In mid-January, MDA announced that it would play a key role in the largest ALS drug discovery project in history — a three-year, $36 million effort to identify biochemical targets and find drugs that work on them.

James Heywood started the ALS Therapy Development Foundation (now ALS TDI) in 1999 after his brother Stephen developed ALS. Stephen Heywood died in November.

The collaboration will be supported by an MDA grant of funds generated by its Augie’s Quest initiative, and by the ALS Therapy Development Institute (ALS TDI, formerly the ALS Therapy Development Foundation). MDA will grant $6 million a year for the next three years and ALS TDI will add its $6 million annual budget to the project. MDA’s funding for this collaboration is above and beyond it existing ALS research expenditures.

Research will take place at the Institute’s 16,000-square-foot lab in Cambridge, Mass. ALS TDI is a nonprofit biotechnology company dedicated to translating research into potential drug treatments. It was started by James Heywood in 1999 after his brother Stephen received an ALS diagnosis. Stephen Heywood died in November 2006.

The Institute will continue its program of drug testing in a mouse model of ALS, but its major focus will be analyzing changes in gene activity over the course of ALS in various mouse models and in patients. Gene activity, also called gene expression, is the extent to which a cell is actively engaged in protein synthesis from a gene’s instructions.

This work will complement the recent identification of genes that may play a role in ALS susceptibility, accomplished through an MDA grant to the Phoenix-based Translational Genomics Research Institute (see “Genome-Wide Search,” January).

Steve Perrin, formerly an executive at the biotechnology company Biogen Idec, is chief scientific officer of ALS TDI. Former Institute vice president of drug discovery Sean Scott is its president, and founder James Heywood is chief executive officer.

Nels Mahle directs TDI’s Mass Spectrometry Core, a system that identifies and measures drugs in spinal tissue.

“The causes of ALS have been a tragic mystery for too long,” said MDA National Chairman Jerry Lewis, noting that Lou Gehrig’s widow, Eleanor, held a voluntary leadership position with MDA for many years. “This project is a giant step toward a solution to that mystery and a cure for ALS.”

ALS Research Roundup

by Margaret Wahl

Neuroscientist and neurologist Timothy Miller, at the University of California-San Diego, says recent MDA funding has allowed his group to move closer to human trials of an experimental compound that blocks abnormal SOD1 genetic instructions.

ALS is caused by a mutated SOD1 gene only about 1 percent to 3 percent of the time. Nevertheless, it’s perhaps the best understood form of the disease and almost the only form used in animal-based ALS studies.

Antisense keeps a cell from processing (making sense of) targeted genetic information (RNA).

Miller says a recent meeting with the Food and Drug Administration (FDA) assured him that he’s on the right track with preclinical testing of the compound’s possible toxicities in animals, a prerequisite for a human trial.

The anti-SOD1 compound makes use of recent developments in the field of gene blocking with so-called antisense pieces of genetic information that keep other genetic information from being processed.

Miller and colleagues Don Cleveland at UCSD, Richard Smith at the Center for Neurologic Study in La Jolla, Calif., Merit Cudkowicz at Harvard University, and Isis Pharmaceuticals in Carlsbad, Calif., are using antisense to block the abnormal RNA instructions that would otherwise result in ALS-causing superoxide dismutase 1 (SOD1) protein molecules. (When cells process a genetic recipe for a protein, they first convert DNA to RNA.)

When Miller and colleagues infused SOD1 antisense molecules into the brains of rats destined to develop ALS because they have mutated SOD1 genes, they saw an 8 percent increase in overall survival in these rodents compared to their untreated counterparts. But when the researchers looked specifically at survival after disease onset, they saw a 30 percent difference in the treated and untreated rodents.

“We’re very encouraged about the extension of survival after onset,” Miller says. “For patients who are symptomatic [show symptoms], I do think this therapy will provide benefit.”

In fact, he believes the benefits in humans might be even better than in the rodents, because the animals produce about 15 times the normal amount of SOD1, while humans, though they make abnormal SOD1, don’t overproduce it.

One potential problem is that the antisense compound can’t distinguish between normal and abnormal SOD1 RNA and therefore blocks both. (People with SOD1-related ALS nearly always have one normal SOD1 gene and one mutated one.) Miller, however, isn’t overly concerned.

“With antisense therapy, you’re not going to reduce the level to zero,” Miller notes. “You’re likely to get about a 50 percent knockdown, which may be a very appropriate level to decrease the toxicity of SOD1 but still maintain enough of the function of the enzyme.”

The human trial will involve infusing SOD1 antisense compounds through an electronic pump into the fluid surrounding the spinal cord. Pending the outcome of the toxicity studies and approval from the FDA, Miller hopes to begin late this year.

Ceftriaxone Trial Seeks Participants

A multicenter trial of ceftriaxone, an antibiotic approved to treat certain infections that may enhance transport of potentially toxic glutamate away from nerve cells, is enrolling participants at 10 U.S. centers. Contact Amy Swartz at Massachusetts General Hospital in Boston at (617) 643-3980 or fmurphy@partners.org. See also www.mda.org/research/view_ctrial.aspx?id=164.


Two New Compounds Target Cell Death by Mitochondria

Trophos, a biotechnology company based in Marseille, France, announced in December that it plans to launch a phase 2-3 study of its experimental compound TRO19622 in ALS in 10 centers in Europe, pending regulatory approvals.

TRO19622 is given orally and is thought to interfere with an early step in the so-called cell death cascade (see “Trophos,” June-July). The cholesterol-like compound apparently prevents microscopic pores in the mitochondria of nerve cells from opening. The mitochondria, which resemble miniature cells, are present in great numbers inside nerve and muscle cells, where they produce needed energy but can also trigger a cell’s self-destruction.

In a phase 1 trial involving 36 people with ALS, TRO19622 was safe and well tolerated. The phase 2-3 trial will determine whether the drug affects survival or function.

Also in December, Maas Biolab, of Albuquerque, N.M., announced it would begin safety testing in animals of its experimental compound Mitogard, with the eventual goal of conducting a clinical trial in ALS patients.

Like TRO19622, Mitogard is thought to interfere with the opening of pores in the mitochondria. It’s based on a much older drug, cyclosporine, which is used to suppress the immune system. It has to be delivered via the spinal fluid to reach the nervous system.

Gene ID May Unlock New Door to Glutamate Control

A new way to reduce levels of the potentially toxic nervous system chemical glutamate may have been identified by MDA grantee David Featherstone and colleagues at the University of Illinois-Chicago.

In a paper published in the Jan. 3 issue of the Journal of Neuroscience, the investigators describe their identification of the gene for a protein they’ve called “genderblind,” whose job is to help regulate glutamate concentrations outside cells. Without genderblind, glutamate levels drop dramatically, a desirable effect in ALS.

Excess glutamate around nerve cells has been implicated as a cause or at least an exacerbating factor in ALS, but attempts to reduce it have been only moderately successful.

Riluzole (Rilutek), the only medication specifically approved for ALS treatment by the U.S. Food and Drug Administration, reduces glutamate levels modestly, probably mainly by interfering with cellular release of the compound.

Ceftriaxone, now being tested in an ALS clinical trial, reportedly increases the transport of glutamate away from the area around nerve cells.

Genderblind (so named because a mutated form of it causes fruit flies to behave in certain ways without regard to their gender) moves glutamate from inside glial cells (supportive cells in the nervous system) to the extracellular (outside cells) area. Blocking it — at least in flies — caused a dramatic fall in extracellular glutamate.

Featherstone says there’s a long road between a fruit fly study and human trials of genderblind blocking agents, if they could be developed for human use, but that it may be worth following.

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FIRST PERSON SINGULAR
In the Beginning

It all started in October 2004, with severe pain in my lower back. Numerous doctors failed to pinpoint the problem. Finally, I went to the Cleveland Clinic, where several tests revealed I had an anterior horn cell lower motor neuron disease. A neurologist referred me to the Eleanor and Lou Gehrig MDA/ALS Center at Columbia Presbyterian Hospital here in New York. On Dec. 22, 2005, Paul Gordon, co-director of the center, told me I have progressive muscular atrophy (PMA), a form of ALS.  

Phyllis and Stan Silver

Our lives changed.  Suddenly I became a person with ALS and my wife, Phyllis, a caregiver. The Internet became vital. I read articles about ALS daily that were frightening because they described what I may someday experience. Talking to others and communicating on MDA’s Living With ALS forum has been beneficial, however. The MDA Web sites (www.mda.org and www.als-mda.org) also contain many interesting leads.

MDA has been a fantastic resource.  On our first clinic day, an MDA representative registered us with the Association.  From that point on, MDA has given us help at crucial times in addition to  unusual opportunities.  Jackie Puerta, our MDA health care service coordinator, provided the chance for Phyllis and me to be interviewed on a radio station.  That was exhilarating! 

We attended Wings Over Wall Street, an MDA fund-raiser, where we mingled with others with ALS and several well-known doctors from MDA/ALS clinics elsewhere in the country. Seeing firsthand the generosity of the attendees was very rewarding. 

Other events during 2006 also turned my personal understanding of having ALS into a meaningful, emotional and social concern: Meeting others with ALS has been a transforming experience for me. I appreciate that the mundane is nonexistent and we can discuss anything that pertains to our concerns regarding this horrible disease.

The MDA support group is both depressing and uplifting.  Though it’s upsetting to meet people unable to speak who have to use assistive devices to express their thoughts, their efforts to attend each meeting and continue communicating are amazing. As time passes, friendships are strengthened there. In this environment the desire  to help others is remarkable.

Different functions, including fund-raisers and awareness-raising events, caused a metamorphosis in my attitude and spirit in living with ALS as I developed bonds with other ALS patients, caregivers and fantastic volunteers.  Being part of their efforts helped me understand the importance of bringing public attention to this disease, and to realize that I could contribute to that mission.

A political first for me, a national ALS advocacy day in Washington, provided a valuable exchange with other people with ALS from across the country and created additional friendships.

I realized that I can still live my life, just in a very different way.  I am still the same person.  My interior hasn’t changed!  But some time passed before I could cope with the inevitability of the degeneration of my exterior.

Now that I have reached the first anniversary of my diagnosis of ALS, the essence of all these events was the ease of communicating with and caring for others who have the commonality of experience. It was the sharing of the inner strength that we all unexpectedly discovered, along with determined spirit and positive attitude, that allows us to push toward a hopeful future.

by Margaret Wahl

When good cells go bad, as they seem to do in ALS, you have to ask the same questions distraught parents sometimes ask about wayward children: Is the problem strictly internal? Are outside influences also to blame? And if they are, what can be done about them?

As far back as 2003, Don Cleveland and colleagues at the University of California-San Diego showed that, in ALS, outside influences in the cellular neighborhood in the nervous system matter.

In their experiments, mice with an ALS-causing genetic mutation in the SOD1 gene were saved from the expected degeneration of their motor neurons (movement-controlling nerve cells that are lost in ALS) if they had enough non-nerve cells without the disease-causing mutation surrounding these neurons. It was as if these healthy cells protected the sick ones, even though the ailing cells harbored the factor that caused the disease.

Last June, Cleveland’s group zeroed in on a particular cell type, the microglia, immune-system cells that live in the brain and spinal cord. They aren’t neurons, but they sense their surroundings and swing into defensive action when they sense that neurons are in trouble. When activated, they can produce helpful proteins, but they also kick off the immune system’s inflammatory response, which can cause collateral damage.

In ALS, researchers believe, distress signals from motor neurons activate microglia, which can then cause further damage

When Cleveland’s group bred mice that produced mutant SOD1 protein in their nerve cells and elsewhere, but hardly at all in their microglia, they lived an average of 99 days longer than mice that produced mutant SOD1 in all their cells, including their microglia, leading the investigators to conclude that relatively healthy microglia benefit animals destined to develop SOD1-related ALS.

Interestingly, limiting this damage didn’t change the onset or the early course of the ALS-like disease that affected these mice. Its effect came in prolonging late-stage ALS and survival.

The researchers concluded that initiation of the ALS disease process (at least in this type of ALS) probably requires damage to motor neurons and maybe other types of cells, but that activated microglia intensify the disease and might be a good target for therapies.

Another Voice

In October, Stanley H. Appel, an MDA research grantee who directs the MDA/ALS Center at Methodist Neurological Institute in Houston, and colleagues, conducted a set of experiments that led to similar conclusions.

These investigators bred mice that had not only an ALS-causing SOD1 mutation, but also lacked an immune system. Against this immunologic clean slate, Appel’s group added either normal immune-system cells, from normal mouse bone marrow; or abnormal immune-system cells, carrying an SOD1 mutation. Among the immune cells were microglia.

As in Cleveland’s experiments, Appel’s experiments showed that mice destined to develop ALS fared better if their microglia didn’t carry an SOD1 mutation. (Appel says those microglia are harder to activate than those with an SOD1 mutation.) Of course, major questions remain. Targeting microglia may be a good idea for therapy, but what kind of therapy? Destroying microglia or keeping them inactive might prevent much of the inflammatory response that clearly contributes to progression of the disease, but it would also eliminate the beneficial effects of these cells. Microglia release neurotrophic (nerve-nourishing) proteins, and they stimulate clearance of potentially toxic substances in the area by cells called astrocytes.

A second burning question is, do findings in the SOD1 mouse model translate into human ALS, when SOD1-related ALS accounts for only 1 percent to 3 percent of human cases of the disease?

Appel says they probably do, because he believes the issue is whether or not microglia are activated. Cells carrying the SOD1 mutation are more active than those without it, he says, and they secrete high levels of compounds that participate in inflammatory reactions, such as TNF-alpha and interleukins.

“It’s clear that all the inflammatory constituents present in the mouse model are present in human sporadic ALS,” Appel says, concluding that “it’s tempting to speculate that microglia and immune cells could be playing a role in man as they do in the mouse model.”

He says that in both mouse and human ALS, there are clumps of proteins and inflammation in the nervous system. In the mouse, clumps of abnormal SOD1 protein molecules are likely involved in activating microglia. In humans, the proteins that clump are different, but the result may be the same.

“In human ALS,” he says, “there are also many aggregated proteins [though not usually SOD1] in motor neurons, so it’s not too much of a leap of faith to assume that such aggregated [clumped] proteins could be released from motor neurons, activate microglia, and amplify the injury to motor neurons. Then some of the same concepts involved in the animal model would be involved in human sporadic disease, with the major difference being a difference in the specific protein aggregates initiating the microglial activation in the mouse versus man.”

Appel says he knows these thoughts are speculative, but, he notes, “our own data and the data of our colleagues seem to be pointing in this direction.” (In December, his group’s analysis of a pilot trial of bone marrow transplantation in people with ALS was nearing completion.)

Critics say applying findings from the SOD1 mouse to human ALS is like looking under a lamppost for dropped keys just because that’s where the best light is. To them, Appel responds, “We may be looking under a lamppost, but I’d say, ‘Show me another light.’ I want to find the keys as much as anyone else. Let’s take every lead.”

by Kathy Wechsler

If you’re coping with an ALS diagnosis while living in a small town or rural area, you may have some additional challenges. Brian Kieth of New Home, Texas, and James Tyler of Halfway, Ore., both have ALS and have experienced problems because of where they live.

Wheelchair Access

Rural areas tend not to have the most accessible accommodations. That’s why it’s important to be creative when dealing with access issues.

Brian Kieth (in wheelchair) and his wife, Catherine (standing to his left), at a family reunion

Kieth lives with his wife, Catherine, in the country’s largest cotton-growing center. Living in a town that has a population of 320, Kieth, whose ALS diagnosis was confirmed in May 2005 and who began using a manual wheelchair later that year, has struggled with the problem of wheelchair access.

“Because we do live in the middle of a cotton field, wheelchair access is definitely a problem,” says Kieth. “The biggest problem we have encountered, to date, has been getting a van to transport my newly acquired power chair.”

The town of New Home has no wheelchair-accessible public transportation, so Kieth began looking to buy an accessible van. At the time, the closest place to purchase an accessible vehicle was 750 miles away in Houston, so Kieth turned to the Internet, where he found an accessible-van manufacturer in Minnesota that would deliver the Dodge Grand Caravan and send someone out to repair the adaptive equipment if necessary.

Because Kieth makes his home in an old house, he’s  had to adapt to a lack of wheelchair access. The narrow doorways make it difficult for Kieth’s wheelchair to fit into the bathroom so, “Showers are a rare treat.”

“We have not completely worked out the showering problem, to date,” says Kieth. “Too often, we have just stayed in a handicapped [hotel] room with a roll-in shower, in Lubbock, just to get a full bathing experience.”

Limited Services

Another problem with living in a rural town is that there are few services available. In order to manage your daily life with ALS, you need to use all available resources.

New Home has a school, post office, launderette, one small grocery store and a single cafe that serves only lunch and dinner. For everything else, including a gas station and durable medical equipment, the Kieths have to drive 30 minutes to Lubbock, which can be tricky in the winter because of icy roads and blowing sand.

When needed, family and community members run errands and take their two teenagers to high school when it rains and the school bus won’t tackle the Kieths’ long and bumpy dirt road. This support is very important to the couple.

“If you don’t have an extensive support system in place, already (i.e., friends, family, a close-knit community), then either move, or start making friends,” Kieth says. “This is not a disease that can be battled alone.”

At the encouragement of doctors Kieth attends clinic every three months at the MDA/ALS Center at Methodist Hospital Neurological Institute in Houston. It takes the couple nine hours to drive there. Such a long drive causes pain in Kieth’s legs from deep-vein thrombosis, a blood clot in the leg’s deep vein.

Finding Support

James Tyler at Eagle Cap Wilderness, about 15 miles from his home in Eastern Oregon

James Tyler, who lives in the small town of Halfway, Ore., and was found to have ALS in July 2005, also has a long drive to his MDA clinic, because locally, there’s only a small medical clinic.

Tyler, 39, who’s still ambulatory but has difficulty with his hands, says his sister drives him and his mother the three hours to the MDA clinic at the Idaho Elks Rehabilitation Hospital in Boise.

Kieth is one of the hosts on MDA’s “Living with ALS” chat and recommends joining the chat to share information, concerns and advice with people across the country who are experiencing similar challenges.

Future Concerns

When you have a progressive neuromuscular disease like ALS, it’s common to worry about the future. If your town is small, there may be some extra concerns.

Tyler, who currently doesn’t need a caregiver to assist him with activities of daily living, is concerned about his future caregiving needs because there aren’t any local home health care agencies. He’s in the process of researching such agencies that are willing to travel to his home in Halfway.

The Eastern Oregon winters will be another concern when walking becomes more difficult for Tyler. Extreme weather makes it harder to function.

“I anticipate that I will have trouble walking when it gets really icy and snowy in my walkway and driveway since we get about 3 feet of snow every year,” Tyler says.

A future concern for Kieth is the response time for emergency crews, because the nearest hospital is 30 to 40 minutes away from his Texas town.

“Another concern is loss of power to the house during thunderstorms and ice storms.” Kieth says, “I cannot sleep without the aid of a Bi-PAP machine.”

He keeps a backup battery with an 8-hour charge.

But, Kieth says, “If it shuts off due to power loss... well, that’s self-explanatory.”

EQUIPMENT CORNER
People with ALS share personal experiences with life-enhancing devices

by Alyssa Quintero

The production of assistive technology (AT) devices and vast technological advances, particularly in communication, have enabled people with ALS to enjoy greater independence, maintain relationships, and contribute to the workplace and the community.

Here’s a look at how computer technology and AT have helped enhance the quality of life for some people with ALS.

A Link to the World

Elizabeth McCarthy of Erie, Pa., who received a diagnosis of ALS in 1979, said that without the use of her computer and EZ Keys communication software from Words+, she’d be isolated from her family and friends, and she’d have to depend on others to read the newspaper or answer e-mails.

Elizabeth McCarthy

McCarthy, 59, who uses the software to communicate with her caregiver, advises other people with ALS to consider an AAC device before they must use one regularly.

McCarthy, who operates her computer by the slight movement of an eye, also uses the computer as an environmental control unit (ECU), controlling virtually any appliance in her home.

Before she started using a DynaWrite device from DynaVox, Cheryl Cook of Webster Groves, Mo., used a Magna Doodle from Fisher Price to communicate her needs. She’d never used a computer before last summer, when she received a diagnosis of ALS.

“I can carry on a conversation, and I can type fairly fast, so it works out well for me,” she said of her DynaWrite. “I don’t feel so left out and isolated, and I can now answer the phone. Learning how to use e-mail allowed me to feel connected with others.”

Cook, 55, who works as a caregiver to an elderly woman, said, “not being able to express myself was like cutting off the essence of who I am.

“Before the communication aid, I didn’t answer the phone because no one understood what I was saying. With the machine, and the help of a good phone with a voice-enhancer, I can carry on conversations over the phone, which has made a big difference,” Cook explained.

She added, “It helps to be able to laugh, too. When I misspell a word and press “speak,” things come out pretty funny sometimes.”

My Mind Is Strong

Paul Carr

Computer technology and advances in AAC devices and access help people with ALS keep thinking, learning and working.

For example, Paul Carr of Hamden, Conn., director of quality management for United Healthcare, explained that his DynaWrite has enabled him to stay active in the work force and to communicate with his family.

“The device has enhanced my quality of life tremendously because without [it], I wouldn’t be able to sustain myself and the disease would take over much faster than it has,” Carr, 51, said.

With his DynaWrite, Carr attends meetings at work, shares his thoughts with co-workers and participates in business-related phone calls.

“Computer tech has enhanced our quality of life, and it’s enabled us to retain our self-esteem,” Carr said.

Steven Nichols, a software engineer from Clifton, Va., works as a part-time Web developer, thanks to
eye-tracking computer technology.

Nichols, 56, who hasn’t had arm, hand or shoulder movement since 1999, has used both the ERICA tablet PC system from Eye Response Technologies and Eyegaze from LC Technologies.

Steven Nichols

Nichols relies on the ERICA system because it’s portable and supports computer access without requiring a second computer like the Eyegaze system.

“Its [the ERICA system’s] effect has been immeasurable,” Nichols said. “It’s not only my communication device for everyday needs and conversation, but it’s my entertainment center and window to the world.”

Nichols also uses the system for Web site developing, financial tracking, investing, paying bills and playing games.

“It [eye technology] has come a long way since I first tried it in 2000,” Nichols explained. “The accuracy of the system is incredible, given the nuances of the eyes, and you can’t beat the speed of direct select over scanning systems.

“Assistive technology in general enables me to be a productive member of society, it affords me a great amount of independence, and it’s allowed me to be the Steven Nichols I was pre-ALS, with the obvious physical limitations.”

In the Cards

Many people with ALS agree that computer technology and AAC devices have changed the hand they thought they’d been dealt when they started to lose the ability to speak or to use a computer mouse. Now an AT user can stay in the game.

And, advances in brain-computer interface technology have reshuffled the future; people may actually be able to use their thoughts to control computers and other devices, and communicate verbally (see “ALS Research Roundup,” November-December).

Roger Surfus of Shell Knob, Mo., who received a diagnosis of ALS in November 2005, uses a Mercury II computer/AAC device. The retired aerospace technical specialist said, “Using your thoughts to control devices for communication would be an excellent advancement” because AAC devices still can’t replicate normal verbal communication.

“Inside, my brain still thinks clearly, and I still feel as sharp as ever,” Surfus, 59, explained. “My brain is functioning at 90 miles per hour, so computer technology will be my saving grace as the disease progresses.”