Gene Editing Fixes Muscular Dystrophy in Dogs

As my readers know, I have been following the development of CRISPR for years. There is a short article written by Alice Park in TIME concerning CRISPR and Duchenne muscular dystrophy. There is also a short video on the page explaining hos CRISPR works. Click on the title below to go to the article.

 What bothers me is that I love beagles.

CRISPR Gene Editing Fixes Muscular Dystrophy in Dogs. Are Humans Next?

The powerful gene editing technology CRISPR is one small step closer to treating a human disease.

In a new paper published in Science, researchers led by Eric Olson, professor and chair of molecular biology at UT Southwestern Medical Center, reported that he and his team successfully used CRISPR to correct the genetic defect responsible for Duchenne muscular dystrophy in four beagles bred with the disease-causing gene. It’s the first use of CRISPR to treat muscular dystrophy in a large animal. (Previous studies had tested the technology on rodents.) In varying degrees, the genetic therapy halted the muscle degradation associated with the disease.

Duchenne is caused by mutations in the dystrophin gene, which codes for a protein essential for normal muscle function. People born with the disease are often eventually confined to wheelchairs as their muscles continue to weaken, and in the later stages, many rely on ventilators to breathe as their diaphragm muscles stop working. Eventually, they develop heart and respiratory failure.

Study: Systemic Delivery of MicroRNA

István Reinhardt emailed me a link to a recent Kennedy’s Disease (SBMA) study. The video is also interesting. Clink on the link below to go to the site or download a PDF copy of the study with this link:  https://www.jove.com/pdf/55724

Systemic Delivery of MicroRNA Using Recombinant Adeno-associated Virus Serotype 9 toTreat Neuromuscular Diseases in Rodents

ABSTRACT

RNA interference via the endogenous miRNA pathway regulates gene expression by controlling protein synthesis through post-transcriptional gene silencing. In recent years, miRNA-mediated gene regulation has shown potential for treatment of neurological disorders caused by a toxic gain of function mechanism. However, efficient delivery to target tissues has limited its application. Here we used a transgenic mouse model for spinal and bulbar muscular atrophy (SBMA), a neuromuscular disease caused by polyglutamine expansion in the androgen receptor (AR), to test gene silencing by a newly identified AR-targeting miRNA, miR-298. We overexpressed miR-298 using a recombinant adeno-associated virus (rAAV) serotype 9 vector to facilitate transduction of non-dividing cells. A single tail-vein injection in SBMA mice induced sustained and widespread overexpression of miR-298 in skeletal muscle and motor neurons and resulted in amelioration of the neuromuscular phenotype in the mice.

In a 2011 post, Ed Meyerthoen explained the defective AR gene. You can read his post by following this link:  https://kennedysdisease.blogspot.com/2011/05/what-is-ar-and-why-is-it-important.html

New Funding for SBMA Research

The MDA announced the funding of $9.9 million dollars in research grants. The grant below is for the study of Kennedy's Disease.

Carlo Rinaldi, Ph.D., associate professor and clinician scientist at the University of Oxford in England, was awarded an MDA Development Grant to study how variants in the gene of the androgen receptor (AR) protein cause spinal-bulbar muscular atrophy (SBMA) and investigate whether a novel antisense oligonucleotide therapy approach can target these toxic variants. The results of the study will provide a better understanding of SBMA disease mechanisms, as well as develop a new therapy potentially capable of treating the disease.

This work has potential implications for other diseases of the motor unit as well, including spinal muscular atrophy (SMA) and ALS. This grant is co-funded by the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM).

Additional information was provided on another page:

“Better understanding of the underlying disease mechanisms, coupled with improvement of gene vector design, therapeutic gene selection, and methods of delivery, have made gene therapy a realistic option for neuromuscular conditions — and neurological diseases in general — for which no treatment option was available until few years ago. Many challenges still lie ahead, but we have good reasons to be very optimistic for the future.”

Carlo Rinaldi, associate professor and clinician scientist at the University of Oxford in England, was awarded an MDA Development Grant totaling $120,000 over 3 years to study the role of androgen receptor isoforms in SBMA pathogenesis and the potential as therapeutic targets. This grant is co-funded by the American Association of Neuromuscular and Electrodiagnostic Medicine (AANEM).

Mutations in the gene encoding the androgen receptor (AR) protein cause spinal and bulbar muscular atrophy (SBMA). SBMA is an adult-onset neuromuscular condition affecting males with unmet clinical need. It is not undestood how mutations in AR lead to primary degeneration of motor neurons and muscle in patients. The activity of AR and other hormone receptors can be modulated in human cells by isoforms and/or splice variants, which may block or enhance their functions.

Dr. Rinaldi and colleagues plan to investigate the role of AR alternative isoforms in mediating SBMA toxicity. By revealing how these isoforms regulate AR activity in health and disease, researchers expect to better understand the mechanisms of disease in SBMA and provide a novel rational therapeutic target. If successful, the work could pinpoint tissue-specific targets for therapy development, with implications not only for SBMA but for other diseases of the motor unit as well, including spinal muscular atrophy and amyotrophoic lateral sclerosis.

Creatine Monohydrate Trial

I found this report on a trial conducted in 2014 and 15. I searched for the final analysis and can’t locate it. Perhaps you will have better luck than me. If so, let me know.

Treatment with Creatine Monohydrate in Spinal and Bulbar Muscular Atrophy: Protocol for a Randomized, Double-Blind, Placebo-Controlled Trial

Yasuhiro Hijikata, MD, PhD, Masahisa Katsuno, MD, PhD, Keisuke Suzuki, MD, PhD, Atsushi Hashizume, MD, PhD, Amane Araki, MD, PhD, Shinichiro Yamada, MD, PhD, Tomonori Inagaki, MD, Daisuke Ito, MD, Akihiro Hirakawa, PhD, Fumie Kinoshita, MSc, Masahiko Gosho, PhD, and Gen Sobue, MD, PhD

Background

Although spinal and bulbar muscular atrophy (SBMA) has been classified as a motor neuron disease, several reports have indicated the primary involvement of skeletal muscle in the pathogenesis of this devastating disease. Recent studies reported decreased intramuscular creatine levels in skeletal muscles in both patients with SBMA and transgenic mouse models of SBMA, which appears to contribute to muscle weakness.

Objective

The present study aimed to examine the efficacy and safety of oral creatine supplementation to improve motor function in patients with SBMA.

Results

Participant enrollment in the trial started from June 2014 and follow-up was completed in July 2015. The study is currently being analyzed.

What and Why

Someone asked why I haven't posted many articles this month. That;s a good question and it deserves an answer.

I have focused much of my time the last couple of months on "Shattered Lives," the latest historical fiction novel I am writing.  It is about Treblinka, the Nazi death camp. I am into the second edit and had to do a few rewrites. The amount of research required to write the book was amazing, but nothing compared to the rewrite and editing process.

I hope to have most the the rewrite work finished soon. Then I can devote more time to the Living with KD blog. In the meantime, if  I read/find something important about Kennedy's Disease, you can be assured it will be posted.

Thanks for your understanding. 'Bruce of many hats'

UCL KD Research Newsletter

Below is the first newsletter from the UCL Kennedy's Disease Research Center. Many thanks to all who provide support as well as search for a treatment and a cure.

FYI - Kennedy’s Disease Clinic

This clinic is linked to the National Register for Kennedy’s Disease and is aimed at providing a central referring point for all patients in the UK. Kennedy’s disease (also known as Spinal Bulbar Muscular Atrophy) is a rare disorder and the Clinic will offer the multi-disciplinary approach available for MND and also provide screening for a number of non-neurological conditions that may associate with Kennedy’s Disease.

Coordinator for this clinic is Jan Clarke (jan.clarke1@nhs.net - Telephone: 020 3448 3517); general enquiries Marcia Forde (marcia.forde@nhs.net - Telephone: 020 3448 8251 - Fax: 020 3448 3633).

_______________________

UCL KD Research Newsletter

Hi and welcome to the inaugural research newsletter from the !

We always enjoy letting you know about exciting developments in KD research and care, and a few members of the KD community have asked to know more about the research happening at UCL, Oxford and further afield – so here we are!

We’re planning to update you with research news four times a year. We would really love to hear your feedback on what you like and what doesn’t work so well, so that we can improve what we are sending you. We really want it to be the most useful and interesting for you that it can be. Please do let us know at sbma@ucl.ac.uk.

KD Clinic

It has been wonderful to see so many faces coming through the KD clinic.

From the medical side we have a new consultant, Dr Carlo Rinaldi, who has many years’ experience in KD. Carlo runs a research group at Oxford University studying ways to develop new treatments for KD. Dr Helen Devine, a registrar, has returned from maternity leave and is joining the clinic alongside her PhD using stem cells to study KD.

KD research

There is plenty of ongoing research linked to the clinic, both in UCL and in Oxford. In some cases people with KD have been directly involved, for example: undergoing muscle MRI scans, or donating blood or skin samples that are currently being analysed in the lab. There are also numerous ongoing studies that use disease models to better understand KD and to find ways of changing its course.

We will include updates of these projects in upcoming newsletters.

Results from Japan using testosterone-lowering drug

Many of you have asked us about the results from a clinical trial recently published by colleagues in Japan.

Background: Our bodies naturally produce testosterone. In people with KD, this testosterone binds to faulty androgen receptors – and that causes damage to the nerves and muscles. Gen Sobue’s KD lab in Japan wanted to see if less testosterone would mean less activity of the androgen receptor – and therefore less damage. There is already a drug called Leuroprelin that makes men produce less testosterone. A team lead by the scientist Atsushi Hashizume ran a long-term trial giving Leuroprelin to some people with KD in order to reduce the levels of testosterone in their bodies, to see if they stayed healthier than others who were not given the drug. The scientists chose people who were similar in terms of age, length of disease and CAG repeat length. The first results were published in 2009 and actually showed that there was no clear benefit to people with KD after 18m of treatment.

Results from this study: Treatment was continued with Leuroprelin after the original study end and now the effect of the drug after up to 11.5 years in the longest-term patients has been published. Encouragingly, the researchers found that, over the observed time period, the people who were given Leuroprelin were less likely to develop pneumonia requiring hospitalisation, and they had a slower progression of disease.

Our view: The positive finding of this study is that reducing the action of testosterone can impact on the disease course of KD. On the cautionary side, however, the benefits are modest, and the drug, when taken chronically, has some side-effects.

In summary, although Leuprorelin may not prove to be clearly beneficial for people with KD, these results show that modifying testosterone can have an impact on disease, which brings optimism for future drug therapies.

Symptom management

We thought it would be useful to hear how you deal with KD’s most common and troublesome symptoms to create a resource for all of us to share, review and access.

So our first question is: what are the best strategies you have found to manage laryngospasm?  If you wish to contribute please e-mail Luca at: luca.zampedri@nhs.net

Best wishes,
Pietro, Carlo, Mike, Linda, Helen, Jan and Luca.

Financially Prepare For Assisted Living

Today's topic is a guest post by Hazel Bridges (hazel@agingwellness.org). Planning for the future is important to most of us living with Kennedy's Disease, but also for any family with senior citizens liiving at home. Thanks, Hazel.

7 Things You Can Do to 

Financially Prepare For Assisted Living

By Hazel Bridges

Medicare is useful in many ways. However, Medicare doesn’t cover very much when it comes to assisted living. As a result, you will need to be prepared for whatever circumstances you might run into in the future. Here’s how you can plan financially for you or a loved one so you can be prepared for whatever curveballs life might throw your way.

Figure Out Which Kind of Housing Is Necessary

As pointed out by a recent Forbes article, when most people think of long-term care, their first thought is nursing homes. However, there are a variety of assisted living facilities that also provide substantial benefits. The trick is finding out which ones are best. Assess your loved one’s needs and see which facilities suit it best. Try to get it right the first time, since moving from home to home can be difficult.

Upgrade Parts of the Home

When it seems like assisted living might be part of the inevitable future for your loved one, consider ways that you can upgrade the home they live in to help them maintain a little bit of independence and keep things easier for everyone. Do small things like installing grab bars in bathrooms, removing loose rugs or carpet on the floor, or installing a chair lift. This helps your loved one live in their home a bit longer, which can free up money for care.

Leverage Life Insurance

Some life insurance plans can be used for what are called advanced death benefits (ADBs), which can help in paying for your loved one’s care. The US Department of Health and Human Services describes ADBs as life insurance features that allow a tax-free advance on your life insurance policy while you are still alive. If you’re unfamiliar with your insurance policy or aren’t sure about the terms of ADBs, talk with your provider about the details of the benefits.

Talk to a Financial Advisor

Many seniors wonder where they can get sound financial advice that can help them or their families financially prepare for an assisted living scenario. A couple of good resources to consider are banks, community center events, and the AARP, all of which will likely have financial advisors who can assist for little to no cost.

Look Into What Tax Breaks You Can Take

Tax breaks are available to seniors whose medical expenses, including some of their assisted living costs, exceed 7.5 percent of their adjusted gross income. If you care for your loved one, you should look into some of the tax benefits that you qualify for because of your role.

Consider Government-Assisted Programs

There are programs like Section 202 Supportive Housing for the Elderly that provide subsidized housing options where seniors can get assistance with tasks like cooking, cleaning, and transportation. One disadvantage of many of these programs is that they have lengthy waiting lists, so if you’re looking into it, get on them now.

Consider a Reverse Mortgage

If your loved one owns a home, they might be able to afford some long-term care by using a reverse mortgage. A reverse mortgage allows the homeowner to borrowmoney against the equity that they have in their home. This money doesn’t have to be paid back to the bank until a future time. However, the amount due on the loan must be paid if your loved one dies or changes their primary residence. A reverse mortgage isn’t right for everyone, so be aware of the financial implications of receiving one and get familiar with the unique contract wording.

It’s important to secure your future. Change can come eventually, or it can come tomorrow. Work regularly to do what you can to ensure you or your loved one’s financial security so you can live worry-free. 

Image via Pixabay