NEUROSCIENCE and NINDS 2005 - An Advocate Perspective

HD Lighthouse Contributing Editor's Comment: All of us at the Lighthouse are so pleased that Dr. Goodman and Dr. Casale were able to attend this important conference and bring back the research news. We are also very grateful to Dr. Goodman for meeting with NINDS officials to share the perspective of HD families.
--Marsha L. Miller, Ph.D.
Posted to the HDL: 02 Dec 2005

The 2005 Neuroscience meeting was held mid November in Washington D.C. It was big. There were about 35,000 attendees and several thousand poster presentations by research laboratories from all over the world; reporting on many different branches of brain biology. Of these, more than a hundred posters related to Huntington’s. Many others related to Parkinson’s and Alzheimer’s had overlap with HD. Most reported on the molecular biology of cell systems disrupted by HD and the techniques used to study them. A significant number reported on work with HD model system therapeutics: There were sessions on RNA interference, growth factors (BDNF), stem cells, and posters describing delivery systems to brain.

Accordingly the summary which follows is not complete, but highlights only a few posters that “caught my eye”.

1. Fellow Lighthouse contributor, Malcolm Casale and coworkers presented work on iron mishandling and the inflammatory response in brain that occurs in human and mouse HD (click here for "Increased Ferritin in Reactive Microglia is Present Early in Stiatum of Huntington's Disease Patients and R6/2 Mice"). This is important because it is another system that can be drug targeted.
2. Another scientist reported sertraline (Zoloft) benefit in mouse studies of this SSRI antidepressant. This particular work is important because the dosage used, unlike the published studies of fluoxetine (Prozac) and paroxitine (Paxil), is at a level well tolerated in people.
3. PsychoGenics Inc., the company with whom High Q has contracted to run high-throughput drug screening in HD mice presented confirmation of previous positive results from the first set of 6 drugs (taken from the Set HD list at www.huntingtonproject.org. These included two butyrate HDAC inhibitors, mithramycin, creatine, trehalose and cystamine. The next set of agent/drugs planned will include tetrabenazine.
4. Several labs presented promising data on curcumin (turmeric) showing that this agent gets into brain, showing some positive results on HD, Alzheimer’s, and Parkinson’s model systems. Though the HD study appeared less successful than in AD and PD, the variability of study systems was too great for rigorous comparison.
5. A laboratory from Germany reported a positive study on trehalose using an HD rat model. This study tracked mRNA changes in brain following trehalose administration. The dosage used was similar to that used in the published mouse studies from Japan.
6. There was an excellent review on “placebo effect” which has been studied in pain syndromes, Parkinson’s, and depression. Scientific studies show that the “hope” generated in these trials activates specific brain areas along the same pathways as those of therapeutic medicines. Unfortunately this effect (so far) has never been shown in Huntington’s. In fact the control group in the first Co-Q 10 trial had worse results for disease progression than that predicted from earlier observational studies. Further, early striatal cell implant studies in HD people disclosed no placebo effect benefit.

In addition to these posters, there was a symposium, Histone Deacetylase as a Therapeutic Target in Neurodegenerative Diseases, in which several speakers discussed the potential benefits of Histone Deacetylase (HDAC) inhibitors in Huntington’s. We were impressed in this symposium that HDAC inhibitors do more than their name indicates. Like many biological molecules, HDAC inhibitors have multiple functions, in particular, some that control inflammation, which has been implicated in HD.

There was an immense quantity of information (much of it disease related) presented and fervently exchanged among the thousands of neuroscience people who thronged the 90 plus poster rows; 2 sets/day. And there was great excitement that the research advances of the past decade were moving closer to benefit in people.

THE ROAD LESS TRAVELED

This conference was huge and bustling, with areas so crowded that it was often hard to get through the aisles that spanned the length of an enormous auditorium. But I did find a less traveled path adjacent to the poster presentations . . . along the single short row of booths set up to represent non-profit disease organizations. It seemed symbolic of the (still big) gap that separates big and exciting neuroscience from its applied benefit to people. We need clinical trials to do that.

NINDS and HD CLINICAL TRIALS

Because this meeting was held near NIH, there was opportunity to meet with NINDS officials regarding clinical trials in HD. Not long ago on Lighthouse (click here for "Walking the Talk"), we asked questions about 2CARE, the large Huntington’s human trial designed to test CoQ-10 as single agent. We report (with gratitude) that since those questions were asked, first steps have been taken by Huntington’s organizations and NINDS to allow better two-way communication.

This is important because we believe that only with two-way communication can common ground be found that will best serve both the immediate short term needs of HD families affected now, and the long term goals of researchers and those HD families not yet affected.

Though not all the questions were answered, more information was shared as follows.

1. 2CARE will go forward. Though it is funded for five years, it will be halted if benefit is shown earlier. This is standard for ethical clinical trials. However, the “how much and how long of benefit” that investigators have defined as necessary for ending the trial was not communicated.
2. It appears that the issue of allowing or defining dosage of other supplement use by participants in 2CARE may not be resolved.
3. Conflict of interest issues are under investigation.
4. NINDS has no mechanism for funding successful early phase clinical trials that can directly lead to phase III; even though this guarantees years of time lost for patients and investigators alike. This is different from the National Cancer Institute (NCI) whose “Center grants” can lead directly from early to late phase testing. This type of system effectively prevents the gaps between early and late phase clinical trials for cancer patients.
5. NINDS granted almost 35 million dollars in 2004 for H.D. efforts. While this sounds like a lot, it is only 2.3% of their total budget. In 2005, they will fund 2CARE and “Transcription and Therapy for HD: from Molecules to Man”. This is a large coordinated work headed by Dr. S. Hersch that includes several basic research projects, and mouse model projects that (hopefully) can directly lead to early phase clinical trials in people. Each of these projects is funded for over a several year time period.
6. NINDS funds clinical trials. But it has not taken on any leadership in clinical trial design. It does not give direction, but reviews and acts (or not) on grant requests received. But at the same time in other areas, NINDS has taken on leadership; by inviting grant applications for its large Neurogenomics and the Human Brain Project, an endeavor to map the brain in manner similar to the Human Genome Project. In the formal announcement of these “big science” projects in 2003 they talked of extending it to clinical trials. Wouldn’t it be great for NINDS, if it extended its “big science” and innovation to the clinical trial arena?

NEXT STEPS

We at Lighthouse, and the population we serve, are grateful to those people in NINDS and in HD organizations who made first steps of two-way communication possible. In these conversations it is clear that HD families, HD advocates, HD clinical investigators and NINDS officials all want successful clinical trials. There are no “bad guys” here, just differences of opinion from those with different perspectives. We are all working towards solutions to hard problems.

As we work for the best possible clinical trial situation for HD, we might all consider the words of Dr. Elias Zerhouni, director of NIH: “Clinical research is no longer doing research to people; it is doing research with people. The cultural change I am talking about is to create communities of research where our patients are our partners in research, not our subjects. The most important consideration is not the research center or network, but how many people are willing to participate in clinical trials and how they are incorporated into research concepts.”

The entire HD community has much more work to do in rising to this challenge.

2CARE or NOT 2CARE

At the end of my conversation with NINDS officials, and in spite of still unanswered questions; I was asked to support enrollment in 2CARE. My answer is still out.

While I fervently want clinical trials now for HD people, it is hard to support a trial that is not designed to test for combinations, the predicted best benefit to people. Further I believe the trial is flawed because it invites noncompliance by limiting the use of other available supplements. Given the choice of readily available supplements, many HD people, including those signed up for trials won’t want to take “just” CoQ-10. This will be especially problematic as other positive pilot trial results soon become available. And as such, the “results” of 2CARE may not be scientifically useful to investigators or HD people.

Barring other evidence, it seems that clinical investigators and NINDS have taken a unilateral approach in 2CARE that has not incorporated Dr. Zerhouni’s model of partnering with HD families while in pursuit of their clinical research. Have they thought that HD people are too stupid, or too frightened, or too unimportant to include? Or, more likely, did they just forget to ask?

SOLUTIONS

Isn’t it in everyone’s best interest to work together, to include HD family perspectives in the clinical trial discussion? Only then can work begin to engineer solutions to clinical trial design that addresses the needs of the entire community; solutions that can serve the needs of HD people of both present and future generation, and the needs of their clinical researchers. There is no rational or insurmountable reason why it has to be “either, or”. And practically speaking, “twin goal” clinical trials will have enthusiastic support from HD families and advocates, which will in turn bring more participants to, and maintain compliance for the successful clinical trials we all want.

Tracked on the Lighthouse:
NINDS2005
2CARE

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