Hanuman Medical Foundation has been funding the Islet Sheet Project with the requirement that we move into the clinic as fast as possible. We restarted the project in 2009 with a plan to perfect the Islet Sheet in laboratory and rodent studies, then move on to the definitive large-animal model of autoimmune (type 1) diabetes: the pancreatectomized dog.

After some delays, in early 2012 we started these dog studies at the Cedars-Sinai’s Diabetes and Obesity Research Institute, under the leadership of its director, Richard Bergman, and principal investigator Marilyn Ader. Just after the first recipient was proven to be 100% diabetic (insulin was undetectable), problems at the institute caused Professor Bergman to table the project. (The problems are resolved now.)

With no other canine facility available to us, we decided to try to develop a new model in collaboration with Jonathan Lakey at UCI, using chemically induced diabetes in the Yucatan mini-pig. Pigs turned out to be unsuitable for curative research with encapsulated islets. The animal is very ornery, its fibrotic response is very strong, and its diabetes is difficult to control with insulin. However, we did learn a great deal. We learned that islets from pigs survive when implanted in genetically distant mini-pigs, and continue to make insulin for many weeks.

Large-Animal Studies Are Essential

For the balance of 2013 we will engage in some focused, small-scale studies to address problems identified in the pig studies. More on that very soon.

Here are some other developments that I’ll discuss in detail in future editions of The Sheet.

• JDRF is funding research at Jonathan Lakey’s UC Irvine laboratory that will study and compare microencapsulated islets with the Islet Sheet. We are providing Islet Sheets gratis. CEO Jeffrey Brewer of JDRF approved the grant in December 2012. It was intended to start in January but was delayed until recently because the University of California and JDRF had difficulty reaching agreement on intellectual property terms.
• JDRF has organized an encapsulation consortium, composed mainly of the academic researchers they fund. However, Rick Storrs and I representing Islet Sheet Medical, along with representatives of three other private companies, were invited to an interesting launch meeting in March. This initiative, being administered by Albert Hwa of JDRF, might evolve into an effective coordinator of efforts to bring encapsulated islets to human trials. Regular phone conferences and an annual meeting in New York are promised.
• On a related topic, we are in touch with several other members of the consortium on joint research. As these reach the practical stage I will report on them.

In memoriam:

Debby King Mustard (1953 – 2013), R.I.P.

In December, my sister Debby had a stroke, which turned out to have been caused by an untreatable brain tumor. For the past six months I’ve taken as much time as I could to visit her in Florida then Ohio. She died on Monday, June 5, with her husband and family present. It was a quiet death. This Friday the family and friends of Debby King Mustard gather to remember her.

The grief of the last six months has led me to much reflection. I am rededicated to our work to cure diabetes.

I have good and bad news to share with readers of The Sheet. First the bad: Scott King’s sister, Debby King Mustard, who was diagnosed last December with inoperable brain cancer, passed away peacefully Sunday morning. Scott and other family members were with her.

The good news is very good. Dr. Jon Lakey of the University of California, Irvine, who has been our chief collaborator for years in developing the Islet Sheet, has been awarded a three-year grant by JDRF to study encapsulated islet transplantation. The grant will provide funding up to about $1.27 million over the three years.

JDRF has been slow to devote major resources to encapsulation research but their thinking has evolved: recently the organization brought together scientists and researchers from more than 25 institutions “to accelerate this technology through a newly formed Encapsulation Consortium.” “We want to continue to build the pipeline of encapsulation technologies,” says JDRF’s Albert Hwa. The award to Jon Lakey was in response to a request for proposals posted by the new consortium.

A major goal of the work to be funded by the grant is to evaluate the performance of the Islet Sheet in Dr. Lakey’s laboratory. Participants in the study will include leading international research groups and a small number of for-profits; for example, Rick Storrs and Scott King of Islet Sheet Medical have been invited to take part.

Hanuman Medical Foundation is very pleased that Dr. Lakey’s leadership in the field of islet encapsulation is being recognized, and that JDRF is paying increased attention to this line of research for curing type 1 diabetes—to which our work is devoted. However, while the grant will further progress generally, none of the funds go directly to Hanuman and the Islet Sheet Project. We still rely chiefly on private donations, and need your support. When Scott resumes his posting very soon, he will be sharing news about an exciting new challenge initiative that promises to take our efforts to a new level.

Gene Therapy in Barcelona

The first in this series comes courtesy of  Lisa Hepner, producer of the documentary film The Human Trial and a diabetic herself. You can read a press release and a publication in Diabetes (click to download the full 2.6MB PDF) concerning a university study in Spain. The press release declares, “Researchers at the Universitat Autònoma de Barcelona have succeeded in completely curing type 1 diabetes in dogs with a single session of gene therapy.” This caught my attention because dogs are the gold-standard animal model of human diabetes.

Is it a cure?  If not, is it progress toward a cure?

The paper in Diabetes  claims, “This study provides the first proof-of-concept in a large animal model for a gene transfer approach to treat diabetes.” That is accurate and represents significant progress. However, the study leaves unanswered important questions on the both the safety and the efficacy of the gene transfer protocol.

In what way did they attempt to cure diabetes?

The study is a pilot study: no two dogs received the same treatment. Using a virus with a clever combination of two genes, they transformed dog leg muscle cells into cells that secrete human insulin. The muscle cells did not turn into islets; rather, the cells under the influence of the virus remained muscle cells but also secreted insulin.

The researchers tested this viral gene therapy in diabetic dogs. Dogs do not spontaneously develop type 1 diabetes and must be made diabetic. The gold standard here is total pancreatectomy (removal of the pancreas). In this study, however, a combination of beta-cell-cytotoxic drugs was used to destroy the dog’s beta cells. Insulin therapy for the diabetic dogs consisted of once or twice daily injections of Lantus on a sliding scale. (The glucose control achieved was poor; see Figure 1. Figure numbers refer to the publication; only one is shown here.)

How well did it work?

It is clear that the gene therapy caused the muscles of the dogs to produce insulin, and that this insulin was involved in control of the dogs’ diabetes. A major flaw in the study is that it never clearly established that the control was coming primarily from the treated muscles rather than from the remaining islet function. In Figure 7E, the levels of human C-peptide are at or below the low end of the normal clinical range in humans (0.5-3 ng/ml). Measurement of C-peptide from dogs would make it clear how much of the diabetes control was coming from insulin secreted by the dogs’ original islets. In our work at UC Irvine in rodents, we have observed that substantial islet function survives after treatment with beta-cell-cytotoxic drugs. Figure 7C-D (below) confirms this.

In the paper’s conclusion, the researchers claim that the muscle cells were responding to glucose with insulin secretion, yet this is not substantiated by the data presented. To do so would require measuring insulin as well as glucose during the oral glucose tolerance test, and demonstrating that the first-phase insulin response was present.  These data are presented in Figure 7F, and indeed show no significant first-phase response, undermining the stated conclusion.

Conclusions

In many respects the paper is important, and one day, when gene therapy is used to treat type 1 diabetes, this work will be viewed as a milestone.  They used the best model, the diabetic dog, and there were no ill effects.  They detected no hypoglycemia even after the dogs were exercised. Clearly the treated muscle cells secreted human insulin.

However, it appears that the muscle cells secreted human insulin at a steady rate. This could also be achieved with Lantus insulin or an implanted device encapsulating a cell line that secretes insulin at a steady rate.  In short, gene therapy, which has risks, achieved insulin delivery available by less risky means.

From human and animal studies it is clear that the survival of 5-10% of the pancretic beta cells can provide a substantial amount of insulin – enough so that much or even most of the metabolic control might come from the remaining islets rather than the gene-treated muscles.

Recommendation

I would suggest that the authors retrieve the (hopefully frozen) samples used to produce the data in 7F, which shows total insulin during the glucose tolerance test, and measure dog C-peptide and human C-peptide in the same samples.  This would provide information on the source of insulin – whether muscle secreting human insulin gene or dog islets secreting dog insulin – and the pattern would show whether both insulin sources are responsive to glucose. If the muscle cells are not responsive to glucose, it might well follow that this gene therapy is not justified by the risk.

There have been many developments on the Islet Sheet Project, which I look forward to telling you about.

The VoxPop people have secured funding for their documentary on finding a cure for diabetes, and have changed the film’s working title to The Human Trial.  (It was formerly Patient 13.) Take a look at the “sizzle reel.” They are doing a great job.

I would like to start by acknowledging Scott King and his team for the great work they are doing to find a cure for diabetes—and, more important, by sending good thoughts to Scott’s sister and their entire family during this challenging time.

When Scott asked if I would be interested in guest-writing for The Sheet, I quickly agreed. I’ve thought a lot about how living with diabetes has affected me, and I found The Sheet to be a good source of information. Scott’s belief in his quest is inspiring,   And it doesn’t hurt that his research seems to find success at every level. Over the years, I have been disappointed by the lack of legitimate advances in treating diabetes, but the Islet Sheet has successfully transitioned from theory to practice, and Scott’s blog has allowed me to feel like an insider who gets to come along on this exciting journey.

Now I’m curious about who else reads The Sheet and is intrigued by Scott’s work. Are most of my fellow readers diabetics, relatives or friends of diabetics, researchers, or other people I haven’t even thought of yet? Whoever you are, I hope this post will provide an opportunity to offer comments about your experiences and shed some light on why this research is important to you.

First, a little background. I grew up in a small town about 30 minutes outside Boston. My suburban New England upbringing was fairly typical—I had two hard-working and loving parents, a brother, four dogs (not all at once), a lot of wicked good friends, and a great public school education. I played soccer and tennis, and loved watching the Sox, the Celtics, and especially WWF wrestling. (C’mon—Hulk Hogan, Ricky the Dragon Steamboat, the Iron Sheik, Brutus the Barber Beefcake … who’s with me?) Fun times growing up in the ’80s, for sure.

Then, one evening in January 1987 when I was eleven, I came down with what seemed like a normal virus. I felt worn down and had a bit of a head cold. Not too unusual, or so it seemed. I went to bed early that night but woke up a few hours later, feeling incredibly thirsty. I proceeded to wake up every hour for the rest of the night. Each time, I would pee, then chug a ton of soda or whatever I could find in the fridge, and go back to bed.

In the morning, my dad asked why I had been up so much during the night. I didn’t realize he’d noticed. I told him I was wicked thirsty but kept peeing. Fortunately, my dad is a bright guy and immediately said, “That’s not normal. Let’s pay the doctor a visit.”

A few hours later we were at my pediatrician’s office, who also happened to specialize in juvenile diabetes (as it was then called)—lucky for me, as I discovered later. Mostly it seemed like any other trip to the doc, but things changed when he returned with the results of my bloodwork. He said something to the effect of, “We need to get Will to the hospital. He has diabetes.” I had no idea what diabetes meant, so I wasn’t scared at first. Remember, I was eleven and pondering more important things, like when could I test out my new skateboard or play with my friends? But the next thing I noticed, my dad dropped his head and let out a sigh. Shortly thereafter we were en route to the local hospital.

My memory of that part is a little vague. I do recall being instructed to get into a hospital gown shortly after arriving. That was when my parents saw how much weight I had lost. My already thin frame had taken a serious beating from the diabetes, and my dad later confided that I looked like the pictures of concentration camp victims.

I also recall the nurses working vigorously to insert an IV into my arm, but because I was so thin they weren’t having any luck. As they grew more and more frustrated, my pediatrician luckily showed up and easily inserted the IV. For the rest of the day I endured frequent blood sugar tests, was introduced to insulin, and practiced injections in oranges—my first taste of growing up diabetic.

So went day one of my life with type 1. For the next 25 years I lived as well I could while listening to a lot of people talk about how a cure would be found. But until I learned about Scott’s research, I didn’t have much reason for hope. Now I believe we have legitimate reason for optimism.

Do you remember the day you or your friend or family member was diagnosed?  Please feel free to share your story in a comment. After all, improving the lives of people who suffer from diabetes is what Scott’s life work is all about. And I’m sure that he and his colleagues would enjoy hearing more about people who could be helped by the Islet Sheet. I certainly would.

I have more stories to share, and you’ll be hearing from me again. I’ll also respond to your feedback. If you can, please support Hanuman Medical Foundation, which supports this great research. Thanks, and happy 2013!

Will Hall, San Francisco

For urgent family reasons, Scott King will take a break from writing his twice-monthly blog posts.  Scott’s sister was suddenly diagnosed with inoperable brain cancer and needs the support of her entire family for a while.  Fortunately, the large-mammal experiments with the Islet Sheet can continue with a minimum of Scott’s attention. He expects to resume his regular postings in January 2013.

Meanwhile, he and we urge you to consider a year-end gift to Hanuman Medical Foundation to help fund the Islet Sheet Project at its current critical stage of research. Your help will be equally welcome in 2013, which will be a crucial year as the team works to confirm the initial positive results of implanting Islet Sheets in diabetic pigs, so that we can progress toward clinical trials.

I am happy to report a most exciting breakthrough: we have demonstrated that Islet Sheets implanted in diabetic pigs keep islets alive and producing insulin for months. This is the most important accomplishment to date, because getting islets to thrive in the first few months is the most difficult milestone. Encapsulation devices fail when the encapsulated islets die, and islets can die for many reasons. The current study shows that the Islet Sheet prevents allograft immune rejection. It also shows that the vascularized membrane that grows around the sheet provides sufficient nutrients to keep the islets alive — and indeed islets are making, storing, and secreting insulin. We estimate that at 65 days >90% of the islets were functional because they stained for insulin with dithizone dye (see figure); only functional islets are stained by dithizone.

In the pigs studied, the need for external insulin was reduced but not completely eliminated, so it appears that the islets were not performing to their full potential. Our initial analysis of these recent results suggests several ways to increase islet function in this model. We are performing additional studies to investigate these. Our team predicts that, since the islets are functional, increasing their functionality is likely. We believe we will be able to completely control a pig’s diabetes with insulin made by the Islet Sheets.

The pig was not our first choice of for a large-animal model, but it was a logical first step because pig islets and diabetic pigs were available at the laboratory of our collaborator Jonathan Lakey. It turns out that there are good reasons why the pig is not a common model for T1D. Pigs are ornery: they resist insulin administration and try to shed CGM sensors, so it is difficult to control their BGs with insulin. And we found that some features of their peritoneal implant response appear to differ from those of dogs and humans.

We would like to expand our studies with two species of diabetic large animals, dogs and nonhuman primates. These are well-established models. A leading diabetes researcher with an established primate diabetes model is eager to begin collaborating with us. We hope we can find resources for this work in 2013.

With more pigs scheduled for Islet Sheet implants in January, and with canine and monkey studies in development, our projected expense for research is growing fast.  The Islet Sheet is potentially a functional cure for T1D (using the JDCA definition). Hanuman Medical Foundation (the sponsor of this site) is the only foundation currently supporting the Islet Sheet project. Other diabetes charities have expressed, at most, mild interest in the Islet Sheet Project, even though some have provided massive funding for another project that has not even selected an encapsulation method to study and thus is many years behind the Islet Sheet.  I don’t think this is the best way to a cure.

If you contribute to any of these charities, I urge you to become educated about cure research and understand how your donations are being used. The T1D charities raise money by telling parents of newly diagnosed diabetic children that they are working for a cure. As I have long believed, and the JDCA has now documented, this is not true; a declining minority of funds is used for research toward a practical cure. The Islet Sheet is a practical cure and is now in the midst of crucial studies that will prove — or disprove — its utility in the coming months.

It is time for donors committed to a cure for type 1 diabetes to hold accountable the charities they fund. I urge you to direct at least some of what you plan to donate to Hanuman Medical Foundation. You will know where your money is going, and you’ll be informed of the result. If the result is good, we will be much closer to a cure.

ViaCyte’s primary mission is to develop technology for transforming human stem cells into islets. To deliver the cells to patients they currently use an encapsulation technology named Encaptra.

The CIRM grant to ViaCyte is its fourth. CIRM is a public agency, which has sold bonds to fund stem cell research. (I don’t think this is a good model for funding research, but that’s a story for another post.) According to CIRM, ViaCyte received:

• in 2009, a Disease Team grant (“Cell Therapy for Diabetes”) in the amount of $19,999,937;
• in 2008, a Tools & Technology grant (“Development of the [REDACTED] Cellular Encapsulation System for Delivery of human ED Cell-derived Pancreatic Islets and Progenitors”) in the amount of $827,072;
• in 2009, an Early Transition grant (“Methods for detection and elimination of residual human embryonic stem cells in a differentiated cell product”) in the amount of $5,405,397;
• and finally, in 2012, a Strategic Partnership grant (“Preclinical and clinical testing of a stem cell-based combination product for insulin-dependent diabetes”) in the amount of $10,075,070: the purpose is “an array of detailed work on the exact format to be tested in humans needs to be completed and submitted to the FDA on the way to clinical trials.”

The total of these four grants, $36,307,476, represents 81% of CIRM funding for diabetes research (about $44 million). That’s an impressive concentration on a single approach.

The Encaptra encapsulation system has a long and tortuous history. Its first incarnation was invented in the 1970s by scientists at Baxter, Inc. in Round Lake, Illinois. Baxter had designed and built this device for delivery of cell products from its genetic engineering division but this was not successful. A joint venture with TransCell was formed (called Neocrin) to develop the device for diabetes. While curative in rodents, it never worked in larger animals, and never worked in any animal when it used primary islets—that is, islets isolated from an adult pancreas. The Neocrin team did succeed in converting the encapsulating membrane to one that would permit survival of xenograft cells, but testing was stopped because the device stimulated excessive host overgrowth. Neocrin returned the device to Baxter, which spun the technology out to TheraCyte (founded to market the device)—which is why it is often called the TheraCyte device.

ViaCyte deemphasizes the encapsulation technology, focusing rather on the stem cells. Its website does not even show the device, but rather a micrograph of the cells inside. Although I have seen photographs of Encaptra at meetings, I cannot find one online. ViaCyte says, “Encaptra® drug delivery system is manufactured from FDA compliant implant grade materials and is being designed with the goal of eliminating the need for continuous immunosuppressant drugs. The Encaptra® drug delivery system is optimized for release of insulin in response to the recipient’s blood glucose and designed for subcutaneous implantation providing complete containment of the product cells with full retrieval capability.”

This meshes with conversations I have had with ViaCyte scientists at scientific meetings. My impression is that they retained the basic concept of the TheraCyte device but reengineered it with new materials and brought manufacturing up to FDA standards. The cells they make from embryonic stem cells (ESCs) achieve their final maturating in the device, and the islets remain alive for months. ViaCyte believes that past failures with the TheraCyte device resulted from overloading and consequent islet necrosis.

ViaCyte was able raise money from CIRM because they are chiefly engaged in product development with ESCs. We have heard informally from CIRM that they could not fund Islet Sheet research because we do not work with ESCs. This is shortsighted on CIRM’s part, I think, but I do understand that they need to remain focused on their mission as sold to the taxpayers of California. The Encaptra device and the Islet Sheet are in the same class of encapsulation devices: namely, macro-capsules. But the materials used are quite different, and the sharpest difference is our approach to the nutrient/insulin exchange interface with the diabetic host.

Perhaps some day ViaCyte may find the Islet Sheet to be a useful alternative. In any case, it’s encouraging to see more funding in this area: besides the $10 million CIRM granted to ViaCyte, in August the Diabetes Research Institute (DRI) in Miami received $4.6 million. We are starting to get promising results from our first large-mammal studies in pigs, and I expect that investment in the Islet Sheet by funding institutions will grow over the next year.

The idea that the universe exists because it can be, and is, observed is supported by both science and religion. In his recent book Phi: A Voyage from the Brain to the Soul, Giulio Tononi writes that consciousness is what is really real. The idea is that the coming and going of matter in a nearly empty universe can be real only if it is seen. Our minds, even with their limits in time and space and comprehension, validate the actual existence of everything we all agree can be seen.

Religion (at least Christianity) posits entities that bring messages from God and return information to God; they are messengers, in Greek, ἄγγελος (angelos). With cheaper cameras and data storage, angels carrying messages are proliferating. When you stroll the streets of a large city, you may be under camera observation most of the time.

A few years ago, at a diabetes support meeting, I met a documentary filmmaker named Lisa Hepner. As Lisa learned more about the Islet Sheet Project, she became interested, both as a diabetic and a documentarian. Our idea seemed like a good one to her. So for a couple years now her company, VoxPop Films, has been angelically observing the development of the Islet Sheet, and of course the people involved.

They have recorded meetings and surgeries, conferences and conversations. When they are at work, you simultaneously get used to them and feel self-conscious. They have enough on me that I think it would be impossible for me ever to be elected to anything.

At some point they named the project Patient 13, which is me.  The name refers to a little joke I made, about how the best place to be in the clinical trial is 13th — because that means the first dozen people treated with the Islet Sheet have proven it safe. (In fact, I hope to be Patient 1.) People seem to like the name.

When we started this, I was prepared to see all the science, entrepreneurship, and clinical trials on film. I had not realized that other parts of my life would be so thoroughly recorded, apparently to make the documentary more interesting. They filmed a fundraiser we held for the Paul Taylor Dance Company (I’m on their board). They recorded my presentation at the Strong on Insulin Group (SOIG), UCLA’s adult type 1 diabetes support group, where Lisa and I met. And most recently they documented a full-length read-through of my new opera, Oomph! As I’m an introvert, all this has been mildly disconcerting, but I am adapting.

I have become friends with Lisa and her husband, Guy Mossman. I really want their documentary to be success. The best way for that to happen is for the Islet Sheet to succeed. So for me that’s one more reason to keep working at it.