

4.  ISBN: CreateSpace says, “An ISBN (number) is required to publish and distribute a book.” They offer four options. The first one is free.

4.ISBN

**Compare the options carefully because once you make your choice it cannot be changed.

Choose the option you want and click Continue.

5.  Interior: Choose black & white or color, paper color (white or cream) and the trim size (size of your book). The most popular trim size is 6” x 9” – trade paperback size. CS does not offer standard paperback size.

5.Interior

Then comes the “fun” part, uploading your book!

You can either hire a CS professional to do it for you, with prices starting at $349, or you can do it yourself.

Do it yourself methods:

A. Upload your work as a print-ready .pdf, .doc, .docx, or .rtf file.

B. Download a Word® Template, either a blank template or a formatted template with sample content designed for the trim size you choose. I use the formatted 6” x 9” template.

Formatted Template.demo 1The thumbnails on the left show how a CS formatted template is set up. Each pair of pages represents the front and back side of one printed page. The left page of each pair would actually be the righthand page in a book, while the right one would be on the left (backside of the right page.)

The midline in each pair represents the outside edge of the page; the left and right outside borders of the pair are the page edge that would be bound, forming the book’s spine. Because more space is necessary on the bound edge, the text must be offset closer to the outside edge (the center line of each pair.) See this spacing difference closer up in the following illustration.

Formatted Template.demo 2

There is a table of contents (TOC) included in the formatted template. If you don’t want a TOC in your book, simply delete that pair of pages. You can also delete the dedication and/or acknowledgements pages if you wish. Conversely, you can add pages to the front matter, such as a list of your published books and/or “Praise for” pages with short review excerpts. I place this type of material before the title page as do many traditional publishers.

TIP: Use section breaks between the elements of your front matter to maintain proper spacing. This also allows you to add page numbers when you come to the body of your story. If you want page numbers in your front matter, use Roman numerals.

Add alternating headers, placing your book title on the righthand pages and your author name on the left.

**Regarding font styles, the CreateSpace conversion program doesn’t recognize all fonts, so it’s best to stick to standard ones unless you want to have problems. I use Times New Roman 12 point for body text, varying sizes for chapter headings and in the front matter. Bold and italics are okay. Be careful to check your font for headers. I got in trouble once when an odd font snuck by me in a header. The CS program didn’t like it!

After you upload your formatted manuscript and it goes through the CS automated print check, view your book page by page using the Interior Reviewer. If CS catches formatting errors, you will need to fix them and re-upload. This can be time consuming, but you want your baby to look good, right? In case you can’t figure out the glitch, email or call CreateSpace Support. Their people helped me through a couple roadblocks when I set up my first book for print.

6. Cover: Choose a finish for your book cover, either matte or glossy.

Next, choose how to submit your book cover. There are three methods:

A. Build Your Cover Online with Cover Creator, a free CS tool to design your book covers. (See #7 below)

B. Professional Cover Design from CS, starting at $399

C. Upload a Print-Ready PDF Cover: CS provides detailed instructions. I pay a cover designer of my choice (less expensive) then upload my covers following this method.

7. Using Cover Creator: Choose from several pages of pre-made CS cover designs (below on left) or design your own cover using a blank template (on right.) First, design the front cover offline using your favorite graphics program.  Make sure your image has a resolution of at least 300 ppi. Anything less than that will be rejected by the CS program.

After the front cover successfully loads, design the back cover. Include a short, catchy blurb, short review excerpts and/or an author photo if you wish. Look at the back of paperback books for ideas, and be careful to leave space for the barcode and trimming, as per CS instructions. Again, your image must be at least 300 ppi. Lastly, set up the spine.

Cover Creator

8.  Complete Setup: Review your project setup to make sure everything looks okay. You can go back and make changes if you need to. When ready, submit for review.

9.  Review: The CreateSpace automated review software ensures your work passes muster for “manufacturing and cataloging”. Note: The automated review may take several hours (up to a day) to be completed. While waiting, you can choose distribution channels, set your book price and fill in the book description info. See #10-12 below.

If the automated review okays everything, you will be asked if you want to proof your book online or order a printed copy (at cost) for your final approval. I always order a print copy because there could still be issues that need correcting. When you are satisfied, give CS the go-ahead to publish your print book.

10.  Distribution Channels: Choose distribution channels. Expanded Distribution used to cost $25 but it is now FREE!

11.  Pricing: Set a price for your book. Use the built in calculator to determine what the royalties will be. Keep in mind that distributors usually discount the book price and Amazon will match the discounted price. If you set your price too low, your proceeds will suffer when the book is discounted. Of course you don’t want to price your book so high that it scares off readers.

12.  Description: Provide a description for your sales page. Assign a BISAC Category; add your author bio; set language, country of publication; choose search keywords; check for adult content if applicable and if you want large print.

In conclusion, take your time, follow directions on the site and, if you ever get stuck, contact CS support. Their people are courteous and helpful

Silver Belles and Stetsons Launch Party TODAY!


Yes! Launch Party day is finally here! Ten bestselling, award-winning authors are hosting the party. Fun and prizes galore! See the banner below for the start time in your time zone.

FB Banner for 10-21-15

 

Schedule for Hosting Authors (Mountain Time):

6:15 to 6:30 Warm Up, pre-party welcome–how parties on FB work (such as clicking refresh), prizes, schedule, lots of fun, when to find YOUR favorite author here, etc. One absentee author’s post (CAIT BRAXTON) will go up during this window.

6:30 Welcome!

6:30 to 6:40—CARRA COPELIN

6:40 to 6:50—KATHLEEN BALL

6:50 to 7:00—PATY JAGER

7:00 to 7:10—LYN HORNER

7:10 to 7:20—SUSAN HORSNELL

7:20 to 7:30—MARGARET TANNER

7:30 to 7:40—HEBBY ROMAN

7:40 to 7:50—CAROLINE CLEMMONS

7:50 to 8:00—KRISTIN HOLT

8:00 (or 8:10) Wrap up and Thank you!

 

Facebook Reminder for 10-21-15

Courting the West: A Boxed Set of Ten Western Romances


Pioneer Hearts

An exciting new boxed set release of ten western romances is available – grab it while you can!

NYT, USA Today and Bestselling authors bring you ten Western romance novels featuring sexy cowboys and sultry heroines. This boxed set is loaded with a variety of sweet to steamy romances designed to entice your senses and warm your heart.

Get your copy at a special .99¢ New Release Price!!

Amazon US http://amzn.to/1NJRRL8
Amazon UK http://amzn.to/1Pvy3KO
B&N Nook http://bit.ly/1LQCaS3
Kobo http://bit.ly/1NeKrMX
Apple iBooks http://apple.co/1PjP1fS

And, join the authors Debra Holland, Kirsten Osbourne, Lily Graison, Cynthia Woolf, Jacquie Rogers, Sylvia McDaniel, Paty Jager, Merry Farmer, Keta Diablo, and Caroline Clemmons at a fun Facebook party on Thursday, October 15 from 7:30 – 9:30 pm CST.

Join the Facebook party here!

View original post

Silver Belles and Stetsons – Cowboys of the Past and the Women Who Loved Them


Pioneer Hearts

I’m so Excited to be part of the Christmas Anthology – Silver Belles and Stetsons ~ by Kathleen Ball

I was invited to be in the Christmas boxed set and I’m honored to be among such great writers-

Silver Belles and Stetsons – Ten Western Romance Christmas Novellas by Amazon bestselling and Award-Winning Authors Available as a boxed set for a limited time.

Pre-Order on Amazon

Bestselling and Award-winning authors bring you ten western romance novellas featuring alpha-cowboys from the past. This boxed set will take you back in time when men were rugged and handsome and the women who loved them courageous and daring.


The Greatest Gift: A Montana Cowboy Christmas by Kathleen Ball. Amazon Bestselling and Award- Wining Author. Looking for the man who ran out on her, Ginger finds a cowboy worthy of love but he doesn’t want or need love.

Catherine’s Cowboy by Cait Braxton, Amazon…

View original post 285 more words