Stem Cell Round: Improving memory, building up “good” fat, nanomedicine

Stem Cell Photo of the Week

roundup03618In honor of brain awareness week, our featured stem cell photo is of the brain! Scientists at the Massachusetts General Hospital and Harvard Stem Cell Institute identified a genetic switch that could potentially improve memory during aging and symptoms of PTSD. Shown in this picture are dentate gyrus cells (DGC) (green) and CA3 interneurons (red) located in the memory-forming area of the brain known as the hippocampus. By reducing the levels of a protein called abLIM3 in the DGCs of older mice, the researchers were able to boost the connections between DGCs and CA3 cells, which resulted in an improvement in the memories of the mice. The team believes that targeting this protein in aging adults could be a potential strategy for improving memory and treating patients with post-traumatic stress disorder (PTSD). You can read more about this study in The Harvard Gazette.

New target for obesity.
Fat cells typically get a bad rap, but there’s actually a type of fat cell that is considered “healthier” than others. Unlike white fat cells that store calories in the form of energy, brown fat cells are packed with mitochondria that burn energy and produce heat. Babies have brown fat, so they can regulate their body temperature to stay warm. Adults also have some brown fat, but as we get older, our stores are slowly depleted.

In the fight against obesity, scientists are looking for ways to increase the amount of brown fat and decrease the amount of white fat in the body. This week, CIRM-funded researchers from the Salk Institute identified a molecule called ERRg that gives brown fat its ability to burn energy. Their findings, published in Cell Reports, offer a new target for obesity and obesity-related diseases like diabetes and fatty liver disease.

The team discovered that brown fat cells produce the ERRg molecule while white fat cells do not. Additionally, mice that couldn’t make the ERRg weren’t able to regulate their body temperature in cold environments. The team concluded in a news release that ERRg is “involved in protection against the cold and underpins brown fat identity.” In future studies, the researchers plan to activate ERRg in white fat cells to see if this will shift their identity to be more similar to brown fat cells.


Mice that lack ERR aren’t able to regulate their body temperature and are much colder (right) than normal mice (left). (Image credit Salk Institute)

Tale of two nanomedicine stories: making gene therapies more efficient with a bit of caution (Todd Dubnicoff).
This week, the worlds of gene therapy, stem cells and nanomedicine converged for not one, but two published reports in the journal American Chemistry Society NANO.

The first paper described the development of so-called nanospears – tiny splinter-like magnetized structures with a diameter 5000 times smaller than a strand of human hair – that could make gene therapy more efficient and less costly. Gene therapy is an exciting treatment strategy because it tackles genetic diseases at their source by repairing or replacing faulty DNA sequences in cells. In fact, several CIRM-funded clinical trials apply this method in stem cells to treat immune disorders, like severe combined immunodeficiency and sickle cell anemia.

This technique requires getting DNA into diseased cells to make the genetic fix. Current methods have low efficiency and can be very damaging to the cells. The UCLA research team behind the study tested the nanospear-delivery of DNA encoding a gene that causes cells to glow green. They showed that 80 percent of treated cells did indeed glow green, a much higher efficiency than standard methods. And probably due to their miniscule size, the nanospears were gentle with 90 percent of the green glowing cells surviving the procedure.

As Steve Jonas, one of the team leads on the project mentions in a press release, this new method could bode well for future recipients of gene therapies:

“The biggest barrier right now to getting either a gene therapy or an immunotherapy to patients is the processing time. New methods to generate these therapies more quickly, effectively and safely are going to accelerate innovation in this research area and bring these therapies to patients sooner, and that’s the goal we all have.”

While the study above describes an innovative nanomedicine technology, the next paper inserts a note of caution about how experiments in this field should be set up and analyzed. A collaborative team from Brigham and Women’s Hospital, Stanford University, UC Berkeley and McGill University wanted to get to the bottom of why the many advances in nanomedicine had not ultimately led to many new clinical trials. They set out looking for elements within experiments that could affect the uptake of nanoparticles into cells, something that would muck up the interpretation of results.


imaging of female human amniotic stem cells incubated with nanoparticles demonstrated a significant increase in uptake compared to male cells. (Green dots: nanoparticles; red: cell staining; blue: nuclei) Credit: Morteza Mahmoudi, Brigham and Women’s Hospital.

In this study, they report that the sex of cells has a surprising, noticeable impact on nanoparticle uptake. Nanoparticles were incubated with human amniotic stem cells derived from either males or females. The team showed that the female cells took up the nanoparticles much more readily than the male cells.  Morteza Mahmoudi, PhD, one of the authors on the paper, explained the implications of these results in a press release:

“These differences could have a critical impact on the administration of nanoparticles. If nanoparticles are carrying a drug to deliver [including gene therapies], different uptake could mean different therapeutic efficacy and other important differences, such as safety, in clinical data.”


Recap of the 2018 Alliance for Regenerative Medicine Cell and Gene Therapy State of the Industry

What happened in the Cell and Gene Therapy sector in 2017, and what should we be looking out for in 2018? Over 500 executives, investors, scientists and patient advocates gathered together yesterday to find out at the Alliance for Regenerative Medicine (ARM) State of the Industry Briefing in San Francisco, California.

ARM Chairman, Robert Preti, and ARM CEO, Janet Lynch Lambert, kicked off the session by discussing how 2017 marked an inflection point for the sector. They underscored the approval of three cell/gene therapies (see slide below) by the U.S. Food and Drug Administration (FDA), a “bright and robust” future pipeline that should yield over 40 approved therapies in the next five years, and an improving regulatory environment that’s accelerating approvals of regenerative medicine therapies. This year alone, the FDA has granted 12 Regenerative Medicine Advanced Therapy (RMAT) designations through the 21st Century Cures Act (see slide below for companies/products that received RMAT in 2017).

In 2017, a total of four cell/gene therapies were approved and the US FDA awarded 12 RMAT designations. This slide is from the 2018 ARM Cell and Gene Therapy State of the Industry Briefing presentation.

Next up was a snapshot of the clinical landscape highlighting a total of 946 ongoing clinical trials at the end of 2017, and their breakdown by disease (see chart below). Oncology (cancer) is the clear winner comprising over 50% of the trials while Cardiovascular (heart) took second with 8.6% and diseases of the central nervous system (brain and spinal cord) took third with 6.5%.

Lambert also gave a brief overview of finances in 2017 and listed some impressive numbers. $7.5 Billion in capital was raised in 2017 compared to $4.2 Billion in 2016. She also mentioned major acquisitions, mergers, partnerships and public financings that paved the way for this year’s successes in cell and gene therapy.

Lambert concluded that while there was significant progress with product approvals, growing public awareness of successes in the sector, regulatory advances and financial maturity, there is a need for further commercial support and a focus on policy making, industrialization and manufacturing.

The Industry Update was followed by two panel sessions.

The first panel focused on cell-based cancer immunotherapies and featured company leaders from Juno Therapeutics, Mustang Bio, Adaptimmune, Novartis, and Fate Therapeutics.

In the cancer field, companies are aggressively pursuing the development of cell-based immunotherapies including Chimeric Antigen Receptor T (CAR-T) cells, modified T-cells and Natural Killer (NK) cells, to name a few. These therapies all involve engineering or modifying human immune cells to identify and target cancer cells that resist first-line cancer treatments like radiation or chemotherapy.

The panelists spoke of a future that involved the development of combination therapies that partner cell-based immunotherapies with other drugs and treatments to better target specific types of cancer. They also spent a significant portion of the panel discussing the issues of manufacturing and reimbursement. On manufacturing, the panel argued that a centralized cell manufacturing approach will be needed to deliver safe products to patients. On reimbursement, they addressed the difficulty of finding a balance between pricing life-saving therapies and navigating reimbursements from insurance companies.

The second panel focused on the state of gene therapy and the outlook for 2018. This panel featured company and academic leaders from CRISPR Therapeutics, Sangamo Therapeutics, BioMarin Pharmaceutical, Adverum Biotechnologies, and the Gladstone Institutes.

ARM Gene Therapy Panel: Martha Rook (MilliporeSigma), Deepak Srivastava (Gladstone Institutes), Amber Salzman (Adverum Biotechnologies), Bill Lundberg (CRISPR Therapeutics), Geoff Nichol (BioMarin Pharmaceutical), Sandy Macrae (Sangamo Therapeutics)

The panel spoke about the difference between gene editing (fixing an existing gene within a cell) and gene therapy (adding a new gene into a cell) technologies and how the delivery of these therapies into tissues and cells is the biggest challenge in the area right now.

Sandy Macrae, President and CEO of Sangamo Therapeutics, made an interesting point when he said that for gene therapy to be successful, companies need to plan two to three years in advance for a phase III trial (the final stage before a product is approved) because manufacturing gene therapies takes a long time. He said the key for success is about having medicines that are ready to launch, not just reporting good results.

Overall, ARM’s State of the Industry provided an exciting overview of the progress made in the Cell and Gene Therapy Sector in 2017 and shared outlooks for 2018 and beyond.

You can access the Live Webcast of ARM’s State of the Industry Briefing including both panel sessions on the ARM website. Be sure to check out our blog featuring our 2018 Stem Cell Conference Guide for more ARM events and other relevant stem cell research meetings in the coming year.

Bye Bye bubble baby disease: promising results from stem cell gene therapy trial for SCID

Evangelina Padilla-Vaccaro
(Front cover of CIRM’s 2016 Annual Report)

You don’t need to analyze any data to know for yourself that Evangelina Vaccaro’s experimental stem cell therapy has cured her of a devastating, often fatal disease of the immune system. All you have to do is look at a photo or video of her to see that she’s now a happy, healthy 5-year-old with a full life ahead of her.

But a casual evaluation of one patient won’t get therapies approved in the U.S. by the Food and Drug Administration (FDA). Instead, a very careful collection of quantitative data from a series of clinical trial studies is a must to prove that a treatment is safe and effective. Each study’s results also provide valuable information on how to tweak the procedures to improve each follow on clinical trial.

A CIRM-funded clinical trial study published this week by a UCLA research team in the Journal of Clinical Investigation did just that. Of the ten participants in the trial, nine including Evangelina were cured of adenosine deaminase-deficient severe combined immunodeficiency, or ADA-SCID, a disease that is usually fatal within the first year of life if left untreated.

In the past, children with SCID were isolated in a germ-free sterile clear plastic bubbles, thus the name “bubble baby disease”. [Credit: Baylor College of Medicine Archives]

ADA-SCID, also referred to as bubble baby disease, is so lethal because it destroys the ability to fight off disease. Affected children have a mutation in the adenosine deaminase gene which, in early development, causes the death of cells that normally would give rise to the immune system. Without those cells, ADA-SCID babies are born without an effective immune system. Even the common cold can be fatal so they must be sheltered in clean environments with limited physical contact with family and friends and certainly no outdoor play.

A few treatments exist but they have limitations. The go-to treatment is a blood stem cell transplant (also known as a bone marrow transplant) from a sibling with matched blood. The problem is that a match isn’t always available and a less than perfect match can lead to serious, life-threatening complications. Another treatment called enzyme replacement therapy (ERT) involves a twice-weekly injection of the missing adenosine deaminase enzyme. This approach is not only expensive but its effectiveness in restoring the immune system varies over a lifetime.

Evangelina being treated by Don Kohn and his team in 2012.  Photo: UCLA

The current study led by Don Kohn, avoids donor cells and enzyme therapy altogether by fixing the mutation in the patient’s own cells. Blood stem cells are isolated from a bone marrow sample and taken back to the lab where a functional copy of the adenosine deaminase gene is inserted into the patient’s cells. When those cells are ready, the patient is subjected to drugs – the same type that are used in cancer therapy – that kill off a portion of the patient’s faulty immune system to provide space in the bone marrow. Then the repaired blood stem cells are transplanted back into the body where they settle into the bone marrow and give rise to a healthy new immune system.

The ten patients were treated between 2009 and 2012 and their health was followed up for at least four years. As of June 2016, nine of the patients in the trial – (all infants except for an eight-year old) – no longer need enzyme injections and have working immune systems that allow them to play outside, attend school and survive colds and other infections that inevitably get passed around the classroom. The tenth patient was fifteen years old at the time of the trial and their treatment was not effective suggesting that early intervention is important. No serious side effects were seen in any of the patients.

Evangelina V

Evangelina Vaccaro (far right), who received Dr. Kohn’s treatment for bubble baby disease in 2012, with her family before her first day of school. Photo: UCLA, courtesy of the Vaccaro family

Now, this isn’t the first ever stem cell gene therapy clinical trial to successfully treat ADA-SCID. Kohn’s team and others have carried out clinical trials over the past few decades, and this current study builds upon the insights of those previous results. In a 2014 press release reporting preliminary results of this week’s published journal article, Kohn described the importance of these follow-on clinical trials for ensuring the therapy’s success:

UCLA Jonsson Comprehensive Cancer Center

Don Kohn

“We were very happy that over the course of several clinical trials and after making refinements and improvements to the treatment protocol, we are now able to provide a cure for babies with this devastating disease using the child’s own cells.”

The team’s next step is getting FDA approval to use this treatment in all children with ADA-SCID. To reach this aim, the team is carrying out another clinical trial which will test a frozen preparation of the repaired blood stem cells. Being able to freeze the therapy product buys researchers more time to do a thorough set of safety tests on the cells before transplanting them into the patient. A frozen product is also much easier to transport for treating children who live far from the laboratories that perform the gene therapy. In November of last year, CIRM’s governing Board awarded Kohn’s team $20 million to support this project.

If everything goes as planned, this treatment will be the first stem cell gene therapy ever approved in the U.S. We look forward to adding many new photos next to Evangelina’s as more and more children are cured of ADA-SCID.

Stem cell and gene therapy research gets a good report card from industry leader


Panel discussion at ARM State of the industry briefing: left to Right Robert Preti, Chair ARM; Jeff Walsh, bluebird bio; Manfred Rudiger, Kiadis Pharma; Barbara Sasu, Pfizer;  Thomas Farrell, Bellicum Pharmaceuticals. Photo courtesy ARM.

The state of the regenerative medicine field is strong and getting stronger. That was the bottom line verdict at the 2017 Cell and Gene Therapies State of the Industry briefing in San Francisco.

The briefing, an annual update on the field presented by the Alliance for Regenerative Medicine (ARM), gave a “by the numbers” look at the field and apart from one negative spot everything is moving in the right direction.

Robert Preti, Chair of ARM’s Board, said worldwide there are more than 750 regenerative companies working in the stem cell and gene therapy space. And those companies are increasingly moving the research out of the lab and into clinical trials in people.

For example, at the end of 2016 there were 802 clinical trials underway. That is a 21 percent growth over 2015. Those breakdown as follows:

Phase 1 – 271 (compared to 192 in 2015)

Phase 2 – 465 (compared to 376 in 2015)

Phase 3 – 66 (compared to 63 in 2015)

The bulk of these clinical trials, 45 percent, are focused on cancer. The second largest target, 11 percent, is on heart disease. The number of trials for neurological disorders and rare diseases are also growing in number.

Preti says the industry is at an important inflection point right now and that this growth is presenting new problems:

“The pipeline of products is robust and the technologies supporting that pipeline is even more robust. The technologies that are fueling the growth in clinical activity have accelerated so fast that we on the manufacturing side are playing catchup. We are at a point where we have to get serious about large scale commercial production.”

Preti also talked about “harmonization” of the regulatory process and the need to have a system that makes it easier for products approved for clinical trials in one country, to get approval for clinical trials in other countries.

Michael Werner, the executive director of ARM, said the organization has played a key role in helping promote the field and cited the recently passed 21st Century Cures Act as “a major win and a powerful statement of ARM’s leadership in this sector.”

But there was one area where the news wasn’t all positive, the ability of companies to raise capital. In 2015 companies raised $11 billion for research. In 2016 it was less than half of that, $5.3 billion.

With that somber note in mind it was appropriate that the panel discussion that followed the briefing was focused on the near-term and long-term challenges facing the field if it was to be commercially successful.

One of the big challenges was the issue of regulatory approval, and here the panel seemed to be more optimistic than in previous years.

Manfred Rüdiger of Kiadis Pharma said he was pleasantly surprised at how easy it was to work with different regulatory agencies in the US, Canada and Europe.

“We used them as a kind of free consultancy service, listening to their advice and making the changes they suggested so that we were able to use the same manufacturing process in Europe and Canada and the US.”

Jeff Walsh of bluebird bio, said the key to having a good working relationship with regulatory agencies like the Food and Drug Administration (FDA) is simple:

“Trust and transparency between you and the regulatory agencies is essential, it’s a critical factor in advancing your work. The agencies respond well when you have that trust. One thing we can’t be is afraid to ask. The agencies will tell you where their line is, but don’t be afraid to ask or to push the boundaries. This is new for everyone, companies and regulators, so if you are pushing it helps create the environment that allows you to work together to develop safe therapies that benefit patients.”

Another big issue was scalability in manufacturing; that it’s one thing to produce enough of a product to carry out a clinical trial but completely different if you are hoping to use that same product to treat millions of people spread out all over the US or the world.

And of course cost is always something that is front and center in people’s minds. How do you develop therapies that are not just safe and effective, but also affordable? How do companies ensure they will get reimbursed by health insurers for the treatments? No one had any simple answer to what are clearly very complex problems. But all recognized the need to start thinking about these now, long before the treatments themselves are even ready.

Walsh ended by saying:

“This is not just about what can you charge but what should you charge. We have a responsibility to engage with the agencies and ultimately the payers that make these decisions, in the same way we engage with regulatory agencies; with a sense of openness, trust and transparency. Too often companies wait too long, too late before turning to the payers and trying to decide what is appropriate to charge.”



Key Steps Along the Way To Finding Treatments for HIV on World AIDS Day

Today, December 1st,  is World AIDS Day. It’s a day to acknowledge the progress that is being made in HIV prevention and treatment around the world but also to renew our commitment to a future free of HIV. This year’s theme is Leadership. Commitment. Impact.  At CIRM we are funding a number of projects focused on HIV/AIDS, so we asked Jeff Sheehy, the patient advocate for HIV/AIDS on the CIRM Board to offer his perspective on the fight against the virus.


At CIRM we talk about and hope for cures, but our actual mission is “accelerating stem cell treatments to patients with unmet medical needs.”

For those of us in the HIV/AIDS community, we are tremendously excited about finding a cure for HIV.  We have the example of Timothy Brown, aka the “Berlin Patient”, the only person cured of HIV.

Multiple Shots on Goal

Different approaches to a cure are under investigation with multiple clinical trials.  CIRM is funding three clinical trials using cell/gene therapy in attempts to genetically modify blood forming stem cells to resist infection with HIV.  While we hope this leads to a cure, community activists have come together to urge a look at something short of a “home run.”

A subset of HIV patients go on treatment, control the virus in their blood to the point where it can’t be detected by common diagnostic tests, but never see their crucial immune fighting CD4 T cells return to normal levels after decimation by HIV.

For instance, I have been on antiretroviral therapy since 1997.  My CD4 T cells had dropped precipitously, dangerous close to the level of 200.  At that level, I would have had an AIDS diagnosis and would have been extremely vulnerable to a whole host of opportunistic infections.  Fortunately, my virus was controlled within a few weeks and within a year, my CD T cells had returned to normal levels.

For the immunological non-responders I described above, that doesn’t happen.  So while the virus is under control, their T cell counts remain low and they are very susceptible to opportunistic infections and are at much greater risk of dying.

Immunological non-responders (INRs) are usually patients who had AIDS when they were diagnosed, meaning they presented with very low CD4 T cell counts.  Many are also older.  We had hoped that with frequent testing, treatment upon diagnosis and robust healthcare systems, this population would be less of a factor.  Yet in San Francisco with its very comprehensive and sophisticated testing and treatment protocols, 16% of newly diagnosed patients in 2015 had full blown AIDS.

Until we make greater progress in testing and treating people with HIV, we can expect to see immunological non-responders who will experience sub-optimal health outcomes and who will be more difficult to treat and keep alive.

Boosting the Immune System

A major cell/gene trial for HIV targeted this population.  Their obvious unmet medical need and their greater morbidity/mortality balanced the risks of first in man gene therapy.  Sangamo, a CIRM grantee, used zinc finger nucleases to snip out a receptor, CCR5, on the surface of CD4 T cells taken from INR patients.  That receptor is a door that HIV uses to enter cells.  Some people naturally lack the receptor and usually are unable to be infected with HIV.  The Berlin Patient had his entire immune system replaced with cells from someone lacking CCR5.

Most of the patients in that first trial saw their CD4 T cells rise sharply.  The amount of HIV circulating in their gut decreased.  They experienced a high degree of modification and persistence in T stem cells, which replenish the T cell population.  And most importantly, some who regularly experienced opportunistic infections such as my friend and study participant Matt Sharp who came down with pneumonia every winter, had several healthy seasons.

Missed Opportunities

Unfortunately, the drive for a cure pushed development of the product in a different direction.  This is in large part to regulatory challenges.  A prior trial started in the late 90’s by Chiron tested a cytokine, IL 2, to see if administering it could increase T cells.  It did, but proving that these new T cells did anything was illusive and development ceased.  Another cytokine, IL 7, was moving down the development pathway when the company developing it, Cytheris, ceased business.  The pivotal trial would have required enrolling 4,000 participants, a daunting and expensive prospect.  This was due to the need to demonstrate clinical impact of the new cells in a diverse group of patients.

Given the unmet need, HIV activists have looked at the Sangamo trial, amongst others, and have initiated a dialogue with the FDA.  Activists are exploring seeking orphan drug status since the population of INRs is relatively small.

Charting a New Course

They have also discussed trial designs looking at markers of immune activity and discussed potentially identifying a segment of INRs where clinical efficacy could be shown with far, far fewer participants.

Activists are calling for companies to join them in developing products for INRs.  I’ve included the press release issued yesterday by community advocates below.

With the collaboration of the HIV activist community, this could be a unique opportunity for cell/gene companies to actually get a therapy through the FDA. On this World AIDS Day, let’s consider the value of a solid single that serves patients in need while work continues on the home run.

NEWS RELEASE: HIV Activists Seek to Accelerate Development of Immune Enhancing Therapies for Immunologic Non-Responders.

Dialogues with FDA, scientists and industry encourage consideration of orphan drug designations for therapies to help the immunologic non-responder population and exploration of novel endpoints to reduce the size of efficacy trials.

November 30, 2016 – A coalition of HIV/AIDS activists are calling for renewed attention to HIV-positive people termed immunologic non-responders (INRs), who experience sub-optimal immune system reconstitution despite years of viral load suppression by antiretroviral therapy. Studies have shown that INR patients remain at increased risk of illness and death compared to HIV-positive people who have better restoration of immune function on current drug therapies. Risk factors for becoming an INR include older age and a low CD4 count at the time of treatment initiation. To date, efforts to develop immune enhancing interventions for this population have proven challenging, despite some candidates from small companies showing signs of promise.

“We believe there is an urgent need to find ways to encourage and accelerate development of therapies to reduce the health risks faced by INR patients,” stated Nelson Vergel of the Program for Wellness Restoration (PoWeR), who initiated the activist coalition. “For example, Orphan Drug designations[i] could be granted to encourage faster-track approval of promising therapies.  These interventions may eventually help not only INRs but also people with other immune deficiency conditions”.

Along with funding, a major challenge for approval of any potential therapy is proving its efficacy. While INRs face significantly increased risk of serious morbidities and mortality compared to HIV-positive individuals with more robust immune reconstitution, demonstrating a reduction in the incidence of these outcomes would likely require expensive and lengthy clinical trials involving thousands of individuals. Activists are therefore encouraging the US Food & Drug Administration (FDA), industry and researchers to evaluate potential surrogate markers of efficacy such as relative improvements in clinical problems that may be more frequent in INR patients, such as upper respiratory infections, gastrointestinal disease, and other health issues.

“Given the risks faced by INR patients, every effort should be made to assess whether less burdensome pathways toward approval are feasible, without compromising the regulatory requirement for compelling evidence of safety and efficacy”, said Richard Jefferys of the Treatment Action Group.

The coalition is advocating that scientists, biotech and pharmaceutical companies pursue therapeutic candidates for INRs. For example, while gene and anti-inflammatory therapies for HIV are being assessed in the context of cure research, there is also evidence that they may have potential to promote immune reconstitution and reduce markers associated with risk of morbidity and mortality in INR patients. Therapeutic research should also be accompanied by robust study of the etiology and mechanisms of sub-optimal immune responses.

“While there is, appropriately, a major research focus on curing HIV, we must be alert to evidence that candidate therapies could have benefits for INR patients, and be willing to study them in this context”, argued Matt Sharp, a coalition member and INR who experienced enhanced immune reconstitution and improved health and quality of life after receiving an experimental gene therapy.

The coalition has held an initial conference call with FDA to discuss the issue. Minutes are available online.

The coalition is now aiming to convene a broader dialogue with various drug companies on the development of therapies for INR patients. Stakeholders who are interested in becoming involved are encouraged to contact coalition representatives.

[i] The Orphan Drug Act incentivizes the development of treatments for rare conditions. For more information, see:

For more information:

Richard Jefferys

Michael Palm Basic Science, Vaccines & Cure Project Director
Treatment Action Group

Nelson Vergel, Program for Wellness Restoration



What Went Down at ARM’s Regenerative Medicine State of the Industry

Every January, downtown San Francisco is taken over by a flock of investors, bankers, biotech companies, and scientists attending the annual JP Morgan Healthcare Conference. This meeting looks at the healthcare advancements over the past year and predicts the disease areas and technologies that will see the most progress and success in 2016.

According to some of the experts at the event, regenerative medicine and stem cell research are experiencing impressive, accelerated advancements, which has peaked the interest of investors, biotech, and pharmaceutical companies.

Because these are such fast paced fields, the Alliance for Regenerative Medicine (ARM) hosts the Annual Regenerative Medicine and Advanced Therapies State of the Industry Briefing during JP Morgan to discuss the recent progress and outlook for the industry in the coming year.

Screen Shot 2016-01-11 at 4.03.30 PM

What happened in 2015 and what’s next?

ARM’s  6th Annual Briefing was open to the public and drew over 300 people on Monday morning. The meeting opened with an industry update from Edward Lanphier, ARM Chairman and President/CEO of Sangamo BioSciences.  Then two panels featuring top leaders from biotech and pharmaceutical companies discussed the 2016 clinical data forecast and the promise of regenerative medicine and advanced therapies in oncology (cancer).

With an upbeat attitude, Lanphier gave an overview of clinical development progress in 2015, with 20 approved products worldwide and over 600 clinical trials both from academia and industry. More than 40% of these ongoing clinical trials are in cancer while approximately 12% are in heart disease/injury. These trials are not limited to Phase 1 either. In 2015, there were 376 in Phase 2 (compared to 200 in 2014) and 64 in Phase 3 (compared to 39 in 2014).

Edward Lanphier

Edward Lanphier

Two other areas Lanphier emphasized were CAR-T and other cell-based immunotherapies and gene therapy programs for rare diseases. He ended with 2015 statistics on clinical milestones in various disease and therapy programs, key company IPOs, the financial landscape, and predictions of major anticipated data from clinical trials in 2016.

It was a lot to take in, but this was definitely a good thing and a sign that the areas of regenerative medicine and advanced therapies are thriving. If you want more details, you can check out ARM’s State of the Industry presentation.

Major Theme: Data is King

The major theme that cropped up during the industry update and panel discussions was the importance of producing meaningful clinical data to get positive outcomes in regenerative medicine.

This was succinctly put by panelist Sven Kili, head of Gene Therapy Development at GlaxoSmithKline:

“I would say “Data is King”. A great idea is fantastic, passion is wonderful, and most companies will buy into a strong management team, but that only gets you so far. After that you need to have data, and you need to have a good plan for going forward.”

Kill added that there’s the need to work with the FDA to change the regulatory process, saying the FDA is, understandably, cautious about working with therapies that can alter a person’s genome permanently. However, he said there needs to be serious discussions with the FDA about how to speed up the process, to make it easier for the most promising projects to get approval.

Edward Lanphier also talked about the industry’s new focus on clinical data and the questions that arise when trying to advance regenerative medicine research into approved treatments and cures for patients:

“How do we communicate the value of curing blindness? How do we think about pricing that? What do we think about [drug] reimbursement?  For rare diseases, we aren’t trying to talk about acute treatments – we are talking about one-time, curative outcomes. And the value and benefit to patients in this is enormous. This is what we are trying to do, and on the cusp of, in terms of generating both approvable data and also the proof of concept data that then allows us to drive that next value inflection point in terms of financings.”

The Future Looks Good

After listening to the briefing, the future of regenerative medicine and advanced therapies certainly looks bright. As Jason Kolbert, head of Healthcare Research at the Maxim Group, said:

“This industry is now rapidly maturing and regenerative medicine and gene therapy have great things in store for the next decade.”

Usman Azam, Global Head of Cell and Gene Therapies at Novartis, had a similar outlook:

“We now are going from proof of concept to commercial availability of a disruptive innovation within seven years. If somebody had said that to me four years ago, I would have said, not possible. But that gives you a sense of how quickly this field is moving.”

Experts Panel

ARM Panel: 2016 Sector Forecast: Upcoming Clinical Data Events

While You Were Away: Gene Editing Treats Mice with Duchenne Muscular Dystrophy

Welcome back everyone! I hope you enjoyed your holiday and are looking forward to an exciting new year. My favorite thing about coming back from vacation is to see what cool new science was published. Because as you know, science doesn’t take a vacation!

As I was reading over the news for this past week, one particular story stood out. On New Year’s Eve, Science magazine published three articles (here, here, here) simultaneously that successfully used CRISPR/Cas9 gene editing to treat mice that have Duchenne muscular dystrophy (DMD).

DMD is a rare, genetic disease that affects approximately 1 in 3,600 boys in the US. It’s caused by a mutation in the dystrophin gene, which generates a protein that is essential for normal muscle function. DMD causes the body’s muscles to weaken and degenerate, leaving patients deformed and unable to move. It’s a progressive disease, and the average life expectancy is around 25 years. Though there are treatments that help prolong or control the onset of symptoms, there is no cure for DMD.

Three studies use CRISPR to treat DMD in mice

For those suffering from this debilitating disease, there is hope for a new therapy – a gene therapy that is. Three groups from UT Southwestern, Harvard, and Duke, used the CRISPR gene editing method to remove and correct the mutation in the dystrophin gene in mice with DMD. All three used a safe viral delivery method to transport the CRISPR/Cas9 gene editing complex to the proper location on the dystrophin gene in the mouse genome. There, the complex was able to cut out the mutated section of DNA and paste together a version of the gene that could produce a functional dystrophin protein.

Dystrophin protein (green) in healthy heart muscle (left), absent in DMD mice (center), and partially restored in DMD mice treated with CRISPR/Cas9 (right). (Nelson et al., 2015)

Dystrophin protein (green) in healthy heart muscle (left), absent in DMD mice (center), and partially restored in DMD mice treated with CRISPR/Cas9 (right). (Nelson et al., 2015)

This technique was tested in newly born mice as well as in adult mice by injecting the virus into the mouse circulatory system (so that the gene editing could happen everywhere) or into specific areas like the leg muscle to target muscle cells and stem cells. After the gene editing treatment, all three studies found restored expression of the dystrophin protein in heart and skeletal muscle tissue, which are the main tissues affected in DMD. They were also able to measure improved muscle function and strength in the animals.

This is really exciting news for the DMD field, which has been waiting patiently for an approved therapy. Currently, two clinical trials are underway by BioMarin and Sarepta Therapeutics, but the future of these drugs is uncertain. A gene therapy that could offer a “one-time cure” would certainly be a more attractive option for these patients.

Charles Gersbach, Duke University

Charles Gersbach, Duke University

It’s important to note that none of these gene editing studies reported a complete cure. However, the results are still very promising. Charles Gersbach, senior author on the Duke study, commented, “There’s a ton of room for optimization of these approaches.”

Strong media coverage of DMD studies

The implications of these studies are potentially huge and suitably, these studies were covered by prominent news outlets like Science News, STAT News, The Scientist, and The New York Times.

What I like about the news coverage on the DMD studies is that the results and implications aren’t over hyped. All of the articles mention the promise of this research, but also mention that more work needs to be done in mice and larger animals before gene therapy can be applied to human DMD patients. The words “safe” or “safety” was used in each article, which signals to me that both the science and media worlds understand the importance of testing promising therapies rigorously before attempting in humans on a larger scale.

However, it does seem that CRISPR gene editing for DMD could reach clinical trials in the next few years. Charles Gersbach told STATnews that he could see human clinical trials using this technology in a few years after scientists properly test its safety. He also mentioned that they first will need to understand “how the human immune system will react to delivery of  the CRISPR complex within the body.” He went on, “The hope for gene editing is that if we do this right, we will only need to do one treatment. This method, if proven safe, could be applied to patients in the foreseeable future.”

Eric Olson, UT Southwestern

Eric Olson, UT Southwestern

Eric Olson, senior author on the UT Southwestern study, had a similar opinion, “To launch a clinical trial, we need to scale up, improve efficiency and assess safety. I think within a few years, those issues can be addressed.”


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HIV/AIDS: Progress and Promise of Stem Cell Research

Our friends at Americans for Cures and Youreka Science have done it again. They’ve produced another whiteboard video about the progress and promise of stem cell research that’s so inspiring that it would probably make Darth Vader consider coming back to the light side. This time they tackled HIV.

If you haven’t watched one of these videos already, let me bring you up to speed. Americans for Cures is a non-profit organization, the legacy of the passing of Proposition 71, that supports patient advocates in the fight for stem cell research and cures. They’ve partnered with Youreka Science to produce eye-catching and informative videos to teach patients and the general public about the current state of stem cell research and the quest for cures for major diseases.

Stem cell cure for HIV?

Their latest video is on HIV, a well-known and deadly virus that attacks and disables the human immune system. Currently, 37 million people globally are living with HIV and only a few have been cured.

The video begins with the story of Timothy Brown, also known as the Berlin patient. In 2008 at the age of 40, he was dying of a blood cancer called acute myeloid leukemia and needed a bone marrow stem cell transplant to survive. Timothy was also HIV positive, so his doctor decided to use a bone marrow donor who happened to be naturally resistant to HIV infection. The transplanted donor stem cells were not only successful in curing Timothy of his cancer, but they also “rebooted his immune system” and cured his HIV.

Screen Shot 2015-12-23 at 2.21.18 PMSo why haven’t all HIV patients received this treatment? The video goes on to explain that bone marrow transplants are dangerous and only used in cancer patients who’ve run out of options. Additionally, only a small percentage of the world’s population is resistant to HIV and the chances that one of these individuals is a bone marrow donor match to a patient is very low.

This is where science comes to the rescue. Three research groups in California, all currently supported by CIRM funding, have proposed alternative solutions: they are attempting to make a patient’s own immune system resistant to HIV instead of relying on donor stem cells. Using gene therapy, they are modifying blood stem cells from HIV patients to be HIV resistant, and then transplanting the modified stem cells back into the same patient to rebuild a new immune system that can block HIV infection.

Screen Shot 2015-12-23 at 4.47.17 PM

All three groups have proven their stem cell technology works in animals; two of them are now testing their approach in early phase clinical trials in humans, and one is getting ready to do so. If these trials are successful, there is good reason to hope for an HIV cure and maybe even cures for other immune diseases.

My thoughts…

What I liked most about this video was the very end. It concludes by saying that these accomplishments were made possible not just by funding promising scientific research, but also by the hard work of HIV patients and patient advocate communities, who’ve brought awareness to the disease and influenced policy changes. Ultimately, a cure for HIV will depend on researchers and patient advocates working together to push the pace and to tackle any obstacles that will likely appear with testing stem cell therapies in human clinical trials.

I couldn’t say it any better than the final line of the video:

“We must remember that human trials will celebrate successes, but barriers will surface along with complications and challenges. So patience and understanding of the scientific process are essential.”

Cell mate: the man who makes stem cells for clinical trials

When we announced that one of the researchers we fund – Dr. Henry Klassen at the University of California, Irvine – has begun his clinical trial to treat the vision-destroying disease retinitis pigmentosa, we celebrated the excitement felt by the researchers and the hope from people with the disease.

But we missed out one group. The people who make the cells that are being used in the treatment. That’s like praising a champion racecar driver for their skill and expertise, and forgetting to mention the people who built the car they drive.

Prof. Gerhard Bauer

Prof. Gerhard Bauer

In this case the “car” was built by the Good Manufacturing Practice (GMP) team, led by Prof. Gerhard Bauer, at the University of California Davis (UC Davis).

Turns out that Gerhard and his team have been involved in more than just one clinical trial and that the work they do is helping shape stem cell research around the U.S. So we decided to get the story behind this work straight from the horse’s mouth (and if you want to know why that’s a particularly appropriate phrase to use here read this previous blog about the origins of GMP)

When did the GMP facility start, what made you decide this was needed at UC Davis?

Gerhard: In 2006 the leadership of the UC Davis School of Medicine decided that it would be important for UC Davis to have a large enough manufacturing facility for cellular and gene therapy products, as this would be the only larger academic GMP facility in Northern CA, creating an important resource for academia and also industry. So, we started planning the UC Davis Institute for Regenerative Cures and large GMP facility with a team of facility planners, architects and scientists, and by 2007 we had our designs ready and applied for the CIRM major facilities grant, one of the first big grants CIRM offered. We were awarded the grant and started construction in 2008. We opened the Institute and GMP facility in April of 2010.

How does it work? Do you have a number of different cell lines you can manufacture or do people come to you with cell lines they want in large numbers?

Gerhard: We perform client driven manufacturing, which means the clients tell us what they need manufactured. We will, in conjunction with the client, obtain the starting product, for instance cells that need to undergo a manufacturing process to become the final product. These cells can be primary cells or also cell lines. Cell lines may perhaps be available commercially, but often it is necessary to derive the primary cell product here in the GMP facility; this can, for instance, be done from whole donor bone marrow, from apheresis peripheral blood cells, from skin cells, etc.

How many cells would a typical – if there is such a thing – order request?

Gerhard: This depends on the application and can range from 1 million cells to several billions of cells. For instance, for an eye clinical trial using autologous (from the patient themselves) hematopoietic stem and progenitor cells, a small number, such as a million cells may be sufficient. For allogeneic (from an unrelated donor) cell banks that are required to treat many patients in a clinical trial, several billion cells would be needed. We therefore need to be able to immediately and adequately adjust to the required manufacturing scale.

Why can’t researchers just make their own cells in their own lab or company?

Gerhard: For clinical trial products, there are different, higher, standards than apply for just research laboratory products. There are federal regulations that guide the manufacturing of products used in clinical trials, in this special case, cellular products. In order to produce such products, Good Manufacturing Practice (GMP) rules and regulations, and guidelines laid down by both the Food and Drug Administration (FDA) and the United States Pharmacopeia need to be followed.

The goal is to manufacture a safe, potent and non-contaminated product that can be safely used in people. If researchers would like to use the cells or cell lines they developed in a clinical trial they have to go to a GMP manufacturer so these products can actually be used clinically. If, however, they have their own GMP facility they can make those products in house, provided of course they adhere to the rules and regulations for product manufacturing under GMP conditions.

Besides the UC Irvine retinitis pigmentosa trial now underway what other kinds of clinical trials have you supplied cells for?

Gerhard: A UC Davis sponsored clinical trial in collaboration with our Eye Center for the treatment of blindness (NCT01736059), which showed remarkable vision recovery in two out of the six patients who have been treated to date (Park et al., PMID:25491299, ), and also an industry sponsored clinical gene therapy trial for severe kidney disease. Besides cellular therapy products, we also manufacture clinical grade gene therapy vectors and specialty drug formulations.

For several years we have been supplying clinicians with a UC Davis GMP facility developed formulation of the neuroactive steroid “allopregnanolone” that was shown to act on resident neuronal stem cells. We saved several lives of patients with intractable seizures, and the formulation is also applied in clinical trials for the treatment of traumatic brain injury, Fragile X syndrome and Alzheimer’s disease.

What kinds of differences are you seeing in the industry, in the kinds of requests you get now compared to when you started?

Gerhard: In addition, gene therapy vector manufacturing and formulation work is really needed by several clients. One of the UC Davis specialties is “next generation” gene-modified mesenchymal stem cells, and we are contacted often to develop those products.

Where will we be in five years?

Gerhard: Most likely, some of the Phase I/II clinical trials (these are early stage clinical trials with, usually, relatively small numbers of patients involved) will have produced encouraging results, and product manufacturing will need to be scaled up to provide enough cellular products for Phase III clinical trials (much larger trials with many more people) and later for a product that can be licensed and marketed.

We are already working with companies that anticipate such scale up work and transitioning into manufacturing for marketing; we are planning this upcoming process with them. We also believe that certain cellular products will replace currently available standard medical treatments as they may turn out to produce superior results.

What does the public not know about the work you do that you think they should know?

Gerhard: The public should know that UC Davis has the largest academic Good Manufacturing Practice Facility in Northern California, that its design was well received by the FDA, that we are manufacturing a wide variety of products – currently about 16 – that we are capable of manufacturing several products at one time without interfering with each other, and that we are happy to work with clients from both academia and private industry through both collaborative and Fee-for-Service arrangements.

We are also very proud to have, during the last 5 years, contributed to saving several lives with some of the novel products we manufactured. And, of course, we are extremely grateful to CIRM for building this state-of-the-art facility.

You can see a video about the building of the GMP facility at UC Davis here.

Gene Therapy Beats Half-Matched Stem Cell Transplant in Side-by-Side Comparison to Treat ‘Bubble Baby’ Disease

If you are born with Severe Combined Immunodeficiency (SCID), your childhood is anything but normal. You don’t get to play with other kids, or be held by your parents. You can’t even breathe the same air. And, without treatment, you probably won’t live past your first year.

The bubble boy.  Born in 1971 with SCID, David Vetter lived in a sterile bubble to avoid outside germs that could kill him. He died in 1984 at 12 due to complications from a bone marrow transplant. [Credit: Baylor College of Medicine Archives]

The bubble boy. Born in 1971 with SCID, David Vetter lived in a sterile bubble to avoid outside germs that could kill him. He died in 1984 at 12 due to complications from a bone marrow transplant. [Credit: Baylor College of Medicine Archives]

This is the reality of SCID, also called “Bubble Baby” disease, a term coined in the 1970s when the only way to manage the disease was isolating the child in a super clean environment to avoid exposure to germs. The only way to treat the disorder was with a fully matched stem cell transplant from a bone marrow donor, ideally from a sibling. But as you may have guessed, finding a match is extraordinarily rare. Until recently, the next best option was a ‘half-match’ transplant—usually from a parent. But now, scientists are exploring a third, potentially advantageous option: gene therapy. Late last year, we wrote about a promising clinical trial from UCLA researcher (and CIRM Grantee) Donald Kohn, whose team effectively ‘cured’ SCID in 18 children with the help of gene therapy. Experts still consider a fully matched stem cell transplant to be the gold standard of treatment for SCID. But are the second-tier contenders—gene therapy and half-matched transplant—both equally as effective? Until recently, no one had direct comparison. That all changes today, as scientists at the Necker Children’s Hospital in Paris compare in the journal Blood, for the first time, half-matched transplants and gene therapy—to see which approach comes out on top. The study’s lead author, Fabien Touzot, explained the importance of comparing these two methods:

“To ensure that we are providing the best alternative therapy possible, we wanted to compare outcomes among infants treated with gene therapy and infants receiving partial matched transplants.”

So the team monitored a group of 14 SCID children who had been treated with gene therapy, and compared them to another group of 13 who had received the half-matched transplant. And the differences were staggering. Children in the gene therapy group showed an immune system vastly improved compared to the half-matched transplant group. In fact, in the six months following treatment, T-cell counts (an indicator of overall immune system health) rose to almost normal levels in more than 75% of the gene therapy patients. In the transplant group, that number was just over 25%. The gene therapy patients also showed better resilience against infections and had far fewer infection-related hospitalizations—all indictors that gene therapy may in fact be superior to a half-matched transplant. This is encouraging news say researchers. Finding a fully matched stem cell donor is incredibly rare. Gene therapy could then give countless families of SCID patients hope that their children could lead comparatively normal, healthy lives. “Our analysis suggests that gene therapy can put these incredibly sick children on the road to defending themselves against infection faster than a half-matched transplant,” explained Touzot. “These results suggest that for patients without a fully matched stem cell donor, gene therapy is the next-best approach.” Hear more about how gene therapy could revolutionize treatment strategies for SCID in our recent interview with Donald Kohn: