ALS drug-discovery research is proceeding on many fronts at the ALS Therapy Development Institute (ALS TDI), an MDA-supported laboratory in Cambridge, Mass., whose mission is to rapidly develop therapeutics for ALS.

ALS TDI scientists updated the ALS community on their efforts during a Web-based seminar on Dec. 10.

Chief Scientific Officer Steve Perrin, and Director of Therapeutic Investigations John McCarty, summarized lab activities and answered submitted questions.

Below are highlights of the seminar, which can be accessed in its entirety through the ALS TDI Web site at www.als.net.

SOD1 blockers

Perrin described the Institute’s testing of a “short hairpin” molecule that targets the genetic instructions for the SOD1 protein. SOD1, when abnormally formed, is a cause of human ALS in a small percentage of cases and forms the basis of the mouse model of the disease most commonly used by researchers.

Perrin said the hairpin construct, when packaged inside an adenoviral delivery vehicle and injected into the muscles of test animals, was not toxic and entered the spinal cord very well.

Researchers at the Institute are now testing the efficacy of the hairpin molecule against SOD1 genetic instructions in mice with mutated SOD1 genes.

Initial observations are that the SOD1-targeting hairpin extended survival of male ALS mice by about 14 days but didn’t help female mice. Perrin said the investigators are considering fine-tuning the strategy and the dosing regimen to see if they can improve the effect in both genders.

The 32-person research group is also investigating delivery vehicles made from adeno-associated viruses (AAVs), which don’t provoke the immune system as much as adenoviruses do. So far, they’ve found type 2 AAV, although it’s well tolerated in mice, doesn’t enter the nervous system robustly from muscle tissue.

The Institute has a collaboration with Asklepios BioPharmaceutical, an MDA-supported biotech company located in Chapel Hill, N.C., to develop new AAV strains designed to enter the spinal cord.

New mouse model

Perrin also described how ALS TDI scientists will soon begin researching, in depth, a mouse that has an ALS-like disease because of a mutation in the gene for the dynein protein, rather than the SOD1 gene. This mouse model, called the LOA (“legs at odd angles”) mouse, has defective transport of molecules through nerve-cell fibers and shows ALS-like symptoms.

Biomarker search

Perrin said the Institute has profiled some 250 human blood samples in search of ALS-specific biological indicators (biomarkers). Initial candidates have been identified, and the project will continue.

Iplex

John McCarty said there is “currently no substantial preclinical data and no significant anecdotal data” supporting the use of Iplex (a combination of insulin-like growth factor 1 and binding protein 3) in ALS. The drug, made by Insmed of Richmond, Va., has recently become available to ALS patients outside Italy, but it’s estimated to cost about $100,000 a year, and each patient’s request for it must be approved by a review board.

Lithium

McCarty reported that Institute scientists have seen no effect of lithium on body weight, neurological function scores or survival in mice with mutated SOD1 genes. The drug is being tested in an MDA-supported clinical trial, following a February 2008 publication saying it slowed disease progression in ALS patients in Italy.

Apocynin

ALS mice treated with the antioxidant apocynin, which was reported to be beneficial in a preclinical ALS study last year, fared no better than untreated mice when rigorously tested at the ALS TDI. The Institute will not pursue further apocynin testing, McCarty said.

Next steps

McCarty noted that drugs reported, even anecdotally, to be beneficial in ALS, are being tested in the laboratory at ALS TDI.

Perrin noted that “if you really want to have better shots on goal, move drugs toward the clinic, you have to understand the disease mechanism better. We have the tools in place, the data in place, to get drugs hitting a disease mechanism, targeting disease biology, and that will be better than in the past.”

MDA has made a three-year, $18 million commitment to ALS TDI through MDA’s Augie’s Quest initiative.

MDA has begun a new research initiative in 2009: MDA Venture Philanthropy (MVP). Designed to bridge a crucial funding gap in the drug development process, MVP will focus on the discovery and clinical application of treatments and cures for neuromuscular diseases, including ALS.

MVP evolved from, and replaces, MDA’s Translational Research program, which has had great success in speeding the progress of promising drugs from the lab into clinical trials. MVP will leverage these gains and its relationships with key industry partners to further refine and hasten the process of turning research into treatments.

The program will seek major gifts (greater than $500,000) from philanthropists, corporations and organizations. MVP’s goal is to fund the completion of the early stages of drug development (moving compounds from the lab to clinical trials) by awarding contracts to companies working on projects that have potential to become treatments. MVP will seek collaboration with pharmaceutical and biotech companies for completion of the final stages required to bring a drug to market.

A separate 501(c)(3) nonprofit with its own board of directors that works in coordination with MDA, MVP is guided by voluntary scientific and business advisory boards composed of top experts and leaders in their respective fields. It will raise donations and fund projects independently of MDA, meaning there will be no drain on funds for MDA’s existing programs of basic research and vital services.

ALS will be a major focus of MVP’s efforts and major-gift donors can choose to direct their money to a portfolio of ALS research projects.

Watch MDA’s Web sites (www.mda.org and www.als-mda.org) for an official announcement and more details about MDA Venture Philanthropy.

Some studies suggest that motor neurons, even when healthy, can be killed by toxic neighbors. If so, converting these “sharks” to “dolphins” might slow the pace of ALS.

Since the earliest descriptions of ALS, it’s been noted that progressive muscle atrophy (shrinkage) and weakness are hallmarks of the disease. For decades the assumption has been that the muscle degeneration results from the loss of muscle-stimulating nerve cells in the spinal cord and brain, known as motor neurons.

But that assumption has been questioned in recent years, with several scientists finding that other types of cells, such as nervous-system support cells called glia, and even muscle itself, may make significant contributions to the disease.

If these other cells do contribute to the disease process, that would be good news, because glia and muscle cells may be easier treatment targets than motor neurons.

Microglia add fuel to fire

In 2006, Don Cleveland and colleagues at the University of California-San Diego showed that, in ALS, outside influences from cells in the nervous-system neighborhood do matter. (See “Outside Agitators,” ALS Newsmagazine, February 2007.) Cleveland’s group focused on the role of microglia, a type of glial cell in the nervous system whose normal job is to protect neurons from microbes that threaten their survival.

The group’s experiments in mice led them to conclude that initiation of the ALS disease process probably requires damage to motor neurons but that activated microglia intensify the disease.

What role do astrocytes play?

Other groups have focused their attention on astrocytes, another type of glial cell. Once thought to be merely “glue” providing structural support, these star-shaped cells are now known to play additional roles in the neuronal environment, such as cleaning up excess glutamate, which can be toxic. But what, if any, contribution do they make in ALS?

On Dec. 10, investigators at the University of Wisconsin-Madison coordinated by Jeffrey Johnson published a paper in the Journal of Neuroscience that showed treating astrocytes alone can delay disease onset and extend survival in mice with an ALS-like disorder.

(Note: these experimental mice, the most common animal “model” of ALS, carry mutated genes for the SOD1 protein. Some 1 percent to 3 percent of human ALS cases can be attributed to SOD1 mutations. At present, no exact mouse model exists for the most common form of ALS because the cause of the disease is unknown.)

The benefit in the Johnson group’s experiments in ALS mice was brought about by increasing astrocyte production of a protective protein called NRF2.

Two other research teams published astrocyte experimental results in the Dec. 4 issue of Cell Stem Cell.

Maria Marchetto at the Salk Institute for Biological Studies in La Jolla, Calif., and colleagues, maintained healthy human motor neurons in a culture dish with normal human astrocytes, or with human astrocytes carrying an ALS-causing mutation. The group found that only the motor neurons that were mixed with the mutation-containing astrocytes died. This toxic effect could be prevented by treating the astrocytes with the antioxidant apocynin, the group found.

Francesco Paolo Di Giorgio and colleagues at Harvard University reported results at the same time from similar experiments. This group of scientists also found that mouse astrocytes carrying an ALS-causing mutation killed healthy human motor neurons in a culture dish.

They determined that the poisonous effect of the mutation-carrying glial cells was at least in part caused by their production of a chemical called prostaglandin D2. Blocking this compound provided partial but significant protection to the motor neurons in the dish.

Important or not?

Many experts are skeptical about major non-neuronal contributions to ALS. Among the doubters of a primary role for non-neurons is Jeffrey Elliott, an MDA grantee at The University of Texas Southwestern Medical Center in Dallas. A study published by Elliott and colleagues in the Journal of Neuroscience in 2000 concluded that, while the presence in mice of mutant SOD1 in astrocytes alone caused significant changes to the astrocytes, it was not sufficient to kill motor neurons or produce an ALS-like disease.

Dutch researchers published a complementary paper in 2008 in the same journal showing that production of mutated SOD1 protein in neurons alone was enough to produce an ALS-like disease in mice.

Together, these two studies lead to a conclusion that the presence of mutated SOD1 protein solely in astrocytes is neither sufficient nor necessary to cause ALS in mice, although neither study rules out a potential contribution from these cells.

Elliott says that, although he believes SOD1-related ALS is neuronally based, involvement of other cell types “may impact the disease.”

Does muscle matter?

In another recent study, MDA grantee Antonio Musaro at the University of Rome coordinated a research team that determined that mice carrying an SOD1 mutation solely in their muscle cells developed severe muscle wasting despite the presence of unharmed, healthy motor neurons.

But, in an earlier study, lowering mutant SOD1 levels in muscle tissue alone failed to improve survival or affect disease onset. Enhancing muscle mass and strength in the mice likewise had no benefit.

Experiments hard to compare

Unfortunately, experiments differ so widely in the questions asked and techniques employed that direct comparisons are impossible.

For instance, investigators recently examining the contribution of glial-cell abnormalities to motor-neuron degeneration note that their experiments were conducted using human motor neurons and may therefore be better at mimicking human ALS than experiments conducted in rodents.

Elliott, however, has a less enthusiastic view of studies conducted in laboratory dishes rather than animals, whether or not they involve human cells. “Cells do not get ALS or weakness,” he says, “so one must be cautious about over-interpreting such results.”

Non-neuronal neighbors could be easier to reach and treat than neurons

If abnormalities in glial cells or muscle fibers make a major contribution to ALS progression or severity, whether or not they can actually cause the disease, treating them could retard progression or reduce severity, and that would be good news.

Motor neurons are hard to reach with therapies, because they’re surrounded by a protective barrier that keeps most substances out of the spinal cord and brain. They’re also delicate, and, once injured, they can’t divide or replace themselves the way many other cell types, including glia, can. Finally, they control movement via long fibers (axons) that extend from the spinal cord to muscles. These can take months to develop and must reach their targets precisely.

Glial cells are also inside the barrier that surrounds the central nervous system, but they divide often, and sick ones can be replaced with healthy ones. And although they communicate with neighboring cells, they don’t do so via long fibers.

Muscles are outside the nervous system, and they’re fairly easy to reach with therapeutic substances. And unlike neurons, muscle fibers can repair themselves, although not as readily as some other cell types do. Replacing damaged muscle fibers, though difficult, is being seriously considered as a strategy for treating muscle diseases and might confer some benefit to ALS patients.

Of more immediate importance, therapeutic genes injected into muscles can, depending on how they’re packaged, travel up nerve fibers into neurons in the spinal cord. MDA grantee Brian Kaspar, at Nationwide Children’s Hospital in Columbus, Ohio, is working on delivering genes for proteins such as insulin-like growth factor 1 (IGF1) to skeletal muscle. IGF1 and other so-called trophic (nourishing) factors may have beneficial effects in nerve and/or muscle cells.

MDA’s clinic and ALS Center directors met in Las Vegas Jan. 25-28 to receive updates on several ALS-related topics.

Among them were the ALS disease process; the relationship of cognitive impairment to ALS; trials of lithium, diaphragm pacing, ceftriaxone and bone marrow transplantation; gene therapy (adding genes); blocking genetic information; and stem cells.

See www.mda.org for more on this meeting; additional details will be in the March issue of ALSN.

’Lightning Fast’ Switch Increases Accuracy, Reduces Fatigue

Although single-switch scanning is considered a slow method for computer access, David Jayne is scanning faster and more accurately with the Impulse switch, which responds to slight muscle movements in his forehead.

In the January issue, we explored the technological wonder of a head mouse, or tracker, and its ability to facilitate hands-free computer access in conjunction with specialized communication software, onscreen keyboards and mouse-clicking solutions.

As technology evolves, new adaptations for hands-free computer access tools help people with ALS communicate, stay online and even drive a wheelchair — all with the slight movement of one working muscle.

More than a switch

For longtime ALS survivors David Jayne and Jack Hurst, AbleNet’s new Impulse computer-access device keeps them online and connected to the world.

Manufactured by Neural Signals for AbleNet, the Impulse switch ($2,100) is wireless and powered by Bluetooth technology. It uses an electrode to measure electromyography (EMG) impulses through small muscle contractions, providing a way to control computers and speech-generating devices with very small movements.

Used in conjunction with a Windows-based computer and the EZ Keys communication software (manufactured by Words+; retail price $1,395), the device provides complete computer control. The adjustable switch sensitivity makes it effective for users who only can manage the slightest muscle movement.

No visible muscle movement is necessary to set off the switch, reducing user fatigue, said Joe Wright, Neural Signals’ vice president of product development. The fact that it’s wireless makes it easier for caregivers to maneuver around the person, he added.

Staying on course

Disability-rights activist David Jayne of Rex, Ga., uses a single-switch scanning computer system for communication, environmental controls and driving his wheelchair. (See “Keep on Keepin’ On, MDA/ALS Newsmagazine, January 2008, and “On My Command,” Quest, May-June 2008.)

(Single-switch scanning is used by people who have one reliable movement to activate a switch. The switch prompts the computer/communication software to scan a variety of options, briefly highlighting each. Once the desired option is highlighted, the user again activates the switch to make the selection.)

Up until nine months ago, Jayne relied on a fiber optics switch attached to his eyeglasses to send commands to his laptop for communication, environmental controls and driving his wheelchair.

Always in search of the most functional and cutting-edge developments in assistive technology, Jayne was encouraged by fellow ALS survivor Jack Hurst to try the Impulse switch. Hurst, 70, of Marietta, Ga., has used the switch for more than a year, dating back to its early development and testing stages.

Jayne, 47, wasn’t excited about changing access methods, but he consulted with Neural Signals to make the switch more functional with an easy setup; compatible with his computer/communication system, particularly his specialized wheelchair-driving software; and able to reboot his computer independently, something he could do with his fiber optics switch system. He’s very happy with the result.

“The switch is lightning fast,” Jayne said via e-mail. “I am scanning faster and driving better than ever as a result of the switch. The adjustable sensitivity can be reduced to the point that sometimes it feels like I’m just thinking of moving the muscle.

“I’m doing everything faster, more accurately and with less effort than ever before.”

A wireless world

Although eye-tracking (also called “eyegaze”) technology can be made to work faster by adjusting the settings, Jayne asserts that the Impulse is the best option for single-switch users like him because he’s constantly changing lighting environments or is in direct sunlight. (Light can interfere with eye-tracking technology.)

Because his laptop controls virtually every aspect of his environment, Jayne demands a reliable system, and “eyegaze technology hasn’t advanced to meet my needs at this time.”

With adhesive strips, the Impulse switch is attached to the left side of Jayne’s forehead, and is activated by electrical activity in the muscle there. Jayne raises his eyebrows to activate the switch and begin scanning; when the desired option is highlighted, he raises his eyebrows again to make the selection.

For example, if Jayne wants to put his wheelchair in reverse, he raises his eyebrows to start scanning the driving software, and when the third line is highlighted, he raises his eyebrows again to scan each icon in the third line. When the down arrow is highlighted, he raises his eyebrows and holds them in position until he’s backed up the desired distance.

Highly responsive

AbleNet’s wireless Impulse switch uses Bluetooth technology to help provide computer access to people with limited movement. The device detects small muscle impulses and can be attached to virtually any part of the body, like the head or jaw, with a disposable sensor.

Like Jayne, Jack Hurst uses the Impulse switch and EZ Keys for full computer access. Hurst, who spends at least eight hours a day on his computer, uses his jaw muscle to activate the switch and send wireless signals to his computer. He bites down to start the scanning process, and when it reaches the desired letter or phrase, bites down again to select the option.

“I use my jaw muscle because it’s not tiring or fatiguing at all, it doesn’t require a lot of force to activate, and it keeps my jaw strong,” Hurst wrote via e-mail.

Jayne added, “The switch’s wireless feature is a wonderful benefit because there are no concerns about becoming disconnected by individuals who aren’t familiar with my equipment, and I thoroughly enjoy that my children and others can hug me without fear of disturbing my communication.”

Jayne said he didn’t realize how much effort he had been expending to trigger the fiber optics switch.

“I was anticipating when to activate the switch ahead of time,” he said. “Now, I activate the switch the instant the desired icon is highlighted [via scanning]. Eliminating the need to anticipate, combined with the minimal effort to activate, has increased my scanning rate and accuracy significantly.”

The switch’s sensitivity can be adjusted so low that it can be activated without any visible muscle movement, Jayne said, giving those who are almost completely paralyzed “hope of continued communication.”

For more information about the Impulse switch, visit www.ablenetinc.com, or call (800) 322-0956. To learn more about the EZ Keys communication software, go to www.words-plus.com, or call (800) 869-8521.

The Lowdown on Following Up

Scheduling, attending and making the most of follow-up visits at your MDA clinic can make the difference between living with ALS and giving in to it.

But oftentimes, people aren’t sure exactly what to expect out of follow-up visits.

It’s a mistake, doctors say, to assume that the only purpose of these visits is to allow the physician to monitor disease progression or record statistics.

To what end?

ALS – like illnesses such as heart disease, lung disease and diabetes — is chronic, and physicians often can give medication or provide care to manage it, notes neurologist Steven Ringel, director of the MDA/ALS Center at the University of Colorado in Denver.“

Much of what we do in medicine is maintenance, not curing,” Ringel explains. “The overall goal is to maximize the quality of life.”

Of course, making the best of life with ALS requires dealing with the symptoms that come with it. To that end, physicians address not only physical symptoms, but psychosocial issues such as depression and the nature of support the individual has at home and in the community.

Many symptoms can be well-managed, “and this helps people do the things they love for as long as they can and want,” says neurologist Merit Cudkowicz, director of the MDA/ALS Center at Massachusetts General Hospital in Charlestown.

Sleep disturbance, pain, cramps, spasticity and difficulty with mobility are just some of the symptoms that can be addressed in a clinic visit, Cudkowicz notes. “We also discuss research updates and offer new treatment trials, if available. The field of ALS research is moving fast, and clinic visits are an opportunity to discuss these new advances and continue to offer hope.”

One further point to consider: Follow-up visits provide important education to physicians, other professionals and students, particularly those just coming into the field. These visits give them the opportunity to see how this little-known disease progresses and what the needs are at different time points.

A matter of timing

The time between diagnosis and the first follow-up visit with an ALS specialist varies depending on the clinic, the physician and the specific needs of the individual. This also is true of the intervals between subsequent follow-up visits.

“This has to be customized,” says neurologist Hiroshi Mitsumoto, director of the Eleanor and Lou Gehrig MDA/ALS Research Center at Columbia University in New York. “It should not be simply routine, ‘every patient, three months.’ It’s dependent on the needs of each person.”

Mitsumoto says the average duration between visits may eventually “settle in” at three months, but scheduling always should be based on needs and medical status.

Likewise, Ringel says he prefers not to be “locked in” to a set one, two or three months when it comes to scheduling that first return visit.

If I have a very anxious patient, I’ll see them for their first follow-up in a few weeks. If I have someone who’s less anxious and pretty calm about it, who understands it and maybe just wanted a second opinion, I’ll usually ask them, ‘when do you think it would be a good time to see me again?’ and then decide together.”

Ringel says it helps to get a series of “data points,” or measurements, particularly in the beginning, in order to determine the rate at which the disease is progressing. “So usually three months is the longest I’ll recommend for a follow-up, but in cases where there’s little to go on, I frequently recommend sooner — especially for the very first visit.”

Keep in mind it’s not always necessary to wait for the next appointment to discuss questions or concerns. Many physicians will address these issues by phone or e-mail between clinic visits.

What to expect

Neurologist David Chad, Director of the MDA/ALS Center at the University of Massachusetts in Worcester, describes the follow-up visit as “a time of fairly intense activity for the patient, caregiver and family.”

These visits often include time spent with a multidisciplinary health care team that can include nurses, neurologists, pulmonologists, physical and/or occupational therapists, nutritionists, speech-language pathologists, social workers and others who evaluate the individual and develop a strategy to manage symptoms in the most effective way possible.

The person with ALS should expect to address several layers of concern at each visit, says Chad, such as:

• How am I doing? How is my breathing status, and is it time to consider noninvasive ventilation? Is it time to consider symptom-control medications or assistive equipment?
• Is there news about a clinical study for which I might be eligible?
• What’s new in the world of ALS care and research?

Follow-up visits also are a time to learn what to anticipate in the future. This might include discussing such things as ventilatory options, feeding tubes, mobility issues and whether the individual’s house can accommodate a wheelchair or other equipment when it becomes necessary.

Ringel notes that providing an understanding of what may happen down the road allows people time “to adjust and cope.”

A group effort

It’s extremely helpful for family caregivers to attend follow-up clinic visits with their loved ones. ALS affects the entire family, so the more education and understanding everyone has about the disease, the better. Open communication can help ensure that everyone’s needs are met.

In fact, one of the roles of the physician, says Ringel, is understanding who’s filling certain caregiver roles, how they’re doing with it and what, if anything, they want or need to address. This helps ease fears and uncertainty and makes daily living with ALS easier on both the individual with ALS and caregivers.

Cudkowicz suggests the caregiver “ask questions, advocate for the patient, share what’s working in the home (and what’s not), and address concerns and fears.”

Chad confirms that this type of support is crucial. “The caregiver/family member is an integral member of the care team, joining the nurses, doctors and therapists, and working collaboratively to achieve the best possible symptom management.”

Making the most

With so much to gain, making the most of follow-up visits is key.

It’s always a good idea to write down ahead of time the things you want to talk about. Ringel suggests keeping a notebook for that purpose.

In addition, Cudkowicz suggests bringing along a list of medications, and contacting the clinic in advance if you want to schedule an appointment with a particular specialist. She also recommends bringing in any equipment for which you want instruction, or that you want the team to evaluate.

Make sure the ALS team coordinates with your family doctor or any other health care professionals you see on a regular basis. In many cases, the ALS physician will notify your other doctors in writing of the ALS diagnosis; if they don’t do it automatically, make a specific request. MDA health care service coordinators often can facilitate this process.

Says Mitsumoto, “Together we provide some kind of hope, whatever kind of hope we can. We’re making a team — physicians and patients — working together to solve a prob-lem. If everyone feels that way, it can only result in success.”