Stem Cell Agency Invests in New Immunotherapy Approach to HIV, Plus Promising Projects Targeting Blindness and Leukemia

HIV AIDS

While we have made great progress in developing therapies that control the AIDS virus, HIV/AIDS remains a chronic condition and HIV medicines themselves can give rise to a new set of medical issues. That’s why the Board of the California Institute for Regenerative Medicine (CIRM) has awarded $3.8 million to a team from City of Hope to develop an HIV immunotherapy.

The City of Hope team, led by Xiuli Wang, is developing a chimeric antigen receptor T cell or CAR-T that will enable them to target and kill HIV Infection. These CAR-T cells are designed to respond to a vaccine to expand on demand to battle residual HIV as required.

Jeff Sheehy

CIRM Board member Jeff Sheehy

Jeff Sheehy, a CIRM Board member and patient advocate for HIV/AIDS, says there is a real need for a new approach.

“With 37 million people worldwide living with HIV, including one million Americans, a single treatment that cures is desperately needed.  An exciting feature of this approach is the way it is combined with the cytomegalovirus (CMV) vaccine. Making CAR T therapies safer and more efficient would not only help produce a new HIV treatment but would help with CAR T cancer therapies and could facilitate CAR T therapies for other diseases.”

This is a late stage pre-clinical program with a goal of developing the cell therapy and getting the data needed to apply to the Food and Drug Administration (FDA) for permission to start a clinical trial.

The Board also approved three projects under its Translation Research Program, this is promising research that is building on basic scientific studies to hopefully create new therapies.

  • $5.068 million to University of California at Los Angeles’ Steven Schwartz to use a patient’s own adult cells to develop a treatment for diseases of the retina that can lead to blindness
  • $4.17 million to Karin Gaensler at the University of California at San Francisco to use a leukemia patient’s own cells to develop a vaccine that will stimulate their immune system to attack and destroy leukemia stem cells
  • Almost $4.24 million to Stanford’s Ted Leng to develop an off-the-shelf treatment for age-related macular degeneration (AMD), the leading cause of vision loss in the elderly.

The Board also approved funding for seven projects in the Discovery Quest Program. The Quest program promotes the discovery of promising new stem cell-based technologies that will be ready to move to the next level, the translational category, within two years, with an ultimate goal of improving patient care.

Application Title Institution CIRM Committed Funding
DISC2-10979 Universal Pluripotent Liver Failure Therapy (UPLiFT)

 

Children’s Hospital of Los Angeles $1,297,512

 

DISC2-11105 Pluripotent stem cell-derived bladder epithelial progenitors for definitive cell replacement therapy of bladder cancer

 

Stanford $1,415,016
DISC2-10973 Small Molecule Proteostasis Regulators to Treat Photoreceptor Diseases

 

U.C. San Diego $1,160,648
DISC2-11070 Drug Development for Autism Spectrum Disorder Using Human Patient iPSCs

 

Scripps $1,827,576
DISC2-11183 A screen for drugs to protect against chemotherapy-induced hearing loss, using sensory hair cells derived by direct lineage reprogramming from hiPSCs

 

University of Southern California $833,971
DISC2-11199 Modulation of the Wnt pathway to restore inner ear function

 

Stanford $1,394,870
DISC2-11109 Regenerative Thymic Tissues as Curative Cell Therapy for Patients with 22q11 Deletion Syndrome

 

Stanford $1,415,016

Finally, the Board approved the Agency’s 2019 research budget. Given CIRM’s new partnership with the National Heart, Lung, Blood Institute (NHLBI) to accelerate promising therapies that could help people with Sickle Cell Disease (SCD) the Agency is proposing to set aside $30 million in funding for this program.

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Congresswoman Barbara Lee (D-CA 13th District)

“I am deeply grateful for organizations like CIRM and NHLBI that do vital work every day to help people struggling with Sickle Cell Disease,” said Congresswoman Barbara Lee (D-CA 13th District). “As a member of the House Appropriations Subcommittee on Labor, Health and Human Services, and Education, I know well the importance of this work. This innovative partnership between CIRM and NHLBI is an encouraging sign of progress, and I applaud both organizations for their tireless work to cure Sickle Cell Disease.”

Under the agreement CIRM and the NHLBI will coordinate efforts to identify and co-fund promising therapies targeting SCD.  Programs that are ready to start an IND-enabling or clinical trial project for sickle cell can apply to CIRM for funding from both agencies. CIRM will share application information with the NHLBI and CIRM’s Grants Working Group (GWG) – an independent panel of experts which reviews the scientific merits of applications – will review the applications and make recommendations. The NHLBI will then quickly decide if it wants to partner with CIRM on co-funding the project and if the CIRM governing Board approves the project for funding, the two organizations will agree on a cost-sharing partnership for the clinical trial. CIRM will then set the milestones and manage the single CIRM award and all monitoring of the project.

“This is an extraordinary opportunity to create a first-of-its-kind partnership with the NHLBI to accelerate the development of curative cell and gene treatments for patients suffering with Sickle Cell Disease” says Maria T. Millan, MD, President & CEO of CIRM. “This allows us to multiply the impact each dollar has to find relief for children and adults who battle with this life-threatening, disabling condition that results in a dramatically shortened lifespan.  We are pleased to be able to leverage CIRM’s acceleration model, expertise and infrastructure to partner with the NHLBI to find a cure for this condition that afflicts 100,000 Americans and millions around the globe.”

The budget for 2019 is:

Program type 2019
CLIN1 & 2

CLIN1& 2 Sickle Cell Disease

$93 million

$30 million

TRANSLATIONAL $20 million
DISCOVER $0
EDUCATION $600K

 

 

Has Regenerative Medicine Come of Age?

Signals logo

For the past few years the Signals blog site –  which offers an insiders’ perspectives on the world of regenerative medicine and stem cell research – has hosted what it calls a “Blog Carnival”. This is an event where bloggers from across the stem cell field are invited to submit a piece based on a common theme. This year’s theme is “Has Regenerative Medicine Come of Age?” Here’s my take on that question:

Many cultures have different traditions to mark when a child comes of age. A bar mitzvah is a Jewish custom marking a boy reaching his 13th birthday when he is considered accountable for his own actions. Among Latinos in the US a quinceañera is the name given to the coming-of-age celebration on a girl’s 15th birthday.

Regenerative Medicine (RM) doesn’t have anything quite so simple or obvious, and yet the signs are strong that if RM hasn’t quite come of age, it’s not far off.

For example, look at our experience at the California Institute for Regenerative Medicine (CIRM). When we were created by the voters of California in 2004 the world of stem cell research was still at a relatively immature phase. In fact, CIRM was created just six years after scientists first discovered a way to derive stem cells from human embryos and develop those cells in the laboratory. No surprise then that in the first few years of our existence we devoted a lot of funding to building world class research facilities and investing in basic research, to gain a deeper understanding of stem cells, what they could do and how we could use them to develop therapies.

Fast forward 14 years and we now have funded 49 projects in clinical trials – everything from stroke and cancer to spinal cord injury and HIV/AIDS – and our early funding also helped another 11 projects get into clinical trials. Clearly the field has advanced dramatically.

In addition the FDA last year approved the first two CAR-T therapies – Kymriah and Yescarta – another indication that progress is being made at many levels.

But there is still a lot of work to do. Many of the trials we are funding at the Stem Cell Agency are either Phase 1 or 2 trials. We have only a few Phase 3 trials on our books, a pattern reflected in the wider RM field. For some projects the results are very encouraging – Dr. Gary Steinberg’s work at Stanford treating people recovering from a stroke is tremendously promising. For others, the results are disappointing. We have cancelled some projects because it was clear they were not going to meet their goals. That is to be expected. These clinical trials are experiments that are testing, often for the first time ever in people, a whole new way of treating disease. Failure comes with the territory.

As the number of projects moving out of the lab and into clinical trials increases so too are the other signs of progress in RM. We recently held a workshop bringing together researchers and regulators from all over the world to explore the biggest problems in manufacturing, including how you go from making a small batch of stem cells for a few patients in an early phase clinical trial to mass producing them for thousands, if not millions of patients. We are also working with the National Institutes of Health and other stakeholders in discussing the idea of reimbursement, figuring out who pays for these therapies so they are available to the patients who need them.

And as the field advances so too do the issues we have to deal with. The discovery of the gene-editing tool CRISPR has opened up all sorts of possible new ways of developing treatments for deadly diseases. But it has also opened up a Pandora’s box of ethical issues that the field as a whole is working hard to respond to.

These are clear signs of a maturing field. Five years ago, we dreamed of having these kinds of conversations. Now they are a regular feature of any RM conference.

The simple fact that we can pose a question asking if RM has come of age is a sign all by itself that we are on the way.

Like little kids sitting in the back of a car, anxious to get to their destination, we are asking “Are we there yet?” And as every parent in the front seat of their car responds, “Not yet. But soon.”

Treatments, cures and clinical trials: an in-person update on CIRM’s progress

Patients and Patient Advocates are at the heart of everything we do at CIRM. That’s why we are holding three free public events in the next few months focused on updating you on the stem cell research we are funding, and our plans for the future.

Right now we have 33 projects that we have funded in clinical trials. Those range from heart disease and stroke, to cancer, diabetes, ALS (Lou Gehrig’s disease), two different forms of vision loss, spinal cord injury and HIV/AIDS. We have also helped cure dozens of children battling deadly immune disorders. But as far as we are concerned we are only just getting started.

Over the course of the next few years, we have a goal of adding dozens more clinical trials to that list, and creating a pipeline of promising therapies for a wide range of diseases and disorders.

That’s why we are holding these free public events – something we try and do every year. We want to let you know what we are doing, what we are funding, how that research is progressing, and to get your thoughts on how we can improve, what else we can do to help meet the needs of the Patient Advocate community. Your voice is important in helping shape everything we do.

The first event is at the Gladstone Institutes in San Francisco on Wednesday, September 6th from noon till 1pm. The doors open at 11am for registration and a light lunch.

Gladstone Institutes

Here’s a link to an Eventbrite page that has all the information about the event, including how you can RSVP to let us know you are coming.

We are fortunate to be joined by two great scientists, and speakers – as well as being CIRM grantees-  from the Gladstone Institutes, Dr. Deepak Srivastava and Dr. Steve Finkbeiner.

Dr. Srivastava is working on regenerating heart muscle after it has been damaged. This research could not only help people recover from a heart attack, but the same principles might also enable us to regenerate other organs damaged by disease. Dr. Finkbeiner is a pioneer in diseases of the brain and has done ground breaking work in both Alzheimer’s and Huntington’s disease.

We have two other free public events coming up in October. The first is at UC Davis in Sacramento on October 10th (noon till 1pm) and the second at Cedars-Sinai in Los Angeles on October 30th (noon till 1pm). We will have more details on these events in the coming weeks.

We look forward to seeing you at one of these events and please feel free to share this information with anyone you think might be interested in attending.

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

 

 

Trash talking and creating a stem cell community

imilce2

Imilce Rodriguez-Fernandez likes to talk trash. No, really, she does. In her case it’s cellular trash, the kind that builds up in our cells and has to be removed to ensure the cells don’t become sick.

Imilce was one of several stem cell researchers who took part in a couple of public events over the weekend, on either side of San Francisco Bay, that served to span both a geographical and generational divide and create a common sense of community.

The first event was at the Buck Institute for Research on Aging in Marin County, near San Francisco. It was titled “Stem Cell Celebration” and that’s pretty much what it was. It featured some extraordinary young scientists from the Buck talking about the work they are doing in uncovering some of the connections between aging and chronic diseases, and coming up with solutions to stop or even reverse some of those changes.

One of those scientists was Imilce. She explained that just as it is important for people to get rid of their trash so they can have a clean, healthy home, so it is important for our cells to do the same. Cells that fail to get rid of their protein trash become sick, unhealthy and ultimately stop working.

Imilce is exploring the cellular janitorial services our bodies have developed to deal with trash, and trying to find ways to enhance them so they are more effective, particularly as we age and those janitorial services aren’t as efficient as they were in our youth.

Unlocking the secrets of premature aging

Chris Wiley, another postdoctoral researcher at the Buck, showed that some medications that are used to treat HIV may be life-saving on one level, preventing the onset of full-blown AIDS, but that those benefits come with a cost, namely premature aging. Chris said the impact of aging doesn’t just affect one cell or one part of the body, but ripples out affecting other cells and other parts of the body. By studying the impact those medications have on our bodies he’s hoping to find ways to maintain the benefits of those drugs, but get rid of the downside.

Creating a Community

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Across the Bay, the U.C. Berkeley Student Society for Stem Cell Research held it’s 4th annual conference and the theme was “Culturing a Stem Cell Community.”

The list of speakers was a Who’s Who of CIRM-funded scientists from U.C. Davis’ Jan Nolta and Paul Knoepfler, to U.C. Irvine’s Henry Klassen and U.C. Berkeley’s David Schaffer. The talks ranged from progress in fighting blindness, to how advances in stem cell gene editing are cause for celebration, and concern.

What struck me most about both meetings was the age divide. At the Buck those presenting were young scientists, millennials; the audience was considerably older, baby boomers. At UC Berkeley it was the reverse; the presenters were experienced scientists of the baby boom generation, and the audience were keen young students representing the next generation of scientists.

Bridging the divide

But regardless of the age differences there was a shared sense of involvement, a feeling that regardless of which side of the audience we are on we all have something in common, we are all part of the stem cell community.

All communities have a story, something that helps bind them together and gives them a sense of common purpose. For the stem cell community there is not one single story, there are many. But while those stories all start from a different place, they end up with a common theme; inspiration, determination and hope.

 

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.”

Gene editing in blood stem cells just got easier

Genome editing is a field of science that’s been around for awhile, but has experienced an explosion of activity and interest in recent years. Chances are that even your grandmother has heard about the recent story where for the first time, gene editing saved a one-year-old girl from dying of leukemia.

Microsoft word versus genome editing

To give you an idea of what this technique involves, think back to the last time you had to write a report. You let all your ideas flow out onto the page, but then realize that certain sentences or paragraphs need to be rearranged, removed, or added. So you copy, paste, and move stuff around with your mouse and keyboard until you’re satisfied.

Image source: Broad Institute

Image source: Broad Institute

Tools for editing the genome (which contain all of our genes) work a similar way, but they cut and paste DNA sequences in the human genome instead of words on a page. Scientists have figured out how to use these “genetic scissors” to delete genes (so they no longer have function) and to correct disease-causing mutations (by pasting in the normal DNA sequence of a gene to restore function). Both these abilities make genome editing a highly valuable tool for scientists to model diseases and to develop therapies to treat them.

There are multiple tools that researchers are currently using to modify the human genome. The main ones are fancifully named ZFNs, TALENs, and CRISPRs. All three use engineered proteins called nucleases to cut strands of DNA at specific locations in the genome. A cell’s DNA repair machinery will then either glue the DNA strands back together (this typically results in the loss of DNA and gene function), or repair the break by copying and pasting in the missing sequence of DNA from a template (you can correct disease-causing mutations this way by providing a donor template). We don’t have time to get into more details about how these tools work, but you can learn more by reading this fact sheet from Science Media Centre.

Some cells are more stubborn than others

While genome editing technologies offer many advantages for modifying human genes, it’s not a perfect science. There are still many limitations and roadblocks that need to be addressed to make sure that these tools can be safely and effectively used as therapies in humans.

Besides the obvious worry about “off-target effects” (when the genetic scissors cut random sections of DNA, which can cause big problems), another issue with genome editing tools is that some types of cells are harder to genetically modify than others.

Such is the case with blood stem cells, also known as hematopoietic stem and progenitor cells (HSPCs), that live in our bone marrow and make all the different blood cells in our body. Initial studies reported difficulty in delivering genome editing tools into human HSPCs, which is a problem if you want to use these tools to help cure patients suffering from genetic blood or immune diseases.

Human blood (red) and immune cells (green) are made from hematopoietic/blood stem cells. Photo credit: ZEISS Microscopy.

Human blood (red) and immune cells (green) are made from hematopoietic/blood stem cells. Photo credit: ZEISS Microscopy.

Have no fear, blood-stem cell editing is here

We are happy to inform you that a CIRM-funded study published today in Nature Biotechnology has developed a solution to the problem of hard-to-edit blood stem cells. Scientists from the USC Keck School of Medicine and from Sangamo BioSciences developed a new delivery method that allows for efficient genome editing of human HSPCs using zinc finger nucleases (ZFNs).

They used a viral delivery system to deliver ZFNs to distinct locations in the genome of HSPCs and successfully inserted a gene sequence that made the cells turn green under a fluorescent microscope. The virus they used was a harmless form of an adeno-associated virus (AAV), which can enter certain cells and delivery the researcher’s DNA cargo with a very low chance of altering or inserting its own DNA into the HSPC genome.

Using an AAV that was exceptionally good at entering HPSCs, they virally delivered ZFNs to specific gene locations in HSPCs that had been isolated from human blood and from fetal liver tissue. They found that delivering the ZFNs as mRNA molecules allowed the protein versions they turned into to be temporarily expressed in HSPCs. This produced a high rate of gene insertion (ranging from 15-40% of cells treated), while keeping off-target effects and cell death low. Even the most hard-to-edit HSPCs, called the primitive HSPCs, were modified. This result was really exciting because no other study has reported gene editing with this level of efficiency in this primitive population of blood stem cells.

The tools work but what about the cells?

After proving that they were able to successfully edit the genomes of HSPCs with high efficiency, they next asked whether the modified cells could grow in culture and create new blood cells when transplanted into mice.

While their method to deliver ZFNs into the HSPCs did cause some of the cells to die (around 20%), the majority that survived were able to multiply in a dish and specialize into various blood cells when grown in cultures. When the modified HSPCs were taken a step further and transplanted into immune-deficient mice (meaning their immune system is compromised and won’t attack transplanted cells), they not only survived, but they also specialized into many different types of blood cells while still retaining their genomic modifications.

Now here is where I want to give the researchers a high five. They decided that once wasn’t enough, and challenged their modified HSPCs to a second round of transplantation. They collected the bone marrow from mice that received the first transplant of modified HSPCs, and transferred it into another immune-deficient mouse. Five months later, they found that the modified cells were still there and had generated other blood cell types. Because these modified HSPCs lasted for so long and through two rounds of transplants, the authors concluded that they had successfully edited the primitive, long-term repopulating HSPCs.

Next stop, the clinic?

In summary, this study offers a new and improved method to genetically modify blood stem cells in all their forms.

So what’s next? The obvious hope is the clinic.

HIV (yellow) infecting a human immune cell. CREDIT: SETH PINCUS, ELIZABETH FISCHER AND AUSTIN ATHMAN, NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES, NATIONAL INSTITUTES OF HEALTH

HIV (yellow) infecting a human immune cell. Photo credit: Seth Pincus, Elizabeth Fischer and Austin Athman, NIH.

It’s a likely future as the study was conducted in collaboration with Sangamo BioSciences. They specialize in ZFN-mediated gene therapy and have a number of preclinical therapeutic programs, many of which focus on genetic diseases that affect the blood and immune system, as well as ongoing clinical trials using ZFNs to treat patients with HIV/AIDs. (One of these trials is funded by CIRM, read more here).

In a USC press release, Dr. Michael Holmes, VP of Research at Sangamo and co-senior author on the paper hinted at future clinical applications:

Michael Holmes, Sangamo BioSciences

Michael Holmes, Sangamo BioSciences

 

Our results provide a strategy for broadening the application of gene editing technologies in HSPCs. This significantly advances our progress towards applying gene editing to the treatment of human diseases of the blood and immune systems.

 

 

Co-senior author and USC Professor Dr. Paula Cannon echoed Dr. Holmes:

Gene therapy using HSPCs has enormous potential for treating HIV and other diseases of the blood and immune systems.

One last question

A question that I had after reading this exciting study was whether other genome editing tools such as CRISPR could produce better results in blood stem cells using a similar viral delivery method.

CRISPR is described as a faster, cheaper, and easier gene editing technology compared to ZFNs and TALENS (for a comparison, check out this fun article by The Jackson Laboratory). And many scientists, both in academia and industry, are pushing CRISPR gene editing towards clinical applications.

When I asked Paula Cannon about which gene editing technology, ZFNs or CRISPRs, is better for therapeutic development, she said:

Paula Cannon, USC Professor

Paula Cannon, USC Professor

In terms of advantages, CRISPRs are easier to work with initially, and this makes them a great lab research tool. But when it comes to developing something for a clinical trial, its much more of a long game, so that initial advantage disappears. The ZFNs I work with have been previously optimized and are well characterized, and the CCR5 ZFNs are already in the clinic so they have a big advantage in that regard when you are trying to develop something for the next clinical application.


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Calling for a cure for HIV/AIDS

Larry Kramer - Photo by David Shankbone

Larry Kramer – Photo by David Shankbone

Larry Kramer is a pivotal figure in the history of HIV/AIDS. His activism on many fronts has been widely credited with changing public health policy and speeding up access to experimental medications for people infected with the virus. So when he says that the fight for treatment is not enough but “The battle cry now must be one word — cure, cure, cure!” People pay attention.

A few years ago it might have been considered dangerously optimistic to use the word “cure” in any conversation about HIV/AIDS, but that’s no longer the case. In fact cure is something that is becoming not just a wildly ambitious dream, but something that scientists are working hard to achieve right now.

On Tuesday, October 6th, we are going to hold an HIV/AIDS Cure Town Hall meeting in Palm Springs. This will be the third event we’ve held and the previous two, in San Francisco and Los Angeles, were hugely successful. It’s not hard to understand why. Our experts are going to be talking about their work in trying to eradicate the AIDS virus from people infected with it.

This includes clinical trials run by Calimmune and City of Hope/Sangamo, plus some truly cutting edge research by Dr. Paula Cannon of the University of Southern California.

The clinical trials are both taking similar, if slightly different, approaches to reach the same goal; functionally curing people with HIV. They take the patient’s own blood stem cells and genetically modify them so that the AIDS virus is no longer able to infect them. They also help boost the patient’s T cells, a key part of a healthy immune system and the virus’ main target, so that they can fight back against the virus. It’s a kind of one-two punch to block and eventually evict the virus.

Timothy Brown; photo courtesy CureAIDSreport.org

Timothy Brown; photo courtesy CureAIDSreport.org

This work is based on the real-life experiences of Timothy Ray Brown, the “Berlin Patient”. He became the first person ever cured of HIV/AIDS when he got a bone marrow transplant from a person with a natural resistance to HIV. This created a new blood supply and a new immune system both of which were resistant to HIV.

Timothy is going to be joining us at the event in Palm Springs to share his story and show that cure is not just a word it’s a goal; one that we can now think of as being possible.

The HIV/AIDS Cure Town Hall event will be held on Tuesday, October 6th in the Sinatra Auditorium at the Desert Regional Medical Center in Palm Springs. Doors open at 6pm and the program starts at 6.30pm. And of course, it’s free.

The search for a cure: how stem cells could eradicate the AIDS virus

It’s hard to overstate just how devastating the AIDS crisis was at its peak in the U.S. – and still is today in many parts of the world. In 1995 almost 51,000 Americans died from the disease, the numbers of new cases were at almost record highs, and there were few effective therapies against the virus.

HIV/AIDS medications

HIV/AIDS medications

Today that picture is very different. New medications and combination therapies have helped reduce the death rate, in some cases turning HIV into a chronic rather than fatal condition. But even now there is no cure.

That’s why the news that the Food and Drug Administration (FDA) has approved a clinical trial, that we are funding, aimed at eradicating HIV in the body, was so welcome. This could be an important step towards the Holy Grail of AIDS therapies, curing the disease.

The project is headed by Dr. John Zaia at City of Hope near Los Angeles. The team, with researchers from Keck Medicine of the University of Southern California (USC) and Sangamo BioSciences, plans on using an individual’s own stem cells to beat the virus.  They will remove some blood stem cells from HIV-infected individuals, then treat them with zinc finger nucleases (ZFNs), a kind of molecular scissors, snipping off a protein the AIDS virus needs to infect those cells.

It’s hoped the re-engineered stem cells, when returned to the body, will help create a new blood and immune system that is resistant to the virus. And if the virus can’t infect any new immune cells it could, theoretically, die off. Check out the video we produced a few years back about the project:

Studies in the lab show this approach holds a lot of promise. In a news release announcing the start of the clinical trial, Dr. Zaia said now it’s time to see if it will work in people:

“While we have a number of drugs that are effective in holding HIV at bay, we have nothing that cures it. In addition, for many patients, these medications come with significant long-term problems so there is a real need for a therapy that can help eradicate the virus from a patient completely. That is where our work is focused.”

Like all Phase 1 trials this one is focused on making sure this approach is safe for people, and identifying what, if any, side-effects there are from the treatment. The first group of patients to be treated consists of people with HIV/AIDS who have not responded well to the existing medications.

This is the second trial that CIRM is funding focused on curing HIV/AIDS. Our first, involving the company Calimmune, began its human clinical trial in July 2013. You can read more about that work here.

We know that the road to a cure will not be simple or straightforward. There have been too many false claims of cures or miracle therapies over the years for any of us to want to fall victim to hope and hype. It may even be that the most realistic goal for these approaches is what is called a “functional cure”, one that doesn’t eliminate the virus completely but does eliminate the need to take antiretroviral pills every day.

But when compared to the dark days of 1995, a functional cure is a world away from certain death.

Searching for a Cure for HIV/AIDS: Stem Cells and World AIDS Day

World-AIDS-Day

It’s been 26 years since the first World AIDS Day was held in 1988—and the progress that the international scientific community has made towards eradicating the disease has been unparalleled. But there is much more work to be done.

One of the most promising areas of HIV/AIDS research has been in the field of regenerative medicine. As you observe World AIDS Day today, we invite you to take a look at some recent advances from CIRM-funded scientists and programs that are well on their way to finding ways to slow, halt and prevent the spread of HIV/AIDS:

Calimmune’s stem cell gene modification study continues to enroll patients, show promise:
Calimmune Approved to Treat Second Group in HIV Stem Cell Gene Modification Study

Is a cure for HIV/AIDS possible? Last year’s public forum discusses the latest on HIV cure research:


Town Hall: HIV Cure Research

The Stem Cell Agency’s HIV/AIDS Fact Sheet summarizes the latest advances in regenerative medicine to slow the spread of the disease.

And for more on World AIDS Day, follow #WorldAIDSDay on Twitter and visit WorldAIDSDay.org.