Biogen / Isis Partnership Readies Autism Drug For Human Clinical Trials

A not well know secondary effect of a drug that Biogen and Isis are jointly developing  may reverse some or all the effects of a specific single gene  type of autism.  This drug will be entering Human Trials in 2014 if all goes well.   In August Biogen and Isis announced a collaboration on a drug that looks extremely promising to treat a form of muscular dystrophy, Myotonic Dystrophy. But it may also reverse the symptoms of autism that occurs in some not well known forms of myotonic dystrophy in children. This could be a sleeper drug that may help with this larger and more pervasive societal problem.

A typical description of myotonic dystrophy is: Myotonic dystrophy is characterized by progressive muscle wasting and weakness. People with this disorder often have prolonged muscle contractions (myotonia) and are not able to relax certain muscles after use. For example, a person may have difficulty releasing their grip on a doorknob or handle. Also, affected people may have slurred speech or temporary locking of their jaw. It is multsystemic and can cause cardiac conduction problems, GI Issues, Hair loss, depression, apathy, loss of executive function and many other issues. Babies who are born with signs and symptoms of myotonic dystrophy have congenital myotonic dystrophy. They have weakness of all their muscles, breathing problems, and developmental delays including mental retardation. Sometimes these medical conditions are so severe they may cause death.

What is not well know and is “hidden” with this complex disease is that the disease  “title” of myotonic dystrophy encompasses 3 diseases each with separate symptoms and issues. The scientists have classified this disease with the adult version in mind and symptoms and the effect on the childhood versions is kept much in the background. This has made it very difficult to diagnosis the childhood versions.  I am not sure what the scientists classify the disease this way but they do. The three types of Myotonic Dystrophy are:

1. Congenital (present at birth)
a. Severe Type (life threatening symptoms at birth)
b. Moderate (no life threatening symptoms at birth
2. Juvenile Type
3. Adult type

The 3 diseases are somewhat interconnected. The progression is directional toward the adult type. So a child with the congenital form will get most of the symptoms of the juvenile form over time. Then at puberty the child will begin to get the adult form symptoms that are delineated above. This progression means that the number of symptoms and the complexity of the disease generally gets increasingly worse over time for those with the childhood forms.

The hidden factor here is that the congenital and Juvenile forms of the disease develop autism spectrum disorder at a very high rate. This rate in some studies is almost as high as 50%. Dr. Ekstrom, from Sweden an expert in the autistic tendencies of children with this disease has published several papers on this problem. Another study in France confirms the autistic tendencies of children. Even children that are not formally diagnosed with the disease may have ADHD, and other autistic like tendencies. Children with the myotonic dystrophy repeat levels that are high tend to have more symptoms of autism Spectrum disorders.

The cause of Myotonic Dystrophy is well known. The base mechanism is an expansion triplet CTG repeat on Chromosome 19. The triplet expansion shows anticipation or each successive generation get more expansions and more intense symptoms of the disease. These expansions are now know to alter the RNA in the cell causing them to mutate into a form where it is difficult for them to leave the cell. These RNA clump together in identifiable Foci in the cells and either prevent proteins from leaving the cell or cause damage as they accumulate. The RNA become Toxic and interfere with some key proteins.

Regarding the cause of many brain related myotonic symptoms,  new brain  research has been published this summer with information that identify the problem in the brain caused by Myotonic Dystrophy. Professor Swanson team has also created a mouse model for the brain in myotonic dystrophy. This brain mimics the effects of myotonic dystrophy on the brain. Thus testing of specific brain issues versus muscle and other organ issues is more viable now.

Several drugs are now being developed to treat and cure the disease. The most advanced trials are that or the Antisense technology that Isis and Biogen are working on. This summer a paper was published showing amazing results in the technology that reversed the symptoms in a mouse model of the disease. To combat the toxic messenger RNA, the researchers used a class of drugs called “antisense compounds.” These compounds bind to abnormal RNA and wave down RNase H, an enzyme that chops up RNA. The results of this study are astonishing. With the team’s most effective compounds, symptoms in the mice were reversed. The level of toxic RNA was reduced by more than 80 percent; stiffness in muscles eased dramatically; the microscopic structure of muscle was improved; and electrical signaling in muscles returned to normal.

This drug is given by injection and does not pass the blood/brain barrier. So two injections would be needed for treatment one for non-brain issues and one for brain related issues. The interesting effect here is that the drug work and worked well and the effects were long lasting for over a year.

The clinical human trials for this drug may begin as early as 2014 and insider information has confirmed that the juvenile/congenital forms maybe a part of the clinical trial. This means that that if the drug is successful that it will mean that Autism and Autism Like disorders for the disease myotonic dystrophy may be reversed. This therapy looks very promising  if the mice to men approach works . Of course its science and what looks promising may not work. Mice to men with drugs is not always successful. The normal very conservative scientific profession is very excited about this disease. One prominent researcher gave a keynote speak in Sept of 2012  at a neuromuscular conference on “Curing Myotonic Dystrophy”

Although the title of this post is very broad, and the drug is intended for myotonic dystrophy, the side effect may well be new insight and perhaps treatment for autism. Just as Viagra was developed for high blood pressure and angina, and its real gem was treatment for impotence……. This new drug for myotonic dystrophy may have immense benefits for the autistic community. Many more drugs such as small molecule drugs are being tested by other researchers as well.

How will this drug help with autism. If as expected the drug reverses autism in kids with myotonic dystrophy (along with other symptoms) the the researchers can pinpoint what is causing the autism in the kids with myotonic dystrophy say neurons, neurotransmitters, enzymes, etc. This will help identify further treatments. Its unlikely that this drug alone will reverse autism except in those with Childhood myotonic dystrophy. It may also help with other issues such as motivation, executive function, apathy, hygpersomnia. If these symptoms which occur in myotonic dystrophy can be reversed the same protocols can be used to search for a cause and effect relationship and isolate the variable that is causing the symptom.

The market size for this drug would be large for the myotonic dystrophy population. With over 30,000 individuals and a cost of at least $20,000 per year would be about $600M per year to treat myotonic dystrophy. EMedtv.com estimates that over 500,000 children under 18 have autism or ASD. This would equate to a market size of about $8 Billion dollars per year. This is surely very interesting to the drug and pharmaceutical industry. Although Isis and Biogen know a bit that this is an Drug that can affect Autism. They may be missing the boat that they have a Drug that may help identify the underlying cause of Autism. Hence the bold headline. Earth to Pharmaceuticals Companies… Here’s a population that you can treat for autism! Someone get a hammer out and knock them on the head a few times. (just figuratively!)

This will also be a huge advance for the general autism population. Although the specific mechanism for autism and other brain abnormalities in myotonic dystrophy is somewhat understood, the antisense therapies seem to work exceedingly well in mouse models. Additional study of the DM1 disease will yield results for autism patients in the future. The cellular basis and how the proteins interact to cause these autism like disorders may give great insight to how to further treat the disease. This ability to identify the cause of autism for one specific type and to treat it give hope to all who suffer with this disease.

Richard Weston
www.myotonicdystrophy.com

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