TO SAVE A CHILD: Why the ICOC Should Reconsider Grant Proposal DR1-01449
from Don C. Reed
The most eagerly anticipated grants of the California Institute for Regenerative Medicine are the disease team grants: major funding, as much as $20,000,000 each.
The posted results of the new grants offers an opportunity for public involvement.
I disagree with one of the projects’ placements, and am speaking up about it.
First, a little background.
The California Institute for Regenerative Medicine (CIRM) has a board of directors, the Independent Citizens Oversight Committee (ICOC). They decide what research projects get funded. A board of reviewers, all from outside the state, studies the proposals and offers opinions, but that is all they are: opinions. By law, the ICOC makes the final decision. This is a vital part of the program, only the California board may decide.
One grant I was positive would get funded was a project to use embryonic stem cells (after differentiating them, of course!) to fight Spinal Muscular Atrophy (SMA) type one. This condition is almost unbelievably cruel: SMA kills infants, often before they reach one year of age.
To my knowledge, there has to date been no funding of research for this terrible problem; that alone was in its favor, a reason to strongly consider any reasonable proposal.
There was also the approach itself to be considered—and, perhaps most important, who was doing it. Was the scientist in charge someone worthy of the public trust?
Now, the application process is a mix of public and private. The scientists apply privately, and then the results are posted (without their names) on the CIRM website.
But after you hang around the field for a while, you get to know who the players are, and there are not that many at the very top.
Certainly, anyone who follows stem cell research closely would recognize the work of Dr. Hans Keirstead, who is to embryonic stem cell therapeutics roughly what Edison was to lightbulbs. It was public knowledge he had been working several years on a SMA project, and would be applying for a CIRM grant to advance the effort. I figured, well, this was one grant proposal that was practically guaranteed.
But when I read the results, to my dismay, the Keirstead SMA project was not recommended for funding—it was listed dead last!
I read the reviewers’ objections on the public page, and was staggered. What was going on here?
“Insufficient preliminary data”… was the key objection, though there were others, some general, some very specific: even one on the way the stem cells would be injected, with reviewers saying it should not be done with a hand-held syringe.
Then I remembered: this is how it has been for Keirstead, all throughout his career. He is a pioneer, taking giant leaps into the unknown; often he is the key source of preliminary data—precisely because he goes first…
Naturally, I wanted to help– hopefully without making things worse!
First, I called up a friend at the California Institute for Regenerative Medicine, to ask if it was legal for me to contact the scientist, and also the ICOC.
I was informed I had a First Amendment right to do so– and they had an equally valid right to ignore me—but the ICOC were state officials, so being contacted by the public was not without precedent.
I tried to reach Dr. Keirstead, to ask him if he would want to use the system developed by the CIRM, to make what is called an “extraordinary petition”, where he objected to the rejection of his project: would he be willing to fight for the grant.
Getting in touch with Keirstead is not easy. Basically, you (or I, anyway) have to be willing to make about a dozen calls, day after day. Also, he has an assistant, Michelle, who is politely savage about guarding access to the scientist’s time. Naturally, I approve of such protection—except when it comes to me, of course!
But at last we connected, and I asked him if he wanted to speak up about the decision on his funding.
He said yes.
I took the reviewers’ objections from the public document, broke them into ten pieces, gave them to him as questions. His answers (hopefully I understood them correctly) are in caps.
OBJECTIONS FROM REVIEWERS:
1. Reviewers cited lack of preliminary data demonstrating
disease-modifying activity of hMNPs.
KEIRSTEAD NOW HAS A GREAT DEAL OF SUCH DATA. THERE SHOULD BE A MECHANISM TO SUBMIT NEW DATA IN THESE DISEASE TEAM APPLICATIONS, AS THE PACE OF PROGRESS IS FAR FASTER THAN CONVENTIONAL RESEARCH.
2. They felt an IND filing in 18 months would be premature.
IN A FORMAL PRE-IND MEETING, THE FDA RULED OTHERWISE. THEY AGREED TO ACCEPT KEIRSTEAD’S IND WITHIN MONTHS.
3. Transplanted cells must replace dying motor neurons, also extend
axons that exit the spinal cord, find target, innervate muscles. Distance is
THIS IS INCORRECT. THE PRIMARY MECHANISM OF ACTION IS NURSING, AND KEIRSTEAD HAS MUCH DATA TO SUPPORT A NURSING ROLE. A FETAL STEM CELL BASED CLINIAL TRIAL WAS JUST APPROVED FOR ALS ON THE BASIS OF NURSING, PROVIDING PRECEDENT FOR THIS APPROACH.
4. No evidence provided of efficacy of therapy in animal model?
KEIRSTEAD NOW HAS A GREAT DEAL OF SUCH DATA; THAT DATA WAS REVIEWED BY THE FDA IN KEIRSTEAD’S RECENT PRE-IND MEETING
5. transplanted hMNPs may not rescue when disease damage done before
THIS IS INCORRECT. THE RATIONALE FOR TRANSPLANTING 2-6 MONTHS AFTER BIRTH IS TO TREAT THE ENDOGENOUS MOTOR NEURONS BEFORE THEY DIE.
6. full spinal cord motor neuron replacement may not be feasible;
incomplete rescue of motor neuron function may not give positive outcome.
KEIRSTEAD’S DATA CLEARLY INDICATES FUNCTIONAL RECOVERY IN PRE-CLINICAL ANIMALS MODELS WITH THIS APPROACH. THIS DATA AND THIS APPROACH WERE REVIEWED BY THE FDA IN KEIRSTEAD’S RECENT PRE-IND MEETING
7. concern that much data was in vitro, may not apply to in vivo.
KEIRSTEAD NOW HAS A GREAT DEAL OF ANIMAL DATA, AND THIS DATA WAS REVIEWED BY THE FDA IN KEIRSTEAD’S RECENT PRE-IND MEETING
8. safety data described, but not presented, making difficult to
SAFETY DATA IS NOW COMPLETE, AND THIS DATA WAS REVIEWED BY THE FDA IN KEIRSTEAD’S RECENT PRE-IND MEETING
9. data needed on lot variability of hMNPs, and safety with dead cells,
which may result in infection.
LOT VARIABILITY DATA IS NOW COMPLETE, AS IS ALL SAFETY DATA REQUIRED BY THE FDA. THIS DATA WAS REVIEWED BY THE FDA IN KEIRSTEAD’S RECENT PRE-IND MEETING
10. objections raised to hand-held syringe
SUCH OBJECTIONS ARE UNFOUNDED. THIS APPROACH WAS REVIEWED BY THE FDA IN KEIRSTEAD’S RECENT PRE-IND MEETING, AND DEEMED SUFFICIENT
11. suggests need for ethics member to address infant participation
AGREED. ETHICS REVIEW HAS BEEN ADDED.
12. recommend pediatrician inclusion on research team.
AGREED. PEDIATRICIAN HAS BEEN ADDED.
Next, I contacted friends in the SMA community, (I didn’t have any, so I had to reach out) and fortunately they were patient with this stranger calling them up– hopefully at least one will be able to come to the meeting and speak, and another will provide written testimony.
I also plan to speak, and (if allowed) here is roughly what I will say:
“Honored members of the Independent Citizens Oversight Committee:
As you know, I am not a scientist. But in the past fifteen years, since my son Roman Reed became paralyzed in a college football accident, I have been on a personal quest to find a cure. The only way that will happen, is for the entire field of regenerative medicine to move forward.
Grant proposal DR1-01449 is just such a pivotal project.
Here are ten reasons why it deserves funding.
- The project has an unparalleled urgency. The condition to be fought is Spinal Muscular Atrophy (SMA), a terrible condition which literally strangles children, weakening and destroying the motor neurons which control all movement, including breathing and swallowing.
2. The goal of the project is to heal the ravages of SMA with an infusion of new and healthy motor neurons: replacing damaged cells with new. This approach is a cornerstone of embryonic stem cell therapy: to replace cells that do not function, or which have died, with cells that are healthy, vibrant, alive. Also, those new cells bring with them neurotrophins and other nourishments to strengthen and save the cells remaining, and help new ones develop.
3. A successful outcome to this battle would not only offer hope to agonized parents of children with SMA, but could benefit our entire field of regenerative medicine. Among the benefits of this project could be: the means to produce large volumes of high purity cells; the restoration of motor nerves; the successful outcome of large animal studies, requested by so many critics; and answer the question of whether transplanted cells can not only survive, but go where they are supposed to go, and link up correctly, and function.
4. Numerous other neurological conditions would benefit from a success, including spinal cord injury, ALS (Lou Gehrig’s Disease), polio, and other forms of SMA.
5. While the investigator’s name was carefully redacted from the proposal, anyone who follows the field can recognize the work of Dr. Hans Keirstead. This is the man whose work gave Proposition 71 its one and only success to build around; this was the experiment highlighted on 60 MINUTES TV and featured in our campaign ads. He a recognized leader in the field.
6. The criticism is made that he lacks sufficient preliminary data to justify the risk of funds. Similar reviewer objections of insufficient preliminary data have been made against researcher’s work throughout his career, because of the pioneering nature of the efforts: however, when he has been funded, he has succeeded. One of his projects, as you know, is now close to human trials: the world’s first.
7. The ICOC has established a policy allowing “extraordinary petitions” so that researchers can have the opportunity to as for a special review of their case when unique situations arise; this is a crystal-clear validation of that policy.
8. Due to positive response from FDA, applicant now has multiples of increased documentation, previously unavailable for reviewers. Documentation has flooded in; exceeds 9,000 pages.
9. Financial bargain: because team has been preparing for 3 years, will not require 4 years of support, but only 18 months.
10. The scientist has already has completed steps toward FDA approval, including: production of motor neuron manufacturing facility to make cells required; small animal proof of concept studies; FDA-reviewed safety studies, showing no adverse effects.
So that part was ready.
Next I emailed several members of the ICOC board, (after all these years I do know some as individuals, and have their emails) asking if we could talk. Several said they would be willing to talk to me, though it was a long shot. Two individuals I specifically did not reach out to were Dr. Susan Bryant and Dr. Os Steward of UC Irvine, both of whom work closely with Hans. I felt it would be unfair of me to ask their help. But I was able to make contact with about eight of the board’s 29 members. Some I have talked to already, the rest I will hopefully speak with today, Monday.
Responses so far include:
1. Success this year not likely;
- Scientist should try again next year for the next disease team grant cycle;
- Keirstead should try for a different kind of grant, a translational grant;
- Keep fighting: this is a public process, and we have every right to be part of it;
- Sounds promising, we will keep an open mind at Wednesday’s meeting!
So that is where we are right now. I will keep working on this issue, advancing it every way I can think of.
Will we succeed Wednesday? I don’t know. In the past decade and a half I have been shot down too many times to not recognize the possibility of defeat.
But I read the testimony from a parent, who buried two children due to SMA.
There really is no fallback position, when faced with a threat like that.
We must prevail.