Tag Archives: myotonic dystrophy

NIH sponsored research shows promise

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April 9, 2019

Small molecule targets cause of adult onset muscular dystrophy

 
 

At a Glance

  • Researchers developed a small molecule that, in mice, blocks the mutated RNA responsible for adult onset muscular dystrophy.
  • The findings suggest a new avenue to develop therapeutics for this condition.
Illustration of DNA and RNAMyotonic dystrophy is caused by mutant DNA that results in toxic messenger RNA

Muscular dystrophy includes over 30 inheritable diseases. These are characterized by progressive weakness and degeneration of the muscles. Some types of muscular dystrophy appear in childhood, while others may not appear until adulthood.

Myotonic dystrophy is the most common form of adult onset muscular dystrophy. People with this disorder experience a delay in relaxing their muscles after using them. Type 1 usually affects the lower legs, hands, neck, and face; whereas, type 2 typically affects the neck, shoulders, elbows, and hips. They are caused by mutations in different genes.

Type 1 is caused by a mutation in the dystrophia myotonica protein kinase (DMPK) gene. This mutation causes three nucleotides, CTG, to repeat multiple times in the gene’s DNA. Most people have between 5 to 34 CTG repeats in this gene; however, people with type 1 myotonic dystrophy have from 50 to 5,000.

These extra repeats result in a toxic messenger RNA (mRNA) that traps proteins and forms clumps within cells. This interferes with many important proteins that regulate muscle gene products, leading to serious defects in the muscle cells.

To test whether a small molecule could target the altered RNA and block it from trapping proteins, a team led by Dr. Matthew Disney at Scripps Research Institute carried out experiments in muscle cells taken from patients with myotonic dystrophy type 1 and a mouse model of the disease. The research was supported in part by NIH’s National Institute of Neurological Disorders and Stroke (NINDS) and an NIH Director’s Pioneer Award. Results were published online on March 29, 2019, in the Proceedings of the National Academies.

The researchers designed a small molecule to specifically target the altered RNA’s 3D structure, which folds into a hairpin shape. They first tested its activity in cells taken from patients with myotonic dystrophy. The molecule, called Cugamycin, cleaved 40% of the DMPKmRNA in cells taken from patients, but not in healthy control cells. It also reduced the mRNA’s binding to MBNL1, an important protein it commonly traps, by about 30%.

The team then tested the molecule in a mouse model of myotonic dystrophy type 1 that has 250 CTG repeats. Mice were treated with Cugamycin every other day for one week. Treated mice showed 40% less of the mutated mRNA in their lower leg muscles than untreated mice. They also showed partial improvement in their ability to relax their lower leg muscles.

The toxic mRNA from the mutated DMPK gene alters the expression of 326 genes in this mouse model. Cugamycin treatment restored the normal expression of 177 of these. In an analysis of more than 15,000 other genes, the researchers found no off-target effects.

“The results suggest that our technology can be used to treat myotonic dystrophy type 1 and similar categories of inherited diseases, and without unintended, off-target effects,” Disney says.

These findings demonstrate that small molecules can be designed to selectively target and destroy mutated RNA molecules that cause human disease. However, more studies are needed before this molecule could be tested in people.

—by Tianna Hicklin, Ph.D.

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Another Drug Company considers Myotonic Dystrophy as a Target Candidate

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FROM MUSCULAR DYSTROPHY NEWS!

 
 
Jose Marques Lopes, PhDBY JOSE MARQUES LOPES, PHD
 

IN NEWS.

Audentes Therapeutics Expanding Treatment Candidates for Duchenne MD and Myotonic Dystrophy Type 1
 

Audentes Therapeutics is expanding its pipeline of potential molecular therapies, expecting to address 80% of patients with Duchenne muscular dystrophy (DMD) and all with myotonic dystrophy type 1 (DM1).

The treatment strategy, called vectorized exon skipping, uses a modified adeno-associated virus (AAV) to deliver antisense oligonucleotides (ASOs) — small molecules complementary to the RNA sequence — to skip over mutated exons, the bits of DNA that contain the information to generate proteins. Such an approach leads to the production of functional and full-length proteins.

According to Audentes, this strategy may be superior in DMD to microdystrophin gene replacement approaches, which produce shorter-than-normal dystrophin — the protein missing in these patients — with potentially less durable clinical benefits. Also, it may be more beneficial than current ASO therapies, whose efficacy is limited by poor distribution in muscle tissue.

“Today’s announcement represents a significant step forward in expanding our scientific platform and deepening our pipeline of product candidates for neuromuscular diseases with high unmet medical need,” Matthew R. Patterson, Audentes chairman and CEO, said in a press release.

Patterson also said Audentes believes that this strategy, combined with the company’s large-scale current good manufacturing practice (CGMP) manufacturing capability, “can deliver best-in-class therapies for the treatment of [DMD] and [DM1].”

To accelerate these programs, Audentes reached a licensing agreement and will partner with the Nationwide Children’s Hospital, as well as two of its experts on neuromuscular diseases — Kevin M. Flanigan, MD and Nicolas S. Wein, PhD.

“We are excited to be collaborating with Audentes to advance these novel, highly differentiated approaches for DMD and DM1,” said Flanigan, director of Nationwide Children’s Center for Gene Therapy.

Audentes and Nationwide Children’s are collaborating to develop AT702, a treatment candidate designed for skipping of exon 2 of the DMD gene — which codes for dystrophin — in patients with exon 2 duplications and mutations in exons 1-5.

In mouse models, AT702 led to dose-dependent increases in production of full-length or near-full-length dystrophin and improvements in muscle function. The company expects to start a Phase 1/2 trial of AT702 at Nationwide Children’s in the fourth quarter of 2019.

Audentes is also conducting preclinical studies of two other vectorized exon-skipping candidates known as AT751 and AT753. These investigational treatments are intended for DMD patients with genotypes amenable for skipping of exons 51 and 53. Both AT751 and AT753 use the same viral vector backbone as AT702, enabling a potentially quicker clinical development, the company says.

Overall, these three potential therapies target over 25% of patients with DMD, with the company planning to leverage its exon-skipping platform to cover up to 80% of DMD patients.

Besides DMD, Audentes and Nationwide Children’s are assessing vectorized RNA suppression and vectorized exon skipping for DM1.  Both strategies have been validated in studies with ASOs and intend to prevent the buildup of toxic RNA of the DMPK protein in cells, a hallmark of DM1.

The company is currently conducting preclinical studies and expects to file an investigational new drug application in the U.S. for its selected DM1 treatment candidate, AT466, in 2020.

Audentes’ current manufacturing capability enables global commercialization of AT132, a potential therapy for X-linked myotubular myopathy and the company’s lead program, as well as continued clinical development of its pipeline programs. The facility is designed for an eightfold expansion of its production capacity.

Audentes recently hosted a conference call and a webcast on the expansion of its AAV technology as well as the DMD and DM1 programs. A replay of the webcast and slides can be found here

Cognitive Behavioral Therapy and Exercise can help with Myotonic Dystrophy

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There is no treatment for myotonic dystrophy…yet. In the interim period a new study shows that behaorial therapy and exercise can help to stem the huge impact this disease has on patients. Here is the conclusion : 

Interpretation Cognitive behavioural therapy increased the capacity for activity and social participation in patients with myotonic dystrophy type 1 at 10 months. With no curative treatment and few symptomatic treatments, cognitive behavioural therapy could be considered for use in severely fatigued patients with myotonic dystrophy type 1.

However, in reviewing the study this approach requires huge amount of medical resources that may not be available. Hours of analysis of the issues with patients and then tailoring the approach to each patient and tweaking it periodically. Working with a medical professionals for hours is very expensive and most health systems ahve no way to accomplish this.

Cognitive behavioural therapy with optional graded
exercise therapy in patients with severe fatigue with myotonic
dystrophy type 1: a multicentre, single-blind, randomised trial


Kees Okkersen, Cecilia Jimenez-Moreno, Stephan Wenninger, Ferroudja Daidj, Jeffrey Glennon, Sarah Cumming, Roberta Littleford,
Darren G Monckton, Hanns Lochmüller, Michael Catt, Catharina G Faber, Adrian Hapca, Peter T Donnan, Gráinne Gorman, Guillaume Bassez,
Benedikt Schoser, Hans Knoop, Shaun Treweek, Baziel G M van Engelen, for the OPTIMISTIC consortium†


Summary
Background Myotonic dystrophy type 1 is the most common form of muscular dystrophy in adults and leads to severe fatigue, substantial physical functional impairment, and restricted social participation. In this study, we aimed to
determine whether cognitive behavioural therapy optionally combined with graded exercise compared with standard care alone improved the health status of patients with myotonic dystrophy type 1.


Methods We did a multicentre, single-blind, randomised trial, at four neuromuscular referral centres with experience in treating patients with myotonic dystrophy type 1 located in Paris (France), Munich (Germany), Nijmegen (Netherlands), and Newcastle (UK). Eligible participants were patients aged 18 years and older with a confirmed
genetic diagnosis of myotonic dystrophy type 1, who were severely fatigued (ie, a score of ≥35 on the checklistindividual strength, subscale fatigue). We randomly assigned participants (1:1) to either cognitive behavioural therapy plus standard care and optional graded exercise or standard care alone. Randomisation was done via a central webbased system, stratified by study site. Cognitive behavioural therapy focused on addressing reduced patient initiative, increasing physical activity, optimising social interaction, regulating sleep–wake patterns, coping with pain, and
addressing beliefs about fatigue and myotonic dystrophy type 1. Cognitive behavioural therapy was delivered over a 10-month period in 10–14 sessions. A graded exercise module could be added to cognitive behavioural therapy in Nijmegen and Newcastle. The primary outcome was the 10-month change from baseline in scores on the DM1-Activ-c scale, a measure of capacity for activity and social participation (score range 0–100). Statistical analysis of the primary outcome included all participants for whom data were available, using mixed-effects linear regression models with
baseline scores as a covariate. Safety data were presented as descriptives

This trial is registered with ClinicalTrials. gov, number NCT02118779.


Findings Between April 2, 2014, and May 29, 2015, we randomly assigned 255 patients to treatment: 128 to cognitive behavioural therapy plus standard care and 127 to standard care alone. 33 (26%) of 128 assigned to cognitive behavioural therapy also received the graded exercise module. Follow-up continued until Oct 17, 2016. The DM1- Activ-c score increased from a mean (SD) of 61·22 (17·35) points at baseline to 63·92 (17·41) at month 10 in the cognitive behavioural therapy group (adjusted mean difference 1·53, 95% CI –0·14 to 3·20), and decreased from 63·00 (17·35) to 60·79 (18·49) in the standard care group (–2·02, –4·02 to –0·01), with a mean difference between groups of 3·27 points (95% CI 0·93 to 5·62, p=0·007). 244 adverse events occurred in 65 (51%) patients in the cognitive behavioural therapy group and 155 in 63 (50%) patients in the standard care alone group, the most common
of which were falls (155 events in 40 [31%] patients in the cognitive behavioural therapy group and 71 in 33 [26%] patients in the standard care alone group). 24 serious adverse events were recorded in 19 (15%) patients in the cognitive
behavioural therapy group and 23 in 15 (12%) patients in the standard care alone group, the most common of which were gastrointestinal and cardiac. Interpretation Cognitive behavioural therapy increased the capacity for activity and social participation in patients with myotonic dystrophy type 1 at 10 months. With no curative treatment and few symptomatic treatments, cognitive behavioural therapy could be considered for use in severely fatigued patients with myotonic dystrophy type 1.

Appendix to Lancet article with Exercise and behavior modificationsDownload

Large BioPharma makes equity investment in Oligonucleotides company

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There is still lots of interest in finding a cure for myotonic dystrophy through oligonucleotides. These are small molecules different than oral ingestion of a pill. Lots of interest in this type of therapy. Here is a press release from bioworld

Lilly’s ‘Avidity’ for oligos pays off for Calif.-based company

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By Michael Fitzhugh
News Editor

Eli Lilly and Co. has agreed to pay privately held Avidity Biosciences LLC $20 million up front and up to $405 million per target to support development of an unspecified number of new antibody oligonucleotide conjugates for immunology and other indications. The multiyear deal, which also includes a $15 million equity investment for Avidity, opens a new front in Lilly’s embrace of oligonucleotide-based drugs, the subject of earlier deals it has struck with Dicerna Pharmaceuticals Inc., Ionis Pharmaceuticals Inc. and Noxxon Pharma AG.

Avidity’s platform, which can leverage transferrin and other transporters to deliver oligonucleotides into multiple tissue types, will allow Lilly to reach beyond hepatocytes — the most accessible domain for such medicines so far — to muscle, heart, tumor and immune cells. Andrew Adams, Lilly’s chief scientific officer for RNA therapeutics, called it “a promising avenue of research toward development of new RNA-based medicines.” With Lilly’s own multimillion-dollar R&D center just up the road from Avidity’s La Jolla, Calif., headquarters, the big pharma company’s scientists won’t even have to drive far.

Arthur Levin, Avidity’s head of R&D, told BioWorld the deal “demonstrates that the technology for oligonucleotides has reached the level of maturity where pharma is jumping back in” while validating Avidity’s technology, too. “The field has made great strides recently using targeted approaches to deliver to hepatocytes. Our technology allows us to deliver oligonucleotide payloads to cells outside of simply hepatocytes, and that’s what attracted Lilly,” he said.

The company also brings expertise in what Kent Hawryluk, Avidity’s chief business officer, told BioWorld are some of “the devilish technical details” that would make it difficult for someone to replicate its approach.

“Each one of the components, the antibody, the conjugation to the antibody, the linker, the nature of the payload, the arrangement of the molecules in space… each one of those is important to optimize,” said Levin. “If you just go in and slap an oligonucleotide payload onto an antibody, you’re probably not going to get the results that we get. That’s where the secret sauce lies, in that combination of making the appropriate modifications to each one of those systems,” he said.

Including the new equity investment by Lilly, Avidity has now raised $50 million from investors including Takeda Ventures, Alethea Capital, Alexandria Real Estate Equities, Brace Pharma, Ecor1 Capital, F-Prime Capital, Moore Venture Partners and Boxer Capital of Tavistock Group. Takeda led the company’s series B round.

The global licensing and R&D agreement with Lilly is the company’s first strategic deal and will provide it not only with support for the partnered candidate, but with nondilutive funding to help advance its muscle-focused internal pipeline.

“It turns out that muscle cells are particularly sensitive to molecules transported in on the transferrin receptor and that’s why we’ve concentrated our lead programs on muscle,” said Levin.

Founded as Avidity Nanomedicines in 2013, the company tweaked its name to reflect that its approach could do more than just deliver siRNAs, an early focus of Avidity Nanomedicines. Today, its lead internal program is focused on myotonic dystrophy type 1, a disease caused by the expansion of CTG repeats in the DMPK gene. Following humanization of an anti-human transferrin receptor antibody, Avidity team members on the project are now working to optimize its siRNA payload. “We’re in the process of scaling up the antibody and moving forward with respect to development in the very near future,” said Levin.

Avidity is also applying its antibody oligonucleotide conjugate technology to Duchenne muscular dystrophy (DMD) where the company said its approach has proved 100-fold more potent than existing oligonucleotide therapies for DMD in a mouse model of the disease, a feat it hopes will allow for reduced dose levels and reduced dosing frequency. In October, the company received an undisclosed equity investment from Cureduchenne to help advance preclinical development of its exon-skipping oligonucleotides for DMD.