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Cuyamycin Molecule looks promising for Myotonic Dystrophy Treatment

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A new study published shows that a small molecule (Potential new treatment) disrupted the long CTG repeats but left short repeats mostly alone.This was tested in mice that had myotonic dystrophy and seemed to work well.  Here is a piece form the journal about the impact of this study

                                                     Significance
Development of small-molecule lead medicines that potently and specifically modulate RNA function is challenging. We designed a small molecule that cleaves r(CUG)exp, the RNA repeat expansion that causes myotonic dystrophy type 1. In cells and in an animal model, the small-molecule cleaver specifically recognizes the 3-dimensional structure of r(CUG)exp, cleaving it more selectively among transcripts containing short, nonpathogenic r(CUG) repeats than an oligonucleotide that recognizes RNA sequence via Watson-Crick base pairing. The small molecule broadly relieves disease-associated phenotype in a mouse model. Thus, small molecules that recognize and cleave RNA structures should be

Cugamycin-Mouse-Model

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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Audentes is developing AT466 for the treatment of myotonic dystrophy type 1.

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Audentes is developing AT466 for the treatment of myotonic dystrophy type 1.

Myotonic dystrophy type 1 (DM1) is a rare, neuromuscular disease that affects multiple organ systems, and is characterized primarily by myotonia and progressive muscle wasting and weakness. DM1 has several forms, which range in age of presentation and severity, including congenital, infantile, juvenile, and adult (classic). There are more than 100,000 patients living with DM1 across the United States, Europe and Japan. The disease is inherited in an autosomal dominant pattern and is caused by a mutation called a CTG trinucleotide repeat in the dystrophia myotonica-protein kinase (DMPK) gene. Patients with DM1 experience reduced quality of life and shortened life expectancy. There are no disease modifying therapies approved for DM1.

Audentes is evaluating vectorized RNA knockdown and vectorized exon skipping to treat DM1. Both approaches are designed to prevent the accumulation of toxic DMPK RNA in affected cells, thereby restoring normal cellular function. RNA knockdown and exon skipping have both been clinically validated in studies with antisense oligonucleotides (ASOs). Combining these approaches with AAV delivery is expected to overcome the biodistribution limitations of ASO-based therapies. Preclinical studies are underway to determine the optimal construct for AT466.

MORE INFO ON AT466 to TREAT Myotonic Dystrophy Type 1 (DM1)

DM1 is caused by a mutation called a CTG trinucleotide repeat in the DMPK gene, resulting in the accumulation of toxic DMPK RNA in affected cells. AT466 is an AAV-antisense candidate, and Audentes is evaluating vectorized RNA knockdown and vectorized exon skipping to treat DM1. Both approaches are designed to prevent the accumulation of toxic DMPK RNA, thereby restoring normal cellular function.

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