Plug me in, baby !!!

Article in New Scientist, Health Magazine about possible re-connecting broken Spinal Cord after few months constant stimulation with electrodes implanted in spinal cord below injury level & extensive physio-training.

 

Paralysis breakthrough: spinal cord damage repaired

 

Paralysis may no longer mean life in a wheelchair. A man who is paralysed from the trunk down has recovered the ability to stand and move his legs unaided thanks to training with an electrical implant.

Andrew Meas of Louisville, Kentucky, says it has changed his life (see “I suddenly noticed I can move my pinkie“, below). The stimulus provided by the implant is thought to have either strengthened persistent “silent” connections across his damaged spinal cord or even created new ones, allowing him to move even when the implant is switched off.

The results are potentially revolutionary, as they indicate that the spinal cord is able to recover its function years after becoming damaged.

Previous studies in animals with lower limb paralysis have shown that continuous electrical stimulation of the spinal cord below the area of damage allows an animal to stand and perform locomotion-like movements. That’s because the stimulation allows information about proprioception – the perception of body position and muscle effort – to be received from the lower limbs by the spinal cord. The spinal cord, in turn, allows lower limb muscles to react and support the body without any information being received from the brain (Journal of Neuroscience, doi.org/czq67d).

Last year, Susan Harkema and Claudia Angeli at the Frazier Rehab Institute and University of Louisville in Kentucky and colleagues tested what had been learned on animals in a man who was paralysed after being hit by a car in 2006. He was diagnosed with a “motor complete” spinal lesion in his neck, which means that no motor activity can be recorded below the lesion.

First, the man had extensive training in which his legs were moved by physiotherapists while his weight was supported by a harness. During this time no improvement was observed.

He then had a 16-electrode array implanted into the lower region of his spinal cord, which stimulated spinal nerves with continuous electrical activity. When the implant was switched on and he was helped into the correct position, he succeeded in holding his own body weight and standing on his first attempt.

Then something unexpected happened. Seven months into training on how to stand using the implant, he tried to move his toe while the stimulation was on. “He just started trying to move his toe,” says Angeli. “He was like, ‘look it’s wiggling!’ Further testing showed that he was able to move his leg and ankle, too – indicating that voluntary signals from the brain were crossing the lesion.

Over time, the volunteer also gained increased bladder control and sexual function, and had better temperature regulation (The Lancet, doi.org/b3spxp). All of these abilities involve input from the brain, confirming information could now be sent across the damaged area of the spine, as long as the stimulation was on.

Reggie Edgerton of the University of California, Los Angeles, who also worked on the study, says that their initial reason for doing the experiment was to utilise proprioception to tell the spinal cord what to do to allow someone to stand. “We had no idea that the stimulation would be working upwards as well, doing something to the connections between the spinal cord and the brain,” he says.

One possible explanation is that new connections grew across the spinal lesion. But since this response to stimulation has never been shown in animals, a more likely explanation is that the stimulation pushed the activity of damaged connections over a threshold needed for them to send information from the brain to the limbs. “There may be ‘silent’ connections that can’t be seen by current imaging techniques, and are too damaged to work by themselves, which can be boosted into crossing a threshold of activation by the stimulation,” says Edgerton.

Another suggestion is that the sensory fibres that allowed this particular patient to retain some feeling in his legs may have been used in motor control. To rule this out, Angeli and her colleagues recruited Meas and another volunteer who had complete motor and sensory paralysis. From the first session with the electrical implant, both were able to move their lower limbs when the stimulation was on.

“We think that the first volunteer may have been able to do it straight away too, but just never tried,” says Angeli, who presented the results at theSociety for Neuroscience Conference in New Orleans last week.

Over time, all three of the volunteers were able to carry out a variety of movements ranging from whole leg flexion to toe extension. Their coordination also improved and they could generate more force from each movement. And after four months of training, the amount of stimulation needed to create the same amount of movement fell.

However, there was a final surprise in store. At the conference, Angeli showed how, after three months, Meas was able to stand and move his lower limbs without the aid of stimulation. “One day he was training with the stimulation and we shut it off and he was still able to move,” she says. “We didn’t expect to see it happen so quickly.”

We now need to learn how to push these silent connections above their threshold, says Edgerton. He thinks it may simply be a case of improving the implants. “We’re using an implant that was build three decades ago and designed to suppress pain.

We thought it would be good enough to show proof of principle, but our volunteers are going crazy because they know what they need to do but the stimulation device isn’t good enough yet to allow them to do it.”

For now, none of the volunteers can walk without support. “We have a feeling that it’s a question of the technology restricting us, that being able to control stimulation to the left and right legs separately might help,” says Angeli.

Brian Noga, who works on spinal damage research at the University of Miami Health System in Florida, says the work clearly demonstrates that even people with the most severe spinal injuries may have some remaining connections.

“It really makes us open our mind to very new possibilities,” says Edgerton. “All those individuals that are considered completely paralysed and know about this experiment, you know they are thinking ‘am I one of those that can do this?’ We just don’t know.”

“I suddenly noticed I could move my pinkie”

“I was cruising towards the highway when this old guy tried to cross the 4-lane road really fast. He hit me and I ejected over to the opposite lane. Luckily someone found me before the traffic got to me.”

On 6 September 2007, Andrew Meas of Louisville, Kentucky, suffered a spinal injury to an area near his neck. This resulted in full paralysis of his trunk and lower limbs. “I took part in 80 sessions of supported standing and locomotor training and nothing happened.”

Then Meas had a 16-lead electrode implanted into the lower segments of his spinal cord. This provides constant electrical stimulation to his lower limbs (see main story). “When it was turned on there was this jolt in my muscles,” he says. He was able to stand and support his body weight.

“It was awesome,” Meas says. Blood pressure, vision and bladder problems have all cleared up. But there were more surprises. Three months after stimulation training started, he was sitting on a mat trying to move different parts of his body when the implant was turned off. “I suddenly noticed that I could move my pinkie toe. I wiggled it.”

Now the voluntary movement is starting to work its way around his body. “I can feel more muscle contraction in the bottom of my left foot and I’m working hard to strengthen that. I can kick my foot out and lift up my knees.”

“When it happened for the first time we were all really excited about it,” he says. “It was amazing – the most normal feeling I’d felt since my injury.”

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Q & A by Dr. Wise Young

Posted on Cure Forum @ CareCure.org October 02  2012

Difference between simplified and scientific look @ Human Trials to Cure Spinal Cord Injury

Question posted by me:

comad's Avatar

Question for Doctor’s & Scientists.

Can you use and how fast you can use other team or scientist research?

For example – I have a feeling that Dr.Wise need something to clear path on “scar tissue” for all stem cells to better connect. Possibly, that’s why the Cethrin [that was proven to be safe and relatively effective in Human acute trial and can get safety approval on chronic rats] is in the game. 
For Dr. Silver’s research on method of Cha’se delivery – there is longer path till comes approved to Human trials if shows effective on chronic injured rats and he and his team can definitely use already organized Human trial network by SCiNEt to speed up the whole thing.
I have feeling that mixing up of those 2 will accelerate everything to the point of having cure within 2 years from now.
However, as collaboration of 2 teams is out of this world and X prize is nowhere on horizon is there any way that one scientist can use results and method’s from another scientist and include in his research / trial?

Answer posted by Dr. Wise Young:

Comad,

To take a therapy to clinical trial in most countries around the world, one must get regulatory approval from the FDA in the United States, the EMA in Europe, the sFDA in China, or various departments of health in other countries. The information used to support the trial does not necessarily have to be published (although peer-reviewed information is generally more credible and impressive) before submission to the regulatory agencies.

The FDA and most regulatory agencies carefully scrutinize any first-in-human drug trials. The treatment must fulfill several strict criteria before an IND (investigational new drug) application is approved. The following are some information that must be provided in the IND application.

1. The FDA requires safety data from one large animal and one small (rodent) animal species, collected under GLP (Good Laboratory Practice) conditions.

2. The trial sponsor must provide detailed data about pharmacokinetics (time course of the drug in the blood) and pharmacodynamics (time course of the drug in the tissue of interest).

3. Information about efficacy or at least rationale for efficacy must be provided.

4. The drug manufacturing method, potency, shelf-life, purity, must be provided. documentation of GMP (Good Manufacturing Practice) must be provided.

5. Based on the product manufactured under GMP conditions, secondary metabolic products, and any side-effects from secondary metabolic byproducts must be studied and described in detail from animal studies.

There is a fallacy amongst inexperienced scientists that efficacy data in animal studies are required or sufficient for IND approval. The first and most important criterion for IND approval is safety. In order to evaluate safety, the FDA must have as much information about the drug as possible to understand the risk that the drug and its secondary metabolic byproducts may pose to human subjects. They must confirm that the drug is being manufactured under GMP conditions (where all procedures and reagents are rigorously documented) and the safety studies are being done under GLP conditions (where all aspects of the rats and the studies are being properly documented).

Animal efficacy data is of course helpful but, when it is not available, therapeutic rationale is often sufficient, if the treatment is safe. Many therapies cannot be tested in animals. Credible rationale for efficacy is often sufficient to allow IND approval. All lot of scientists have focused on showing efficacy in animal studies and then don’t do all the other studies that are necessary to obtain IND approval. As a result, few treatments ever go to clinical trial. If a drug company doesn’t take the responsibility and expense of carrying out the safety and manufacturing studies, the treatment seldom goes to trial.

Cethrin is a very good example of how a drug is developed from spinal cord injury. I have long been a strong supporter of Lisa McKerracher and her passionate approach to getting Cethrin into clinical trial. After she discovered that C3 (a bacterial toxin that blocks rho) has some effects on spinal cord regeneration, she formed a company called Bioaxone to develop the drug further. She soon found that the drug doesn’t get into the nervous system as well needed to stimulate regeneration and therefore modified the C3 toxin by appending a transport sequence to the molecule so that neurons would pick it up, calling this new molecule Cethrin. She then did all the animal studies showing that this drug works, raised about $15 million to get all the safety studies and GMP manufacturing of the drug established, and took it to Phase I/II clinical trial in 48 patients with spinal cord injury. The study showed impressive (although not controlled) benefit for the patients, compared with historic recovery of patients with ASIA A. Over 60% of cervical spinal cord injury patients converted from ASIA A to ASIA C, for example.

The task of taking the treatment to phase III trial is a daunting one and Lisa sold the license for Cethrin to Boston Life Sciences (BLS), which changed its name to Alseres. This coincided with the 2008 stock market crash and Alseres was unable to raise funding for the phase III trial, returning the license to Lisa McKerracher last year. She re-formed Bioaxone in the United States and is now raising the money for the phase III trial. Cethrin is a drug that has been shown to be safe in human and has had promising results in phase I/II studies in the United States and Canada. Despite this, she is having trouble raising the money for phase III trials in the United States and therefore have turned to Asia.

Regarding chondroitinase, Acorda Therapeutics is working on safety and other studies necessary to get chondroitinase ready for IND approval. They have some studies that still have to be done, including GMP manufacturing of the drug and pharmacokinetics and pharmacodynamic studies of different routes of administration. If Jerry Silver has a small molecule that can block the CSPG receptor, this would essentially scoop chondroitinase as a potential therapy for spinal cord injury. So, you can imagine how this does not necessarily encourage Acorda Therapeutics to invest millions of dollars into doing more safety studies of chondrotinase in animal spinal cord injury models. Nevertheless, Accorda is doing so, perhaps because it will take time and expense to move a first-in-human drug into clinical trial.

ChinaSCINet must make sure that therapies are ready for trial before it can do the trials. As much as I would like to take chondroitinase and other therapies to trial, it must fulfil the criteria required for regulatory approval. Otherwise, we cannot take the treatment to trial. I not only have to ensure that a treatment will receive regulatory approval but I must convince 25 principle investigators in ChinaSCINet to devote the time and resources to testing a treatment. This is one of the reasons why I hold many meetings in China, from workshops to symposia. ChinaSCINet has an important educational role as a clinical trial network.

This is also true of any company or sponsor trying to get a therapy to trial. One must not only convince the regulatory agency but also the investigators. Sure, some companies can shell out millions of dollars to investigators, who then become hired hands. I assure your that ChinaSCINet does not have this kind of money or aspiration. The network decides on the most promising therapies to test. All investigators in the trial •volunteer• their time to operate on the patients and to take care of them. They must be convinced of the therapeutic promise and safety before they will embrace the trial.

Wise.