Baseball’s loss is CIRM’s gain as Stanford’s Linda Boxer is appointed to Stem Cell Agency Board

Boxer

Dr. Linda Boxer: Photo courtesy Stanford University

One of the things that fascinates me is finding out how people end up in the job they have, the job they love. It is rare that the direction they started out on is the one they end on. Usually, people take several different paths, some intended, some unintended, to get to where they want to be.

A case in point is Dr. Linda Boxer, a renowned and respected researcher and physician at the Stanford School of Medicine, and now the newest member of the CIRM Board (you can read all about that in our news release).

In Dr. Boxer’s case, her original career path was a million miles from working with California’s stem cell agency:

“The first career choice that I recall as a young child was professional baseball—growing up in Minnesota, I was a huge Twins fan—I did learn fairly quickly that this was not likely to be a career that was available for a girl, and it wasn’t clear what one did after that career ended at a relatively young age.”

Fortunately for us she became interested in science.

“I have always been curious about how things work—science classes in grade school were fascinating to me. I was given a chemistry kit as a birthday gift, and I was amazed at what happened when different chemicals were mixed together: color changes, precipitates forming, gas bubbles, explosions (small ones, of course).

Then when we studied biology in middle school, I was fascinated by what one could observe with a microscope and became very interested in trying to understand how living organisms work.

It was an easy decision to plan a career in science.  The tougher decision came in college when I had planned to apply to graduate school and earn a PhD, but I was also interested in human health and disease and thought that perhaps going to medical school made more sense.  Fortunately, one of my faculty advisors told me about combined MD/PhD programs, and that choice seemed perfect for me.”

Along the way she says she got a lot of help and support from her colleagues. Now she wants to do the same for others:

“Mentors are incredibly important at every career stage.  I have been fortunate to have been mentored by some dedicated scientists and physicians.  Interestingly, they have all been men.  There were really very few women available as mentors at the time—of course, that has changed for the better now.  It never occurred to me then that gender made a difference, and I just looked for mentors who had successful careers as scientists and physicians and who could provide advice to someone more junior.

One of the aspects of my role now that I enjoy the most is mentoring junior faculty and trainees.  I don’t think one can have too many mentors—different mentors can help with different aspects of one’s life and career.  I think it is very important for established scientists to give back and to help develop the next generation of physicians and scientists.”

Dr. Boxer is already well known to everyone at CIRM, having served as the “alternate” on the Board for Stanford’s Dr. Lloyd Minor. But her appointment by State Controller Betty Yee makes her the “official” Board member for Stanford. She brings a valuable perspective as both a scientist and a physician.

The Minnesota Twins lost out when she decided to pursue a career in science. We’re glad she did.

 

Advertisements

How Parkinson’s disease became personal for one stem cell researcher

April is Parkinson’s disease Awareness Month. This year the date is particularly significant because 2017 is the 200th anniversary of the publication of British apothecary James Parkinson’s “An Essay on the Shaking Palsy”, which is now recognized as a seminal work in describing the disease.

Schuele_headshotTo mark the occasion we talked with Dr. Birgitt Schuele, Director Gene Discovery and Stem Cell Modeling at the Parkinson’s Institute and Clinical Center in Sunnyvale, California. Dr. Schuele recently received funding from CIRM for a project using new gene-editing technology to try and halt the progression of Parkinson’s.

 

 

What got you interested in Parkinson’s research?

People ask if I have family members with Parkinson’s because a lot of people get into this research because of a family connection, but I don’t.  I was always excited by neuroscience and how the brain works, and I did my medical residency in neurology and had a great mentor who specialized in the neurogenetics of Parkinson’s. That helped fuel my interest in this area.

I have been in this field for 15 years, and over time I have gotten to know a lot of people with Parkinson’s and they have become my friends, so now I’m trying to find answers and also a cure for Parkinson’s. For me this has become personal.

I have patients that I talk to every couple of months and I can see how their disease is progressing, and especially for people with early or young onset Parkinson’s. It’s devastating. It has a huge effect on the person and their family, and on relationships, even how they have to talk to their kids about their risk of getting the disease themselves. It’s hard to see that and the impact it has on people’s lives. And because Parkinson’s is progressive, I get to see, over the years, how it affects people, it’s very hard.

Talk about the project you are doing that CIRM is funding

It’s very exciting. The question for Parkinson’s is how do you stop disease progression, how do you stop the neurons from dying in areas affected by the disease. One protein, identified in 1997 as a genetic form of Parkinson’s, is alpha-synuclein. We know from studying families that have Parkinson’s that if you have too much alpha-synuclein you get early onset, a really aggressive form of Parkinson’s.

I followed a family that carries four copies of this alpha-synuclein gene (two copies is the normal figure) and the age of onset in this family was in their mid 30’s. Last year I went to a funeral for one of these family members who died from Parkinson’s at age 50.

We know that this protein is bad for you, if you have too much it kills brains cells. So we have an idea that if you lower levels of this protein it might be an approach to stop or shield those cells from cell death.

We are using CRISPR gene editing technology to approach this. In the Parkinson’s field this idea of down-regulation of alpha-synuclein protein isn’t new, but previous approaches worked at the protein level, trying to get rid of it by using, for example, immunotherapy. But instead of attacking the protein after it has been produced we are starting at the genomic level. We want to use CRISPR as a way to down-regulate the expression of the protein, in the same way we use a light dimmer to lower the level of light in a room.

But this is a balancing act. Too much of the protein is bad, but so is too little. We know if you get rid of the protein altogether you get negative effects, you cause complications. So we want to find the right level and that’s complex because the right level might vary from person to person.

We are starting with the most extreme levels, with people who have twice as much of this protein as is normal. Once we understand that better, then we can look at people who have levels that are still higher than normal but not at the upper levels we see in early-onset Parkinson’s. They have more subtle changes in their production or expression of this protein. It’s a little bit of a juggling act and it might be different for different patients. We start with the most severe ones and work our way to the most common ones.

One of the frustrations I often hear from patients is that this is all taking so long. Why is that?

Parkinson’s has been overall frustrating for researchers as well. Around 100 years ago, Dr. Lewy first described the protein deposits and the main neuropathology in Parkinson’s. About 20 years ago, mutations in the alpha-synuclein gene were discovered, and now we know approximately 30 genes that are associated with, or can cause Parkinson’s. But it was all very descriptive. It told us what is going on but not why.

Maybe we thought it was straight forward and maybe researchers only focused on what we knew at that point. In 1957, the neurotransmitter dopamine was identified and since the 1960s people have focused on Parkinson’s as a dopamine-deficient problem because we saw the amazing effects L-Dopa had on patients and how it could help ease their symptoms.

But I would say in the last 15 years we have looked at it more closely and realized it’s more complicated than that. There’s also a loss of sense of smell, there’s insomnia, episodes of depression, and other things that are not physical symptoms. In the last 10 years or so we have really put the pieces together and now see Parkinson’s as a multi-system disease with neuronal cell death and specific protein deposits called Lewy Bodies. These Lewy Bodies contain alpha-synuclein and you find them in the brain, the gut and the heart and these are organs people hadn’t looked at because no one made the connection that constipation or depression could be linked to the disease. It turns out that Parkinson’s is much more complicated than just a problem in one particular region of the brain.

The other reason for slow progress is that we don’t have really good models for the disease that are predictive for clinical outcomes. This is why probably many clinical trials in the neurodegenerative field have failed to date. Now we have human induced pluripotent stem cells (iPSCs) from people with Parkinson’s, and iPSC-derived neurons allow us to better model the disease in the lab, and understand its underlying mechanisms  more deeply. The technology has now advanced so that the ability to differentiate these cells into nerve cells is better, so that you now have iPSC-derived neurons in a dish that are functionally active, and that act and behave like dopamine-producing neurons in the brain. This is an important advance.

Will this lead to a clinical trial?

That’s the idea, that’s our hope.

We are working with professor Dr. Deniz Kirik at the University of Lund in Sweden. He’s an expert in the field of viral vectors that can be used in humans – it’s a joint grant between us – and so what we learn from the human iPS cultures, he’ll transfer to an animal model and use his gene vector technology to see if we can see the same effects in vivo, in mice.

We are using a very special Parkinson’s mouse model – developed at UC San Francisco – that has the complete human genomic structure of the alpha-synuclein gene. If all goes well, we hope that ultimately we could be ready in a couple of years to think about preclinical testing and then clinical trials.

What are your hopes for the future?

My hope is that I can contribute to stopping disease progression in Parkinson’s. If we can develop a drug that can get rid of accumulated protein in someone’s brain that should stop the cells from dying. If someone has early onset PD and a slight tremor and minor walking problems, stopping the disease and having a low dose of dopamine therapy to control symptoms is almost a cure.

The next step is to develop better biomarkers to identify people at risk of developing Parkinson’s, so if you know someone is a few years away from developing symptoms, and you have the tools in place, you can start treatment early and stop the disease from kicking in, even before you clinically have symptoms.

Thinking about people who have been diagnosed with a disease, who are ten years into the disease, who already have side effects from the disease, it’s a little harder to think of regenerative medicine, using embryonic or iPSCs for this. I think that it will take longer to see results with this approach, but that’s the long-term hope for the future. There are many  groups working in this space, which is critical to advance the field.

Why is Parkinson’s Awareness Month important?

It’s important because, while a lot of people know about the disease, there are also a lot of misconceptions about Parkinson’s.

Parkinson’s is confused with Alzheimer’s or dementia and cognitive problems, especially the fact that it’s more than just a gait and movement problem, that it affects many other parts of the body too.

Results are in: The Winners of our 2017 #StemCellResolution Campaign

We asked and you answered! In January, we launched our first Stem Cell Resolution campaign to raise awareness about the importance of stem cell research. We challenged scientists, students, institutes and the public to make a #StemCellResolution and share it on social media.

The goal of our campaign was to start a larger conversation about why stem cell research is important not just to advance science but to develop cures for diseases that currently have none.

Our campaign ran for the month of January, and we had global participation on multiple social media platforms including Twitter, Instagram, videos and blogs. Some resolutions involved answering important research questions while others involved empowering the public to pursue and understand scientific evidence to make their own informed decisions about the benefits of stem cell treatments for treating disease.

I was thoroughly impressed with everyone’s enthusiasm towards supporting and sharing this campaign that I plan to hold it again next year. But for now, I’ll announce the winners of our 2017 #StemCellResolution campaign. We picked the most inspiring resolution for each social media category and a few honorable mentions. The winner of each category will receive CIRM Stem Cell Champions t-shirts.

You can view the full list of this year’s stem cell resolutions on our Storify.


Twitter

Winner: Hamideh Emrani (@HamidehEmrani)

Hamideh is a science and technology communicator and the founder of Emrani Communications. 

Honorable Mention: Christine Liu (@Christineliuart)

Christine is a neuroscience phd student at UC Berkeley and a science communicator and artist.

Instagram

Winner: Pedro Soria Jr. (@shadowtype)

Pedro is a former CIRM Bridges student who is conducting stem cell research in neural regeneration at Western University in Southern California.

My Stem Cell Resolution for 2017 is to create a social media page dedicated to educating, enlightening and disseminating information about past, current, and future stem cell related studies to the general public, as well as those in science, in order to bring to light the importance of stem cell research. My objective is to bring people together regardless of whether or not they Originate from the natural sciences and spark an interest in this emerging field. Coming from a family where I'm first generation Mexican American and the only scientist has shown me the importance of communication amongst those that have little knowledge of the natural world especially people that come from countries that aren't scientifically advanced. Both my parents are born and raised in Michoacan, Mexico, in a small mountain town called Ario de Rosales. Back in my parents day, most people were farmers that worked from sun rise to sunset in order to feed and provide for their families. Naturally, they had little time for education because of the need to survive but had a positive work ethic, which I was lucky to inherit. My parents came to America for an opportunity to improve their situations and provide for themselves and families back home. They worked so hard to obtain what they have and to give me the chance they never had, which I'm so deeply grateful for each and every day of my life!! I had always felt destined for more than mediocre and enjoy taking on challenges to improve myself mentally, physically and spiritually. As a stem cell scientist, it is my responsibility to share my knowledge with everyone I encounter in order to bring change to this world. I wouldn't be where I am if it weren't for the support of my family, friends, professors, colleagues and of course #CIRM . Please join me on this journey and spread the word to anyone that will listen because we're all on this ride together in one way or another. That is my #stemcellresolution #soriaclan #bringingchange #cellculture Look out for my social media page #cellculture for all your stem cell info and check out the @cirm_stemcells to see what this beautiful institute is doing this year!!! #StemCellResolution

A post shared by Pedro Soria Jr. (@shadowtype) on

Video

Winner: Samantha Yammine (@SamanthaZY)

Samantha Yammine is a science communicator and a PhD candidate in Dr. Derek van der Kooy’s lab at the University of Toronto. You can learn more about Sam and her research on her website. She also recently wrote a guest blog for CIRM about a Keystone stem cell conference that you can find here.

Honorable Mentions: Paul Knoepfler (@pknoepfler)

Paul is a biomedical scientist at UC Davis, a science writer, advocate, and cancer survivor. He writes a popular stem cell blog called the Niche.

Honorable Mention: Catia B (@apulgarita)

Catia is a PhD student at MIT and is conducting research on programming & stem cells. She is originally from Portugal and has a personal blog about traveling and the PhD lifestyle.

Honorable Mention: Gladstone trainees (@Gladstone_GO)

Gladstone students and postdocs stepped up to the challenge and filmed stem cell resolutions about their research.

Blog

Winner: Sophie Arthur (@SophArthur)

Soph is a PhD student in Southampton, K studying embryonic stem cell metabolism. Her goal is to find ways to maintain the pluripotent quality of stem cells. She has a personal science communications blog called Soph Talks Science.

 An excerpt from Soph’s blog is below. I highly recommend reading the entire piece as it is very engaging and inspiring!

“For my Stem Cell Resolution – I couldn’t decide on one, so instead, I’ve made 4! Oops!

First, I want to raise awareness that stem cell biology is as important as stem cell treatments! There is lots of hype over stem cell treatments across the globe, but I want to stress that there are only a handful that have actually been approved! I could very well be biased as I’m studying stem cells and their biological mechanisms that exist normally in our bodies – but I want to stress the importance of this work. Simple biology – as I think it will hold the key to all the future stem cell medicine! Once we know how stem cells work in our bodies we can exploit that to make the treatments, or even learn more about our normal development!

 Honorable Mention: Stacey Johnson (@msstaceyerin)

Stacey is the Director of Communications and Marketing for CCRM, the Centre for Commercialization of Regenerative Medicine in Canada. She also is a regular contributor to CCRM’s Signals Blog.

“Since I’m not a scientist, a student or a patient, but I regularly communicate about stem cells to raise awareness and educate the public, my #stemcellresolution is to use this forum to spread the news – what I do best – about this fun and important challenge.”

Read Stacey’s full blog here.


 Thank you and see you next year!

Science communications is a vital tool that scientists and science enthusiasts need to leverage now more than ever to support stem cell research. Speaking out through social media or blogs is a great way to do this, and I want to congratulate all those that participated this year. I’m grateful for your support!

We look forward to doing this again next year and this time, you’ll have an entire year to ponder your next #StemCellResolution.

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

arm

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.”

 

 

Your Guide to Awesome Stem Cell Conferences in 2017

Welcome to 2017, a year that will likely be full of change and new surprises. I’m hoping that some of these surprises will be in regenerative medicine with new stem cell therapies showing promise or effectiveness in clinical trials.

A great way to stay on top of new advances in stem cell research is to attend scientific conferences and meetings. Some of them are well known and highly attended like the International Society for Stem Cell Research (ISSCR) conference, which this year will be in Boston in June. There are also a few smaller, more intimate conferences focusing on specific topics from discovery research to clinical therapies.

There are loads of stem cell meetings this year, but a few that I would like to highlight. Here’s my abbreviated stem cell research conference and meeting guide for 2017. Some are heavy duty research-focused events and probably not suitable for someone without a science background; they’re also expensive to sign up for. I’ve marked those with an * asterix.


January 8-12th, Keystone Symposium (Fee to register)*

Keystone will be hosting two concurrent stem cell meetings in Tahoe next week, which are geared for researchers in the field. One will be on neurogenesis during development and in the adult brain and the other will be on transcriptional and epigenetic control in stem cells. CIRM is one of the co-funders of this meeting and will be hosting a panel focused on translating basic research into clinical trials. Keystone symposiums are small, intimate meetings rich with scientific content and great for networking. Be on the look out for blog coverage about this meeting in the coming weeks.


February 3rd, Stanford Center for Definitive and Curative Medicine Symposium (Free to the public)

This free symposium at Stanford University in Palo Alto, CA will present first-in-human cell and gene therapies for a number of disorders including bone marrow, skin, cardiac, neural, uterine, pancreatic and neoplastic disorders. Speakers include scientists, translational biologists and clinicians. Irv Weissman, a Stanford professor and CIRM grantee focused on translational cancer research, will be the keynote speaker. Space is limited so sign up ASAP!


March 23rd, CIRM Alpha Stem Cell Clinics Symposium (Free to the public)

This free one-day meeting will bring together scientists, clinicians, patient advocates, and other partners to describe how the CIRM Alpha Stem Cell Clinics Network is making stem cell therapies a reality for patients. The City of Hope Alpha Clinic is part of a statewide effort funded by CIRM to develop a network of “Alpha Clinics” that has one unifying goal: to accelerate the development and delivery of stem cell treatments to patients.

City of Hope Medical Center and Alpha Stem Cell Clinic

City of Hope Medical Center and Alpha Stem Cell Clinic


June 14-17th, International Society for Stem Cell Research (Fee to register)*

The Annual ISSCR stem cell research conference will be hosted in Boston this year. This is an international conference focusing on new developments in stem cell science and technology. CIRM was one of the funders of the conference last year when ISSCR was in San Francisco. It’s one of my favorite research events to attend full of interesting scientific presentations and great for meeting future collaborators.


For a more comprehensive 2017 stem cell conference and meeting guide, check out Paul Knoepfler’s Niche blog.

‘Right To Try’ laws called ‘Right To Beg’ by Stem Cell Advocates

In recent years, ‘Right to Try’ laws have spread rapidly across the US, getting approved in 32 states, with at least three more states trying to pass their own versions.

The organization behind the laws says they serve a simple purpose:

‘Right To Try’ allows terminally ill Americans to try medicines that have passed Phase 1 of the FDA approval process and remain in clinical trials but are not yet on pharmacy shelves. ‘Right To Try’ expands access to potentially life-saving treatments years before patients would normally be able to access them.”

That certainly sounds like a worthy goal; one most people could get behind. And that’s what is happening. Most ‘Right To Try’ laws are passed with almost unanimous bi-partisan support at the state level.

Beth Roxland

Beth Roxland

But that’s not the view of Beth Roxland, an attorney and health policy advisor with an extensive history in both regenerative medicine and bioethics. At the recent World Stem Cell Summit Roxland said ‘Right To Try’ laws are deceptive:

“These are not patient friendly but are actually patient unfriendly and could do harm to patients. The problem is that they are pretending to do something that isn’t being done. It gives patients a sense that they can get access to a treatment, but they don’t have the rights they think they do. This is a right to ask, not a right to get.”

Roxland says the bills in all 32 states are almost all identical, and use the same cookie-cutter language from the Goldwater Institute – the libertarian organization that is promoting these laws. And she says these laws have one major flaw:

“There is no actual right provided in the bill. The only right is the right to try and save your life, “by requesting” from a manufacturer a chance to try the therapy. The manufacturer doesn’t have to do anything; they aren’t obliged to comply. The bills don’t help; they give people false hopes.”

Roxland says there isn’t one substantiated case where a pharmaceutical company has provided access to a therapy solely because of a ‘Right To Try’ law.

However, Starlee Coleman, the Vice President for Communications at the Goldwater Institute, says that’s not true. She says Dr. Ebrahim Delpassand, a cancer specialist in Texas, has testified before Congress that he has treated dozens of patients under his state’s ‘Right To Try’ law. You can see a video of Dr. Delpassand here.

Coleman says ;

“We think the promise of ‘Right To Try’ is self-evident. If one doctor alone can treat 80 patients in one fell swoop, but the FDA can only manage to get 1200 people through its expanded access program each year, we think the potential to help patients is significant.”

Other speakers at the panel presentation at the World Stem Cell Summit said these laws can at the very least play an important role in at least raising the issue of the need for people battling terminal illnesses to have access to experimental therapies. Roxland agreed it was important to have that conversation but she pointed out that what often gets lost in the conversation is that these laws can have hidden costs.

  • 13 states may withdraw hospice eligibility to people who gain access to an early or experimental intervention
  • 4 states may withdraw home care
  • 6 states say patients taking part in these therapies may lose their insurance
  • Several states allow insurers to deny coverage for conditions that may arise from patients getting access to these therapies
  • 30 states say the companies can charge the patients for access to these therapies

Roxland says the motives behind the ‘Right To Try’ laws may be worthy but the effect is misleading, and diverts attention from efforts to create the kind of reforms that would have real benefits for patients.

Here is a blog we wrote on the same topic last year.

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.

jeff-sheehy

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:  http://www.fda.gov/ForIndustry/DevelopingProductsforRareDiseasesConditions/ucm2005525.htm

For more information:

Richard Jefferys

Michael Palm Basic Science, Vaccines & Cure Project Director
Treatment Action Group richard.jefferys@treatmentactiongroup.org

Nelson Vergel, Program for Wellness Restoration programforwellness@gmail.com

 

 

Failed stem cells may cause deadly lung disease

pf

Breathing is something we take for granted. It’s automatic. We don’t need to think about it. But for people with pulmonary fibrosis, breathing is something that is always on their minds.

Pulmonary fibrosis (PF) is a disease where the tissue in your lungs becomes thick and stiff, even scarred, making it difficult to breathe. It can be a frightening experience; and it doesn’t just affect your lungs.

Because your lungs don’t work properly they aren’t able to move as much oxygen as you need into your bloodstream, and that can have an impact on all your other organs, such as your brain and heart. There are some treatments but no cures, in large part because we didn’t know the cause of the disease. Many patients with PF live only 3-5 years after diagnosis.

Now a new CIRM-funded study from researchers at Cedars-Sinai has uncovered clues as to the cause of the disease, and that in turn could pave the way to new treatments.

The study, published in the journal Nature, found that a class of stem cells in the lung, called AEC2s, are responsible for helping repair damage caused by things such as pollution or infection. People who have PF have far fewer of these AEC2 cells, and those cells also had a much lower concentration of a chemical substance called hyaluronan, which is essential for repair damaged tissue.

They tested this theory with laboratory mice and found that by removing hyaluronan the mice developed thick scarring in their lungs.

In a news release from Cedars-Sinai Carol Liang, the study’s first author, said knowing the cause of the problem may help identify potential solutions:

“These findings are the first published evidence that idiopathic pulmonary fibrosis is primarily a disease of AEC2 stem cell failure. In further studies, we will explore how the loss of hyaluronan promotes fibrosis and how it might be restored to cell surfaces. These endeavors could lead to new therapeutic approaches.”

Knowing that a problem with AEC2 cells causes PF means the researchers can now start testing different medications to see which ones might help boost production of replacement AEC2 cells, or help protect those still functioning.

Stem cell agency funds clinical trials in three life-threatening conditions

strategy-wide

A year ago the CIRM Board unanimously approved a new Strategic Plan for the stem cell agency. In the plan are some rather ambitious goals, including funding ten new clinical trials in 2016. For much of the last year that has looked very ambitious indeed. But today the Board took a big step towards reaching that goal, approving three clinical trials focused on some deadly or life-threatening conditions.

The first is Forty Seven Inc.’s work targeting colorectal cancer, using a monoclonal antibody that can strip away the cancer cells ability to evade  the immune system. The immune system can then attack the cancer. But just in case that’s not enough they’re going to hit the tumor from another side with an anti-cancer drug called cetuximab. It’s hoped this one-two punch combination will get rid of the cancer.

Finding something to help the estimated 49,000 people who die of colorectal cancer in the U.S. every year would be no small achievement. The CIRM Board thought this looked so promising they awarded Forty Seven Inc. $10.2 million to carry out a clinical trial to test if this approach is safe. We funded a similar approach by researchers at Stanford targeting solid tumors in the lung and that is showing encouraging results.

Our Board also awarded $7.35 million to a team at Cedars-Sinai in Los Angeles that is using stem cells to treat pulmonary hypertension, a form of high blood pressure in the lungs. This can have a devastating, life-changing impact on a person leaving them constantly short of breath, dizzy and feeling exhausted. Ultimately it can lead to heart failure.

The team at Cedars-Sinai will use cells called cardiospheres, derived from heart stem cells, to reduce inflammation in the arteries and reduce blood pressure. CIRM is funding another project by this team using a similar  approach to treat people who have suffered a heart attack. This work showed such promise in its Phase 1 trial it’s now in a larger Phase 2 clinical trial.

The largest award, worth $20 million, went to target one of the rarest diseases. A team from UCLA, led by Don Kohn, is focusing on Adenosine Deaminase Severe Combined Immune Deficiency (ADA-SCID), which is a rare form of a rare disease. Children born with this have no functioning immune system. It is often fatal in the first few years of life.

The UCLA team will take the patient’s own blood stem cells, genetically modify them to fix the mutation that is causing the problem, then return them to the patient to create a new healthy blood and immune system. The team have successfully used this approach in curing 23 SCID children in the last few years – we blogged about it here – and now they have FDA approval to move this modified approach into a Phase 2 clinical trial.

So why is CIRM putting money into projects that it has either already funded in earlier clinical trials or that have already shown to be effective? There are a number of reasons. First, our mission is to accelerate stem cell treatments to patients with unmet medical needs. Each of the diseases funded today represent an unmet medical need. Secondly, if something appears to be working for one problem why not try it on another similar one – provided the scientific rationale and evidence shows it is appropriate of course.

As Randy Mills, our President and CEO, said in a news release:

“Our Board’s support for these programs highlights how every member of the CIRM team shares that commitment to moving the most promising research out of the lab and into patients as quickly as we can. These are very different projects, but they all share the same goal, accelerating treatments to patients with unmet medical needs.”

We are trying to create a pipeline of projects that are all moving towards the same goal, clinical trials in people. Pipelines can be horizontal as well as vertical. So we don’t really care if the pipeline moves projects up or sideways as long as they succeed in moving treatments to patients. And I’m guessing that patients who get treatments that change their lives don’t particularly

First spinal cord injury trial patient gets maximum stem cell dose

kris-boesen

Kris Boesen, CIRM spinal cord injury clinical trial patient.

There comes a pivotal point in every experiment where you say “ok, now we are going to see if this really works.” We may be at that point in the clinical trial we are funding to see if stem cells can help people with spinal cord injuries.

Today Asterias Biotherapeutics announced they have given the first patient in the clinical trial the highest dose of 20 million cells. The therapy was administered at Santa Clara Valley Medical Center (SCVMC) in San Jose, California where Jake Javier – a young man who was treated at an earlier stage of the trial – was treated. You can read Jake’s story here.

The goal of the trial is to test the safety of transplanting three escalating doses of AST-OPC1 cells. These are a form of cell called oligodendrocyte progenitors, which are capable of becoming several different kinds of nerve cells, some of which play a supporting role and help protect nerve cells in the central nervous system – the area damaged in spinal cord injury.

In a news release, Dr. Edward Wirth, Asterias’ Chief Medical Officer, says this could be a crucial phase in the trial:

“We have been very encouraged by the early clinical efficacy and safety data for AST-OPC1, and we now look forward to evaluating the 20 million cell dose in complete cervical spinal cord injury patients. Based on extensive pre-clinical research, this is in the dosing range where we would expect to see optimal clinical improvement in these patients.”

To be eligible, individuals have to have experienced a severe neck injury in the last 30 days, one that has left them with no sensation or movement below the level of their injury, and that means they have typically lost all lower limb function and most hand and arm function.

In the first phase individuals were given 2 million cells. This was primarily to make sure that this approach was safe and wouldn’t cause any problems for the patients. The second phase boosted that dose to ten million cells. That was thought to be about half the therapeutic dose but it seemed to help all those enrolled. By 90 days after the transplant all five patients treated with ten million cells had shown some level of recovery of at least one motor level, meaning they had regained some use of their arms and/or hands on at least one side of their body. Two of the patients experienced an improvement of two motor levels. Perhaps the most impressive was Kris Boesen, who regained movement and strength in both his arms and hands. He says he is even experiencing some movement in his legs.

All this is, of course, tremendously encouraging, but we also have to sound a note of caution. Sometimes individuals experience spontaneous recovery after an accident like this. The fact that all five patients in the 10 million cell group did well suggests that this may be more than just a coincidence. That’s why this next group, the 20 million cell cohort, is so important.

As Steve McKenna, Chief of the Trauma Center at SCVMC, says; if we are truly going to see an improvement in people’s condition because of the stem cell transplant, this is when we would expect to see it:

“The early efficacy results presented in September from the 10 million cell AIS-A cohort were quite encouraging, and we’re looking forward to seeing if those meaningful functional improvements are maintained through six months and beyond. We are also looking forward to seeing the results in patients from the higher 20 million cell AST-OPC1 dose, as well as results in the first AIS-B patients.”

For more information about the Asterias clinical trial, including locations and eligibility requirements, go here: www.clinicaltrials.gov, using Identifier NCT02302157, and at the SCiStar Study Website (www.SCiStar-study.com).

We can never talk about this clinical trial without paying tribute to a tremendous patient advocate and a great champion of stem cell research, Roman Reed. He’s the driving force behind the Roman Reed Spinal Cord Injury Research Act  which helped fund the pioneering research of Dr. Hans Keirstead that laid the groundwork for this clinical trial.