You can bank on CIRM

Way back in 2013, the CIRM Board invested $32 million in a project to create an iPSC Bank. The goal was simple;  to collect tissue samples from people who have different diseases, turn those samples into high quality stem cell lines – the kind known as induced pluripotent stem cells (iPSC) – and create a facility where those lines can be stored and distributed to researchers who need them.

Fast forward almost seven years and that idea has now become the largest public iPSC bank in the world. The story of how that happened is the subject of a great article (by CIRM’s Dr. Stephen Lin) in the journal Science Direct.

Dr. Stephen Lin

In 2013 there was a real need for the bank. Scientists around the world were doing important research but many were creating the cells they used for that research in different ways. That made it hard to compare one study to another and come up with any kind of consistent finding. The iPSC Bank was designed to change that by creating one source for high quality cells, collected, processed and stored under a single, consistent method.

Tissue samples – either blood or skin – were collected from thousands of individuals around California. Each donor underwent a thorough consent process – including being shown a detailed brochure – to explain what iPS cells are and how the research would be done.

The diseases to be studied through this bank include:

  • Age-Related Macular Degeneration (AMD)
  • Alzheimer’s disease
  • Autism Spectrum Disorder (ASD)
  • Cardiomyopathies (heart conditions)
  • Cerebral Palsy
  • Diabetic Retinopathy
  • Epilepsy
  • Fatty Liver diseases
  • Hepatitis C (HCV)
  • Intellectual Disabilities
  • Primary Open Angle Glaucoma
  • Pulmonary Fibrosis

The samples were screened to make sure they were safe – for example the blood was tested for HBV and HIV – and then underwent rigorous quality control testing to make sure they met the highest standards.

Once approved the samples were then turned into iPSCs at a special facility at the Buck Institute in Novato and those lines were then made available to researchers around the world, both for-profit and non-profit entities.

Scientists are now able to use these cells for a wide variety of uses including disease modeling, drug discovery, drug development, and transplant studies in animal research models. It gives them a greater ability to study how a disease develops and progresses and to help discover and test new drugs or other therapies

The Bank, which is now run by FUJIFILM Cellular Dynamics, has become a powerful resource for studying genetic variation between individuals, helping scientists understand how disease and treatment vary in a diverse population. Both CIRM and Fuji Film are committed to making even more improvements and additions to the collection in the future to ensure this is a vital resource for researchers for years to come.

Building the World’s Largest iPSC Repository: An Interview with CIRM’s Stephen Lin

This blog originally appeared on RegMedNet and was provided by Freya Leask, Editor & Community Manager of RegMedNet. In this interview, Stephen Lin, Senior Science Officer at the California Institute Regenerative Medicine (CIRM), discusses the scope, challenges and potential of CIRM’s iPSC Initiative. 

 

Stephen Lin

Stephen Lin received his PhD from Washington University (MO, USA) and completed his postdoctoral work at Harvard University (MA, USA). Lin is a senior science officer at CIRM which he joined in 2015 to oversee the development of a $32 million repository of iPSCs generated from up to 3000 healthy and diseased individuals and covering both complex and rare diseases. He also oversees a $40 million initiative to apply genomics and bioinformatics approaches to stem cell research and development of therapies. Lin is the program lead on the CIRM Translating Center which focuses on supporting the process development, safety/toxicity studies and manufacturing of stem cell therapy candidates to prepare them for clinical trials. He was previously a scientist at StemCells, Inc (CA, USA) and a staff scientist team lead at Thermo Fisher Scientific (MA, USA).

Q: Please introduce yourself and your institution.

I completed my PhD at Washington University in biochemistry, studying the mechanisms of aging, before doing my postdoc at Harvard, investigating programmed cell death. After that, I went into industry and have been working with stem cells ever since.

I was at the biotech company StemCells, Inc for 6 years where I worked on cell therapeutics. I then joined what was Life Technologies which is now Thermo Fisher Scientific.  I joined CIRM in 2015 as they were launching two new initiatives, the iPSC repository and the genomics initiative, which were a natural combination of my experience in both the stem cells industry and in genetic analysis.  I’ve been here for a year and a half, overseeing both initiatives as well as the CIRM Translating Center.

Q: What prompted the development of the iPSC repository?

Making iPSCs is challenging! It isn’t trivial for many research labs to produce these materials, especially for a wide variety of diseases; hence, the iPSC repository was set up in 2013. In its promotion of stem cells, CIRM had the financial resources to develop a bank for researchers and build up a critical mass of lines to save researchers the trouble of recruiting the patients, getting the consents, making and quality controlling the cells. CIRM wanted to cut that out and bring the resources straight to the research community.

Q: What are the challenges of storage so many iPSCs?

Many of the challenges of storing iPSCs and ensuring their quality are overcome with adequate quality controls at the production step. The main challenge is that we’re collecting samples from up to 3000 donors – the logistics of processing that many tissue samples from 11 funded and nonfunded collectors are difficult. The lines are being produced in the same uniform manner by one agency, Cellular Dynamics International (WI, USA), to ensure quality in terms of pluripotency, karyotyping and sterility testing.

Once the lines are made, they are stored at the Coriell Institute (NJ, USA). During storage, there is a challenge in simply keeping track of and distributing that many samples; we will have approximately 40 vials for each of the 3000 main lines. Both Cellular Dynamics and Coriell have sophisticated tracking systems and Coriell have set up a public catalog website where anyone can go to read about and order the lines. Most collections don’t have this functionality, as the IT infrastructure required for searching and displaying the lines along with clinical information, the ordering process, material transfer agreements and, for commercial uses, the licensing agreements was very complex.

Q: Can anyone use the repository?

Yes, they can! There is a fee to utilize the lines but we encourage researchers anywhere in the world to order them. The lines are mostly for research and academic purposes but the collection was built to be commercialized, all the way from collecting the samples. When the samples were collected, the patient consent included, among other things, banking, distribution, genetic characterization and commercialization.

The lines also have pre-negotiated licensing agreements with iPS Academia Japan (Kyoto, Japan) and the Wisconsin Alumni Research Foundation (WI, USA). Commercial entities that want to use the cells for drug screening can obtain a license which allows them to use these lines for drug discovery and drug screening purposes without fear of back payment royalties down the road. People often forget during drug screening that the intellectual property to make the iPSCs is still under patent, so if you do discover a drug using iPSCs without taking care of these licensing agreements, your discovery could be liable to ownership by that original intellectual property holder.

Q: Will wider access to high quality iPSCs accelerate discovery?

That’s our hope. When people make iPSCs, the quality can be highly variable depending on the lab’s background and experience, which was another impetus to create the repository. Cellular Dynamics have set up a very robust system to create these lines in a rigorous quality control pipeline to guarantee that these lines are pluripotent and genetically stable.

Q: What diseases could these lines be used to study and treat?

We collected samples from patients with many different diseases – from neurodevelopmental disorders including epilepsy and neurodegenerative diseases such as Alzheimer’s, to eye disease and diabetes – as well as the corresponding controls. We also have lines from rare diseases, where the communities have no other tools to study them, for example, ADCY5 related dyskinesia. You can read our recent blogs about our efforts to generate new iPSC lines for ADCY5 and other rare diseases here and here.

Q: What are your plans for the iPSC initiative this year?

We’re currently the largest publicly available repository in the world and we aren’t complete yet. We have just under half of the lines in with the other half still being produced and quality controlled. Something else we want to do is add further information to make the lines more valuable and ensure the drug models are constantly improving. The reason people will want to use iPSCs for human disease modeling is whether they have valuable information associated with them.  For example, we are trying to add genetic and sequencing information to the catalog for lines that have it. This will also allow researchers to prescreen the lines they are interested in to match the diseases and drugs they are studying.

Q: Does the future for iPSCs lie in being utilized as tools to find therapeutics as opposed to therapeutics themselves?

I think the future is two pronged. There is certainly a future for disease modeling and drug screening. There is currently an initiative within the FDA, the CiPA initiative, is designed to replace current paradigms for drug safety testing with computational model and stem cell models. In particular, they hope to be able to screen drugs for cardiotoxicity in stem cells before they go to patients.  Mouse and rodent models have different receptors and ion channels so these cardiotoxic effects aren’t usually seen until clinical trials.

The other avenue is in therapeutics. However, this will come later in the game because the lines being used for research often can’t be used for therapeutics. Patient consent for therapeutic use has to be obtained at sample collection, the tissue should be handled in compliance with good lab practice and the lines must be produced following good manufacturing process (GMP) guidelines. They must then be characterized to ensure they have met all safety protocols for iPSC therapeutics.

There is already a second trial being initiated in Japan of an iPSC therapeutic to treat macular degeneration, utilizing allogenic lines that are human leukocyte antigen-compatible and extensively safety profiled. Companies such as Lonza (Basel, Switzerland) and Cellular Dynamics are starting to produce their own GMP lines, and CIRM is funding some translation programs where clinical grade iPSCs are being produced for therapeutics.


Further Reading

Fujifilm is Expanding Its Focus to Regenerative Medicine

Fujifilm began as a photography company, but today is a well-known multinational imaging and information technology corporation. More recently, it’s expanded its focus (pun intended) on developing innovative technologies in the healthcare and regenerative medicine space.

The news that Fujifilm was expanding into regenerative medicine was surprising to some given the company’s expertise in areas unrelated to stem cell research, but with the acquisition of Cellular Dynamics International, a company from Madison, Wisconsin that specializes in large-scale manufacturing of human cells, and the revamping of Fujifilm’s Japan Tissue Engineering subsidiary, which is developing regenerative treatments for damaged skin and cartilage, Fujifilm has solidified its position as a competitive company that’s accelerating the pace of regenerative medicine to develop treatments for patients with unmet medical needs.

Mr. Ban

Mr. Toshikazu Ban

So what progress has Fujifilm made in regenerative medicine and what advancements are they making towards the clinic? You’ll find the answers to these burning questions in my interview with Mr. Toshikazu Ban, Corporate Vice President, General Manager of Regenerative Medicine Business Division at Fujifilm Corporation. Enjoy!

Q: Why did Fujifilm decide to enter the regenerative medicine space?

TB: At first glance, Fujifilm may seem an unlikely candidate to become a leader in regenerative medicine, yet its engagement in the healthcare industry goes back many decades. Founded in 1934, Fujifilm started offering X-ray film just two years later. By 1983, Fujifilm became the first in the world to offer a digital X-ray diagnostic imaging system.

Today, Fujifilm has been able to expand the use of its core fundamental technologies in cosmetics and supplements and pharmaceuticals. Combined, these have allowed Fujifilm to transform into a major healthcare company committed to prevention, diagnosis and treatment.

Unfortunately, there are still many diseases for which there are no effective treatments, and millions wait in hope of their discovery. Regenerative medicine treatment has the potential to cure diseases that cannot be cured by drugs. Fujifilm feels a sense of responsibility to apply its technology in a way that helps make promising treatments a reality.

Q: What advantages do you think Fujifilm has over other healthcare companies in regenerative medicine?

TB: Fujifilm’s advanced engineering technology provides tremendous possibilities in the regenerative medicine space.

The chief component in photographic film is gelatin, which is derived from collagen. Fujifilm has developed a human-type recombinant peptide which can be scaffolds for growing cells and restoring tissue.  The human-type recombinant peptide is non-animal based, has high cellular adhesiveness, is flexible, safe, biocompatible, biodegradable and bioabsorbable. Cells survive better when they are combined with our recombinant peptide because it holds the cells better and allows space in between so that oxygen and other critical growth factors can reach the cells.

Fujifilm also has two subsidiaries that provide synergies and efficiencies to be more competitive in the regenerative medicine field, Cellular Dynamics International, Inc., (FCDI), and Japan Tissue Engineering Co., Ltd. (J-TEC).

In 2015, FCDI announced the launch of a stem cell bank with funding from CIRM to create induced pluripotent stem (iPS) cell lines for each of 3,000 healthy and diseased volunteer donors across 11 common diseases and disorders to be made available through the CIRM human pluripotent stem cell (hPSC) Repository.

The lines available from the CIRM stem cell bank directly complement FCDI’s ability to provide differentiated cells corresponding to each of the iPSC lines, which will allow researchers to model the diseases represented, better understand disease progression, perform more targeted drug discovery, and ultimately lead to better treatments.

A lot of pharmaceutical companies use these cells to test for the screening and toxicity of new drug candidates. If iPS cells can improve the productivity including efficacy and safety, the technology can greatly reduce time and cost as well as the drop-out rate in clinical development.

In 2014, J-TEC became a consolidated Fujifilm Group subsidiary. J-TEC launched the first two regenerative medicine products to receive approval from the Japanese government (one product is used to treat severe burns, while the other is used to replace damaged cartilage in knees).

J-TEC Lab (Image courtesy of Fujifilm)

J-TEC Lab (Image courtesy of Fujifilm)

Q: Can you describe some of the stem cell therapies you’re developing for the clinic for major diseases?

TB: FCDI plans to start iPS cell therapy clinical studies in the U.S. for age related macular degeneration in the year 2017, and clinical studies for retinitis pigmentosa, Parkinson’s and heart failure around 2019.

In March 2015, Fujifilm announced it had developed diabetes therapies in animal tests. CellSaic is a three-dimensional mosaic structure that combines cells with a recombinant peptide (RCP) scaffold made from micro-sized petaloid pieces of the protein. In a study involving type 1 diabetic mice, we created a CellSaic of human mesenchymal stem cells and cells from pancreatic islets and transplanted them in the mice. The purpose of the study was to verify whether using the recombinant peptide as a scaffold would increase the survival rate of the transplanted cells compared with just transplanting the cells alone. We also wanted to demonstrate a reduction in blood glucose levels of the diabetic mice since the recombinant peptide was able to sustain the viability of the pancreatic islet cells.

The study showed that seven days after the transplantation, CellSaic had a significantly more prominent introduction of blood vessels, which provide passageways for nutrients, oxygen and waste product to get to, and away from, the cells.  In addition, 28 days after transplantation, the test group of diabetic mice with the recombinant peptide-based CellSaic scaffold saw blood glucose levels lowered to the level equivalent to that of the healthy mice. In contrast, the diabetic mice who received pancreatic islets alone showed no change in blood glucose levels. 

Q: When you move into clinical trials, do you anticipate US trial sites in parallel with those in Japan?

TB: FCDI plans to start clinical trials of iPS cell treatments in the US. J-TEC conducts clinical trials for autologous cultured corneal epithelium and plans to start clinical trials for allogeneic cultured dermis in Japan. Currently we plan to conduct these clinical trials where these companies are located. We may expand the clinical trials of the products to other countries in the future.

Q: Can you speak to Japan’s regulatory system for stem cell therapies and how this could give Fujifilm a leg up on developing stem cell treatments more rapidly?

TB: The go-to market conditions for regenerative medicine in Japan have become more favorable since the November 2014 implementation of the Pharmaceutical and Medical Device Law, which has significantly cut the time it takes to gain marketing approval in Japan and created more interest in this sector.

Within regenerative medicine, academic institutions have shown remarkable progress. The mission of the industry is to apply findings from academia to patients and deliver high-quality treatments at a reasonable cost.

Note: Technologies that pertain to Japan Tissue Engineering Co., Ltd. (J-TEC) are not approved for use in the US.

You can learn more about Fujifilm’s latest efforts to “make regenerative medicine a reality” by visiting its Innovation website.