Research Roundup

by Margaret Wahl

CytRx to test arimoclomol at higher dose

Editor's note: On Jan. 22, CytRx announced that the Food and Drug Administration has placed a temporary hold on the arimoclomol trial while it reviews additional data from completed animal studies. See CytRx Provides Update on Phase IIb Arimoclomol Clinical Trial for ALS.

Merit Cudkowicz at Massachusetts General Hospital is one of the principal investigators for the arimoclomol trial.

In December, the Los Angeles biopharmaceutical company CytRx announced it would compare its experimental compound arimoclomol at 400 milligrams three times a day to a placebo (inactive substance) in approximately 390 people with ALS at 30 to 40 North American centers.

The principal investigators on this CytRx-funded study are neurologist and MDA research grantee Merit Cudkowicz at Massachusetts General Hospital in Boston, and Jeremy Shefner, a neurologist and neuroscientist who directs the MDA/ALS Center at SUNY Upstate Medical University in Syracuse, N.Y.

Arimoclomol activates so-called chaperone molecules (see “Chaperone molecules,” below), which can repair damaged proteins or mark them for destruction. Damaged, misfolded and clumped proteins are known to play a role in familial ALS due to SOD1 gene mutations, and they’re likely to be detrimental to cells in other forms of the disease.

In June, CytRx announced that arimoclomol was safe and well tolerated at 100 milligrams three times daily and that function declined less rapidly in the arimoclomol-treated patients when they were compared to an earlier group of untreated patients.

Healthy volunteers have tolerated arimoclomol at 400 milligrams three times a day for 28 days and at 600 milligrams three times daily for a week.

For more information, contact Elizabeth Simpson at Massachusetts General Hospital at (877) 458-0631 (toll-free) or esimpson1@partners.org.

Chaperone molecules

Arimoclomol stimulates production of chaperone molecules, which attempt to maintain quality control by repairing damaged proteins; or, if they can’t, by tagging them for a cellular disposal system.

Multinational study implicates DPP6 gene variant as risk factor for ALS

A specific variation in a gene known as DPP6 is significantly associated with susceptibility to ALS in a large group of people of European ancestry, says a study published online Dec. 16 in Nature Genetics.

When Leonard van den Berg at University Medical Center in Utrecht, the Netherlands, with colleagues in that country, as well as Belgium, Sweden and the United States, studied all the DNA of 1,767 people with ALS and 1,916 without the disease, they found that those with the disease were 1.3 times more likely than the unaffected subjects to have this particular variant in the DPP6 gene.

U.S.-based researchers in the group included Jennifer Schymick and Bryan Traynor of the U.S. National Institutes of Health in Bethesda, Md., and Roel Ophoff, of the University of California-Los Angeles.

The study participants were from the Netherlands, Sweden and Belgium.

Researchers say heat shock protein 70 could be acting at the junctions between nerve and muscle fibers.

DPP6 is located on chromosome 7 and carries instructions for a protein found mostly in the brain, where it modifies the biological activity of several nervous-system chemicals (neuropeptides) and alters a mechanism that controls potassium flow.

ALS is thought to be clearly inherited (familial) only about 10 percent of the time, but most experts in the disease believe that genetic factors alter susceptibility to sporadic (nonfamilial) ALS.

A recent study of this type (known as a whole genome association study) conducted at the National Institutes of Health failed to find any ALS-associated genetic variants. However, this past August, an MDA-supported whole genome study conducted at the Translational Genomics Research Institute in Phoenix identified a variant in a gene called FLJ10986 as a significant contributor to ALS susceptibility in a large sample of Americans with and without the disease.

Protecting nerve-muscle junctions may protect nerve cells

Injections of a molecule known as “heat shock protein 70” allowed mice with a genetic form of ALS because of mutated SOD1 genes to live longer than untreated mice. These treatments also prolonged survival of nerve cells in the spinal cord and delayed the onset of ALS symptoms. Heat shock protein 70 is a molecular “chaperone,” and its normal role is to maintain quality control standards for cellular proteins (see “CytRx to test arimoclomol”).

Carolanne Milligan at Wake Forest University School of Medicine in Winston-Salem, N.C., led a research team that compared untreated mice destined to develop ALS with similar mice that were treated with abdominal injections of heat shock protein 70 three times weekly. They published their results Nov. 28 in the Journal of Neuroscience.

Although heat shock protein 70 and other proteins of its type are known to have protective effects on cells subjected to various stresses, the researchers expected that any protection against ALS-related damage would happen in the central nervous system.

To their surprise, they found that the protein ended up mainly in the skeletal muscles of the mice, not in the nerve cells, which have been assumed to be the primary sites of ALS damage. They say it’s possible that heat shock protein 70 could be acting in the periphery of the body, at the junctions between nerve and muscle fibers, rather than in the central nervous system, and that protecting these junctions may in turn protect nerve cells. Reducing neuromuscular junction damage “may prove to be an effective therapeutic target in ALS,” they note.

ALS TDI collaborating with Aptagen to develop ALS-specific ‘bullets’

The ALS Therapy Development Institute will work with Aptagen of Jacobus, Pa., to develop molecular bullets targeting ALS-affected cells.

The MDA-supported ALS Therapy Development Institute in Cambridge, Mass., has entered into an agreement with Aptagen of Jacobus, Pa., to develop constructs known as “aptabodies” that recognize and stick to molecules associated with ALS disease progression.

For many years, scientists have used antibodies, which are proteins made by the immune system, to home to and interact with specific proteins, for research and as treatments. Antibodies are highly useful, but they can only target proteins and generally require knowledge of the protein being targeted.

In contrast, aptabodies can recognize and stick to a wider range of molecular structures than just proteins and require no prior knowledge of their potential targets.

The investigators hope to use aptabodies to identify specific compounds unique to the ALS disease process and to make molecular “bullets” that take therapeutic agents to specific, ALS-affected tissues or cells after systemic injection.

Laughing/crying episodes more common than once thought

A new study suggests that pseudobulbar affect (PBA), also known as involuntary emotional expression disorder (IEED), may be more common in ALS than previously believed.

PBA is characterized by episodes of uncontrollable laughing or crying that are out of proportion to or inappropriate to environmental triggers. It’s thought to be a result of brain changes that can occur in ALS and other neurological disorders.

Jennifer Murphy, a psychologist at the University of California at San Francisco who presented her group’s findings at an international ALS meeting in December, determined that 52 percent (15 out of 29) of people with ALS who were not specially selected from a general ALS clinic population had PBA when a new questionnaire was used to assess them.

PBA is usually assessed using the Center for Neurologic Study-Lability Scale (CNS-LS), a seven-item, self-administered questionnaire that provides a measure of the perceived frequency of laughing/crying episodes.

On the CNS-LS, only 34 percent of this study’s sample (10 out of 29) were classified as having PBA.

Murphy and colleagues developed a more comprehensive questionnaire, which they call the PBAQ, which asks questions of both the person with ALS and his or her caregiver. Murphy said the PBAQ may help identify people with PBA who lack insight into their behavior.

Avanir Pharmaceuticals is testing a new medication directed at PBA (see “Avanir opens phase 3 trial”).

Avanir opens phase 3 trial of PBA drug

Avanir Pharmaceuticals in Aliso Viejo, Calif., has opened a large-scale (phase 3), multicenter study of its drug Zenvia to people with ALS or multiple sclerosis who have uncontrollable episodes of laughing or crying diagnosed as PBA (see “Laughing/crying”). The compound has shown promise in earlier studies.

Participants will be randomly assigned to receive a placebo or Zenvia, which is a combination of dextromethorphan and quinidine, at one of two dosage levels for three months. They’ll keep diaries of their crying and laughing episodes and respond to questionnaires about their condition.

More information is available at www.pbatrial.com or at (866) 740-4333.

Anti-SOD1 compound on path to clinical trials

Timothy Miller at Washington University in St. Louis says his MDA-supported studies to test a compound that blocks the genetic instructions for SOD1 are moving ahead. Mutations in the gene for SOD1 cause ALS in 1 percent to 3 percent of people with the disease.

The compound, ISIS 333611, made by Isis Pharmaceuticals of Carlsbad, Calif., is known as an antisense oligonucleotide. In December, the U.S. Food and Drug Administration (FDA) granted orphan drug status to ISIS 333611, which gives Isis special economic incentives for its development.

As the year ended, Miller’s group had nearly finished toxicity studies in rats and said it plans to open a phase 1 trial for ALS patients with known SOD1 mutations by fall 2008, depending on the FDA’s reaction to the toxicity data.

“Without the grants that we have received, the project would not be moving forward or would be moving at a snail’s pace,” Miller said. “The MDA grant will allow us to bring this to human trials in the near future.”

by Kathy Wechsler

The novel You’re Not You tells the story of a college sophomore, Bec, who is uncertain about her chaotic personal life and future career interests and options. When she answers a want ad seeking a part-time caregiver for Kate, a married, professional woman in the late stages of ALS, she doesn’t expect to learn valuable lessons about life, love and trust.

As Bec becomes involved in the lives of Kate and her husband, Evan, the fine lines between friendship and employee obligation begin to blur. You’re Not You tackles the controversial topic of deciding when to die and how this decision affects others, and the under-represented issues of personal control and sexuality among people with disabilities.

You’re Not You so compellingly portrays these themes that you may wonder if it’s based on a true story. It’s easy to relate to both Bec and Kate, and their devoted friendship is one that closely resembles the bond between caregiver and client. Kate and Evan’s deteriorating relationship and the impact (both physical and emotional) of ALS on Kate also ring true.

Interview with the author

Michelle Wildgen of Madison, Wis., is a writer and editor whose works include fiction, essays, reviews, and food writing. She’s currently senior editor of the literary quarterly Tin House Magazine and an editor with Tin House Books. You’re Not You is her first novel.

Author Michelle Wildgen

Q. What would you say is the theme of this book?

A. Tough question. I actually try not to think in terms of one theme for a story or book, since I like to attempt to get at a feeling of complexity and I find if I am thinking of one overarching theme I may not let myself reach as broadly as I would like. But as far as ideas I kept returning to, I would say that it’s about the limits of our duties to others, and the confusion over where those limits lie. And about what happens when a normal life gets shifted in a way that makes every single aspect new and different — for both Kate and Bec.

Q. Why did you decide to use ALS as the vehicle to express your ideas?

A. I met [individuals with ALS] through friends. I had never had the specific idea of writing about ALS before, though I look back and see I had written about various kinds of disability or illness before I wrote this. The failure of the body to do what it once did, or what it does for others, and all the complications it leads to, is something I’ve returned to a few times. I was very struck by the need to have someone speak for you when illness has made communication difficult for all but a few. I had never really considered that before, how much this change affects all aspects of life. Voice plays a role in so many other things: identity, power, intimacy.

Q. How did you do the research for this book?

A. I spoke to a couple people to get an idea what a day in a life [of someone with ALS] might be like, how one gets out of bed, eats, etc. From there I did research on the Web and read a few books to get a sense of what was involved. I had to read up to get some sense of the basics, but at the same time I didn’t want research to dictate the story rather than characters dictating it.

Q. What did you learn while doing the research?

A. I became really interested in the issues of voice —literal voice, in this case — and just how one makes life work with that particular set of physical limitations. The issue of breathing and respirators was one I didn’t know much about. I read a book that had been written by a woman with ALS, and she wrote about having trouble breathing one day, but trying very hard not to call for help. She had a husband and young children, and up to that point she had been able to stay home and be in her own family life, and her fear was that if she called for help, she would be in the hospital and not in their lives in the same way.

Q. How did you put what you’d learned into the story?

A. I think I recall her saying she wasn’t strong enough, that she had had to call for help, and I had the idea that Kate might feel this way as well, but that Evan would disagree, [which] shifted their whole relationship, and shifted Bec’s role as well. It solidified what I already had begun to see in those relationships: how Evan and Kate could not agree on the acuteness of her situation and how to approach it, Bec’s uncertainty of her role, and the consequences of Bec’s tendency to refuse to think too far ahead. For example, Bec makes some promises but does not fully consider what they mean.

You’re Not You, by Michelle Wildgen, 288 pages, 2007, $14.00, Picador, (888) 330-8477, www.picadorusa.com.

Following Sam

“I’m a 58-year-old retired truck parts dealer in St. Louis. I was a three- to four-times-a-week racquetball player, part-time classical musician, and full-time husband, father and grandfather.” With these words in March 2006, Sam Goldstein inaugurated a series of occasional reports in the MDA/ALS Newsmagazine, written with his wife Jo-Ann, about the experience of living with ALS. Sam received his diagnosis of limb-onset ALS in August 2005. This is the last installment of his series.

by Jo-Ann Goldstein

With a heavy heart, I have to tell you that Sam passed away on October 12, 2007. As many of you know from the “Following Sam” articles, he had an amazing outlook on life and positive attitude. When I was asked to write this final chapter, I realized that this is, by far, the most difficult piece to write because I have so many mixed feelings and private thoughts.

We felt very cheated with such a quick progression of Sam’s ALS symptoms — he only lived 26 months from diagnosis. The last month was extremely difficult because he lost his ability to talk, was in a lot of pain, and basically “gave up the fight.” It was difficult for the entire family, but the fabulous hospice staff truly helped us all. Their care and compassion was extraordinary and they were here for me, our kids and grandchildren.

Over 400 friends and family came to pay their respects and celebrate Sam’s life. Several family members shared wonderful stories and favorite memories about Sam. There were many smiles and laughter mixed with tears.

The most ironic thing happened as we arrived at the cemetery — we heard the lively music of a bluegrass band playing on the schoolyard across the street for their fall festival. Knowing Sam’s love and passion for music, it seemed the most fitting tribute ever.

I have been adjusting fairly well to my new stage in life by jumping back into work and spending lots of time with family and friends. Of course, there are times of grief and loneliness, but I try to remember the good times we had in our 37 years together. The short time spent living and caring for “Sam with ALS” does not define who he was and it certainly is not the way he wanted to be remembered.

I know that we ALL hope for a cure and treatment for this horrid disease soon. With all the research that is currently being conducted worldwide, finding a key breakthrough would be the best memorial we can leave for our dear ones and future generations.

In the Market for New Wheels?
10 tips for acquiring an adapted vehicle

by Bill Norman

The “boxy” shape and economical interior design of the Honda Element lends itself to modification for wheelchair transport.

Accessible public transit, such as taxis and buses with adaptive equipment, unfortunately cannot always be relied on to show up when needed, even in urban areas. That means personal acquisition of an adapted vehicle becomes a serious consideration for people using wheelchairs.

Adapted vehicles come in a bewildering variety of shapes, sizes, configurations, capabilities and price ranges. Where to begin the selection process? Some basic issues need to be addressed.

1) Don’t rush your decision. Never buy an adapted vehicle, or the components for one, from a dealership or on the Internet on your first visit. Mike Krawczyk, marketing manager for Bruno Independent Living Aids, advises having a needs assessment done by a professional who deals in adaptive equipment. “You need to think not only about your present physical condition, but also about where you’ll be in two, three or more years,” he says. (For more on this, see “When Your Plan is a Van,” Quest March-April 2004.)

2) Several of the major U.S. auto manufacturers, including Chrysler, Ford and General Motors, offer rebates of up to $1,000 as part of their “mobility” programs. In addition, the Veterans Administration offers financial assistance (“Automobile Grants”) to veterans whose ALS is service-connected. And don’t forget that the cost of vehicle adaptations is tax deductible on federal taxes.

3) If buying a van or minivan, the adaptations most likely to be needed include a ramp or wheelchair lift; sufficient room inside to allow pivoting the chair; tie-downs in the floor to secure the chair during transit; and enough height to ensure head clearance.

4) Power rather than manual adaptive equipment, such as power tie-downs, can help people preserve their independence longer. But if cost is a concern, go with manual equipment that can be operated by a friend or family member, suggests Frank Baughman, sales support manager for Freedom Motors USA. “You’re not hoping to achieve total independence. You’re most interested in getting from point A to point B without having to spend a lot of cash.” Because of ALS’ sometimes rapid progression, adapted driving controls may not be a good investment.

5) Cars can be adapted with rotating seats that pivot 90 degrees and descend outside the car door, allowing the person with ALS to be transferred to the seat from a wheelchair. The seat then rises and re-enters the vehicle. One model is the Turning Automotive Seating system from Bruno Independent Living Aids.

6) Consider buying used. A brand spanking new $40,000 machine depreciates dramatically as soon as it’s driven off the dealer’s lot. (For more on buying used adapted vehicles, see Quest magazine, May-June 2007, “Used Adapted Vans Increase Your Buying Power.”)

7) Or don’t buy at all – lease or rent. Vehicle leases usually run two and three years, but in addition to the “advertised” leases so common in the newspaper, savvy shoppers may be able to swing a “negotiated” lease that requires less money up front, lower monthly payments and less cost to operate the vehicle over the span of the lease. The downside, of course, is that the vehicle reverts to the lessor when the lease is up. A good reference for examining the benefits and possible pitfalls of leasing is www.carinfo.com. Rentals also are an option; longer-term rentals tend to be more economical. (To learn more about leasing and rental options, see "Show Me the Money," Quest July-August 2006.)

8) When buying, haggle separately for the vehicle alone (with no adaptive equipment). Once bargaining for the vehicle has been finalized, purchasers can continue with compiling a package of add-on gear. Why bother? Dealers sometimes offer a “complete” or “lump sum” package with all the adaptive bells and whistles strapped on at the time of purchase. That gives them the opportunity to mark up and blend costs of the added accessories, and perhaps the vehicle, too. Best to start with two separate and distinct commodities. People who plan to trade in an existing vehicle to purchase an adapted one still should keep the transactions separate. That is, don’t even bring up the topic of a trade-in until the dealer is at his/her rock bottom price for the new machine.

This van has been adapted with a rear wheelchair entry ramp.

9) When negotiating for the cost of adaptive components (ramp, tie-downs, etc.), including installation, compare the costs of these items among several different dealers so you’ll have some leverage when horse trading for the lowest price.

10) “Credit insurance” isn’t mandatory, no matter what the dealer may say. This insurance pays off a vehicle loan in case the borrower dies or becomes too disabled to make payments. In addition, you may not need to agree to a “mandatory” arbitration agreement. These agreements require customers, in the event of a dispute, to submit their case to an arbiter who is usually selected in advance by the dealership. Customers are required to waive their right to sue, to appeal or to participate in a class action lawsuit. In recent years, mandatory arbitration agreements have been challenged in court in areas such as employment, insurance policies, apartment rentals and credit card applications. Check the fine print in contracts carefully to ensure that an arbitration agreement requirement isn’t tucked away among the verbiage.

The process of acquiring an adapted vehicle to transport someone with ALS can be demanding and time-consuming, but the amount of effort you expend will have direct payoffs in the convenience and level of care you’ll experience later.