CIRM supported study of gene silencer blocks ALS degeneration, saves motor function

Dr. Martin Marsala, UC San Diego

Amyotrophic Lateral Sclerosis (ALS), also known as Lou Gehrig’s disease, is a neurodegenerative disease that destroys the nerve cells in the brain and spinal cord. As a result of ALS, the motor neurons that enable bodily movement and muscle control are harmed, which can make it difficult to move, speak, eat, and breathe. This condition usually affects people from age 40 to 70, but individuals in their 20s and 30s have also been known to develop ALS. Unfortunately there is no cure for this condition.

However, a study supported by CIRM and conducted by Dr. Martin Marsala at UC San Diego is using a mouse model to look at an approach that uses a gene silencer to protect motor neurons before or shortly after ALS symptoms start to develop.

The gene silencer works by turning off a targeted gene and is delivered via injection. In the case of ALS, previous research suggests that mutations in a gene called SOD1 may cause motor neuronal cell death, resulting in ALS. For this study, Dr. Marsala and his team injected the gene silencer at two sites in the spinal cord in adult mice expressing an ALS-causing mutation of the SOD1 gene. The mice injected did not yet display symptoms of ALS or had only begun showing symptoms.

In mice not yet showing ALS symptoms, they displayed normal neurological function with no onset ALS symptoms after treatment. Additionally, near complete protection of motor neurons and other cells was observed. In mice that had just began showing ALS symptoms, the injection blocked further disease progression as well as further harm to remaining motor neurons. Both of these groups of mice lived without negative side effects for the duration of the study.

In a news release, Dr. Marsala talks about what these results mean for the study of ALS.

“At present, this therapeutic approach provides the most potent therapy ever demonstrated in mouse models of mutated SOD1 gene-linked ALS.”

The next steps for this research would be to conduct additional safety studies with a larger animal model in order to determine an optimal, safe dose for the treatment.

The full results of this study were published in Nature Medicine.

In addition to supporting this research for ALS, CIRM has funded two clinical trials in the field as well. One of these trials is being conducted by BrainStorm Cell Therapeutics and the other trial is being by Cedars-Sinai Medical Center.

One family’s fight to save their son’s life, and how stem cells made it possible

CIRM’s mission is very simple: to accelerate stem cell treatments to patients with unmet medical needs. Anne Klein’s son, Everett, was a poster boy for that statement. Born with a fatal immune disorder Everett faced a bleak future. But Anne and husband Brian were not about to give up. The following story is one Anne wrote for Parents magazine. It’s testament to the power of stem cells to save lives, but even more importantly to the power of love and the determination of a family to save their son.

My Son Was Born With ‘Bubble Boy’ Disease—But A Gene Therapy Trial Saved His Life

Everett Schmitt. Photo: Meg Kumin

I wish more than anything that my son Everett had not been born with severe combined immunodeficiency (SCID). But I know he is actually one of the lucky unlucky ones. By Anne Klein

As a child in the ’80s, I watched a news story about David Vetter. David was known as “the boy in the bubble” because he was born with severe combined immunodeficiency (SCID), a rare genetic disease that leaves babies with very little or no immune system. To protect him, David lived his entire life in a plastic bubble that kept him separated from a world filled with germs and illnesses that would have taken his life—likely before his first birthday.

I was struck by David’s story. It was heartbreaking and seemed so otherworldly. What would it be like to spend your childhood in an isolation chamber with family, doctors, reporters, and the world looking in on you? I found it devastating that an experimental bone marrow transplant didn’t end up saving his life; instead it led to fatal complications. His mother, Carol Ann Demaret, touched his bare hand for the first and last time when he was 12 years old.

I couldn’t have known that almost 30 years later, my own son, Everett, would be born with SCID too.

Everett’s SCID diagnosis

At birth, Everett was big, beautiful, and looked perfectly healthy. My husband Brian and I already had a 2-and-a-half-year-old son, Alden, so we were less anxious as parents when we brought Everett home. I didn’t run errands with Alden until he was at least a month old, but Everett was out and about with us within a few days of being born. After all, we thought we knew what to expect.

But two weeks after Everett’s birth, a doctor called to discuss Everett’s newborn screening test results. I listened in disbelief as he explained that Everett’s blood sample indicated he may have an immune deficiency.

“He may need a bone marrow transplant,” the doctor told me.

I was shocked. Everett’s checkup with his pediatrician just two days earlier went swimmingly. I hung up and held on to the doctor’s assurance that there was a 40 percent chance Everett’s test result was a false positive.

After five grueling days of waiting for additional test results and answers, I received the call: Everett had virtually no immune system. He needed to be quickly admitted to UCSF Benioff Children’s Hospital in California so they could keep him isolated and prepare to give him a stem cell transplant. UCSF diagnosed him specifically with SCID-X1, the same form David battled.

Beginning SCID treatment

The hospital was 90 miles and more than two hours away from home. Our family of four had to be split into two, with me staying in the hospital primarily with Everett and Brian and Alden remaining at home, except for short visits. The sudden upheaval left Alden confused, shaken, and sad. Brian and I quickly transformed into helicopter parents, neurotically focused on every imaginable contact with germs, even the mildest of which could be life-threatening to Everett.

When he was 7 weeks old, Everett received a stem cell transplant with me as his donor, but the transplant failed because my immune cells began attacking his body. Over his short life, Everett has also spent more than six months collectively in the hospital and more than three years in semi-isolation at home. He’s endured countless biopsies, ultrasounds, CT scans, infusions, blood draws, trips to the emergency department, and medical transports via ambulance or helicopter.

Gene therapy to treat SCID

At age 2, his liver almost failed and a case of pneumonia required breathing support with sedation. That’s when a doctor came into the pediatric intensive care unit and said, “When Everett gets through this, we need to do something else for him.” He recommended a gene therapy clinical trial at the National Institutes of Health (NIH) that was finally showing success in patients over age 2 whose transplants had failed. This was the first group of SCID-X1 patients to receive gene therapy using a lentiviral vector combined with a light dose of chemotherapy.

After the complications from our son’s initial stem cell transplant, Brian and I didn’t want to do another stem cell transplant using donor cells. My donor cells were at war with his body and cells from another donor could do the same. Also, the odds of Everett having a suitable donor on the bone marrow registry were extremely small since he didn’t have one as a newborn. At the NIH, he would receive a transplant with his own, perfectly matched, gene-corrected cells. They would be right at home.

Other treatment options would likely only partially restore his immunity and require him to receive infusions of donor antibodies for life, as was the case with his first transplant. Prior gene therapy trials produced similarly incomplete results and several participants developed leukemia. The NIH trial was the first one showing promise in fully restoring immunity, without a risk of cancer. Brian and I felt it was Everett’s best option. Without hesitation, we flew across the country for his treatment. Everett received the gene therapy in September 2016 when he was 3, becoming the youngest patient NIH’s clinical trial has treated.

Everett’s recovery

It’s been more than two years since Everett received gene therapy and now more than ever, he has the best hope of developing a fully functioning immune system. He just received his first vaccine to test his ability to mount a response. Now 6 years old, he’s completed kindergarten and has been to Disney World. He plays in the dirt and loves shows and movies from the ’80s (maybe some of the same ones David enjoyed).

Everett knows he has been through a lot and that his doctors “fixed his DNA,” but he’s focused largely on other things. He’s vocal when confronted with medical pain or trauma, but seems to block out the experiences shortly afterwards. It’s sad for Brian and me that Everett developed these coping skills at such a young age, but we’re so grateful he is otherwise expressive and enjoys engaging with others. Once in the middle of the night, he woke us up as he stood in the hallway, exclaiming, “I’m going back to bed, but I just want you to know that I love you with all my heart!”

I wish more than anything that Everett had not been born with such a terrible disease and I could erase all the trauma, isolation, and pain. But I know that he is actually one of the lucky unlucky ones. Everett is fortunate his disease was caught early by SCID newborn screening, which became available in California not long before his birth. Without this test, we would not have known he had SCID until he became dangerously ill. His prognosis would have been much worse, even under the care of his truly brilliant and remarkable doctors, some of whom cared for David decades earlier.

Everett Schmitt meeting David Vetter’s mom Carol Ann Demaret. Photo – Brian Schmitt

When Everett was 4, soon after the gene therapy gave him the immunity he desperately needed, our family was fortunate enough to cross paths with David’s mom, Carol Ann, at an Immune Deficiency Foundation event. Throughout my life, I had seen her in pictures and on television with David. In person, she was warm, gracious, and humble. When I introduced her to Everett and explained that he had SCID just like David, she looked at Everett with loving eyes and asked if she could touch him. As she touched Everett’s shoulder and they locked eyes, Brian and I looked on with profound gratitude.

Anne Klein is a parent, scientist, and a patient advocate for two gene therapy trials funded by the California Institute for Regenerative Medicine. She is passionate about helping parents of children with SCID navigate treatment options for their child.

You can read about the clinical trials we are funding for SCID here, here, here and here.

CIRM-funded therapy helps “bubble babies” lead a normal life

Ja’Ceon Golden; ‘cured” of SCID

At CIRM we are very cautious about using the “c” word. Saying someone has been “cured” is a powerful statement but one that loses its meaning when over used or used inappropriately. However, in the case of a new study from U.C. San Francisco and St. Jude Children’s Research Hospital in Memphis, saying “cure” is not just accurate, it’s a celebration of something that would have seemed impossible just a few years ago.

The research focuses on children with a specific form of Severe Combined Immunodeficiency (SCID) called X-Linked SCID. It’s also known as “bubble baby” disease because children born with this condition lack a functioning immune system, so even a simple infection could be fatal and in the past they were kept inside sterile plastic bubbles to protect them.

In this study, published in the New England Journal of Medicine, researchers took blood stem cells from the child and, in the lab, genetically re-engineered them to correct the defective gene, and then infused them back into the child. Over time they multiplied and created a new blood supply, one free of the defect, which helped repair the immune system.

In a news release Dr. Ewelina Mamcarz, the lead author of the study, announced that ten children have been treated with this method.

“These patients are toddlers now, who are responding to vaccinations and have immune systems to make all immune cells they need for protection from infections as they explore the world and live normal lives. This is a first for patients with SCID-X1.”

The ten children were treated at both St. Jude and at UCSF and CIRM funded the UCSF arm of the clinical trial.

The story, not surprisingly, got a lot of attention in the media including this fine piece by CNN.

Oh, and by the way we are also funding three other clinical trials targeting different forms of SCID. One with UCLA’s Don Kohn,  one with Stanford’s Judy Shizuru, and one with UCSF’s Mort Cowan

Gene therapy gives patient a cure and a new lease on life

Brenden Whittaker (left), of Ohio, is a patient born with a rare genetic immune disease who was treated at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center in a CIRM funded gene therapy trial. Dr. David Williams (on right) is Brenden’s treating physician.
Photo courtesy of Rose Lincoln – Harvard Staff Photographer

Pursuing an education can be quite the challenge in itself without the added pressure of external factors. For Brenden Whittaker, a 25 year old from Ohio, the constant trips to the hospital and debilitating nature of an inherited genetic disease made this goal particularly challenging and, for most of his life, out of sight.

Brenden was born with chronic granulomatous disease (CGD), a rare genetic disorder that affects the proper function of neutrophils, a type of white blood cell that is an essential part of the body’s immune system. This leads to recurring bacterial and fungal infections and the formation of granulomas, which are clumps of infected tissue that arise as the body attempts to isolate infections it cannot combat. People with CGD are often hospitalized routinely and the granulomas themselves can obstruct digestive pathways and other pathways in the body. Antibiotics are used in an attempt to prevent infections from occurring, but eventually patients stop responding to them. One in two people with CGD do not live past the age of 40.

In Brenden’s case, when the antibiotics he relied on started failing, the doctors had to resort to surgery to cut out an infected lobe of his liver and half his right lung. Although the surgery was successful, it would only be a matter of time before a vital organ was infected and surgery would no longer be an option.

This ultimately lead to Brenden becoming the first patient in a CGD gene therapy trial at the Dana-Farber/Boston Children’s Cancer and Blood Disorders Center.  The trial, lead by UCLA’s Dr. Don Kohn thanks to a CIRM grant, combats the disease by correcting the dysfunctional gene inside a patient’s blood stem cells. The patient’s corrected blood stem cells are then reintroduced, allowing the body to produce properly functioning neutrophils, rebooting the immune system.

It’s been a little over three years since Brenden received this treatment in late 2015, and the results have been remarkable. Dr. David Williams, Brenden’s treating physician, expected Brenden’s body to produce at least 10 percent of the functional neutrophils, enough so that Brenden’s immune system would provide protection similar to somebody without CGD. The results were over 50 percent, greatly exceeding expectations.

Brenden Whittaker mowing the lawn in the backyard of his home in Columbus, Ohio. He is able to do many more things without the fear of infection since participating in the trial. Photo courtesy of Colin McGuire

In an article published by The Harvard Gazette, Becky Whittaker, Brendan’s mother, is quoted as saying, ““Each day that he’s free of infection, he’s able to go to class, he’s able to work at his part-time job, he’s able to mess around playing with the dog or hanging out with friends…[this] is a day I truly don’t believe he would have had beyond 2015 had something not been done.”

In addition to the changes to his immune system, the gene therapy has reinvigorated Brenden’s drive for the future. Living with CGD had caused Brenden to miss out on much of his schooling throughout the years, having to take constant pauses from his academics at a community college. Now, Brenden aims to graduate with an associate’s degree in health sciences in the spring and transfer to Ohio State in the fall for a bachelor’s degree program. In addition to this, Brenden now has dreams of attending medical school.

In The Harvard Gazette article, Brenden elaborates on why he wants to go to medical school saying, ” Just being the patient for so long, I want to give back. There are so many people who’ve been there for me — doctors, nurses who’ve been there for me [and] helped me for so long.”

In a press release dated February 25, 2019, Orchard Therapeutics, a biopharmaceutical company that is continuing the aforementioned approach for CGD, announced that six patients treated have shown adequate neutrophil function 12 months post treatment. Furthermore, these six patients no longer receive antibiotics related to CGD. Orchard Therapeutics also announced that they are in the process of designing a registrational trial for CGD.

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

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


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

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

Multiple Shots on Goal

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

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

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

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

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

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

Boosting the Immune System

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

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

Missed Opportunities

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

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

Charting a New Course

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

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

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

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

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

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

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

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

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

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

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

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

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

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

For more information:

Richard Jefferys

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

Nelson Vergel, Program for Wellness Restoration



Genes+Cells: Stem cells deliver genes to make T cells resistant to HIV

This summer the first patients will be enrolled in a clinical trial using a form of genetic scissors to alter the DNA in their stem cells to give their immune systems a desired trait—resistance to HIV. The procedure will alter the patients’ blood-forming stem cells so that they can permanently make immune system T cells that HIV cannot infect. For the lead researcher on the team at City of Hope in Duarte, California, this trial caps some 25 years of effort to use genetic manipulation to halt the insidious virus.

That researcher, John Zaia, first began using gene therapy techniques to help patients resist the virus in the early 1990s, but the

John Zaia

John Zaia

first techniques were not very efficient in making the needed genetic alterations. Then the death of a test patient in a trial for another disease put the entire field on hold for many years. But the logic of making people genetically resistant to HIV was so compelling Zaia periodically tried new techniques and has reason to believe he is working with one now that can get the job done.

The molecular scissors, technically called zinc finger nucleases, can very precisely splice open a persons DNA and inactivate specific genes. For patients with HIV they target the gene for CCR5, which is a protein on the surface of T cells that HIV needs to use like a lock and key to get into the cells. If it cannot get in, it cannot infect. The scissor has been developed by a company in Richmond, California, Sangamo Biosciences, and researchers working with the company have already reported results showing the process works in adult T cells. Zaia’s team hopes to take those positive results to the next level by altering the blood-forming stem cells, which should be able to supply a much larger and permanent supply of HIV-resistant T cells.

With the great success of antiretroviral therapy, many question the need for intervention at this level. Not HIV advocate Mathew Sharp. Read about his journey with HIV and why he became a subject of that early zinc finger trial in adult T cells, saw improvement and holds out hope for even better therapies in the future.

Zaia’s trial is one of four CIRM-funded projects in or near clinical trials that seek to use genetic manipulation to give a person’s immune cells a desired trait. Two seek to confer resistance to HIV and two seek to make the cells better at fighting cancer.

The Clinical Trial

To be in the trial, patients must:
Have no detectable virus on viral therapy
Have CD4 cell counts between 200 and 500
Not positive for virus that does not require CCR5 for entry
Have no CCR5 mutations already in their cells

Enrollment centers
Two in Los Angeles, one in Connecticut, one in San Francisco

Treatment location
All patients will be treated at the CIRM Alpha Stem Cell Clinic at City of Hope (link) and will require a 28-day stay at or near the clinic.

Zaia expects to complete the 12-patient enrollment in about a year and he hopes that in the following months he will be able to report that the genetic manipulation worked and a significant portion of the blood forming stem cells have the altered gene and can pass it on to the T cells they make. Even though this will be a huge milestone, providing proof in principal that the therapy may work, he is already thinking about ways to make the process more efficient and less time consuming. The current process would be difficult to rollout to large-scale therapy. But he says “it is doable” to make an approach that could be widely available.

In this video HIV advocate and CIRM board member Jeff Sheehy looked forward to the launch of this trial when CIRM began the preclinical part of the project five years ago.

In this video HIV advocate and CIRM board member Jeff Sheehy looked forward to the launch of this trial when CIRM began the preclinical part of the project five years ago.

CIRM recently funded Paula Cannon at the University of Southern California—who worked with Zaia in the lead-up to this first trial—to develop a next generation of the gene editing process. She hopes to find a way to use the molecular scissors directly in patients rather than having to harvest their stem cells from their bone marrow, alter them in the lab and then infuse them back into the patient. Each of those steps causes inefficiency and the loss of cells and Zaia hopes that the possibility of doing the genetic manipulation directly in patients might be the ultimate way to go.

[Always wanting to take multiple shots on goal when we are dealing with a disease like HIV, CIRM funds a team at Calimmune also aimed at conferring immunity against HIV. The Calimmune therapy targets both the production of the CCR5 that the virus needs to enter cells and a viral fusion step. This dual approach has been shown to be effective against broad strains of HIV in pre-clinical studies. The company began a clinical trial in June 2013 and hopes to report results in 2016.]

One patient’s quest for something better

Antiretroviral therapy does a great job knocking down HIV in the body, look where it has gotten us! However, it’s not perfect and is not globally accessible with large segments of patients even in developed countries like the U.S. not receiving adequate therapy.

Mathew Sharp, right, with Timothy Brown, the "Berlin Patient" whose stem cell transplant for leukemia proved a gene variant on the surface of T cells could effectively cure HIV.

Mathew Sharp, right, with Timothy Brown, the “Berlin Patient” whose stem cell transplant for leukemia proved a gene variant on the surface of T cells could effectively cure HIV.

I have been a big proponent of antiretroviral therapy, even though it took me 15 years to finally construct a regimen that got me to undetectable virus levels. But the drugs never restored my T cells to normal.

After taking the drugs for so many years I have become tired of taking twice-daily dosing. I find myself missing doses. While my doctor and I are trying to construct a once-a-day regimen, it may become impossible for me with my particular viral strains.

I enrolled in a gene therapy trial for people who were stable on therapy but had never achieved higher T cells counts. After one infusion of a new technology called zinc-finger nuclease developed by Sangamo, I was able to double my T cells and they have remained that way for five years. But that therapy targeted adult T cells, not the stem cells of the current trial and as a result I have had to remain on antiviral therapy.

My outcome is great but with current research the hope is that scientists can even cure HIV so that no virus remains in the body and patients can stop antiviral meds. I remain hopeful that someday I will no longer have to be reminded that I have AIDS with my twice-daily dose, and be cured.

People with HIV deserve a cure. Despite effective antiretroviral therapy we live with a “persistent” virus that continues to affect our immune systems and may affect the aging process, significantly reducing life spans.

I am 58 years old and I worry that despite my current good health, complications related to viral persistence that are today killing people with HIV, may very well be my demise.

Mathew Sharp

Genes + Cells: Stem Cells deliver genes as “drugs” & hope for ALS

This month a lab animal will become the initial patient in the final steps in Clive Svendsen’s 15-year quest to provide the first meaningful therapy for people with ALS, also known as Lou Gehrig’s disease. If that animal and subsequent ones in this required study have good results—no side effects from the treatment—Svendsen plans to take that data to the Food and Drug Administration in November to seek approval to begin a human clinical trial.

Clive Svendsen has been on a 15-year quest to develop an ALS therapy

Clive Svendsen has been on a 15-year quest to develop an ALS therapy

A native of England, Svendsen first started trying to merge gene therapy and stem cell therapy at Cambridge working with Parkinson’s disease. But after moving to the University of Wisconsin in 2000 and being approached by the ALS Association he switched to ALS. He has continued the work since moving to Cedars-Sinai in Los Angeles in 2010 where he receives CIRM funds to do the necessary animal tests as well as for the first human trial.

By contrast, Nanci Ryder’s voyage with ALS has only been a few short months. Since being diagnosed with the disease in August 2014 she has thrown herself into learning about it. “The only power I have ever felt over the adversity of a life threatening disease is knowledge.” She has also enlisted the help of many of the celebrity actor-clients of her public relations firm to advocate for ALS research funding, even though she knows the research may not move fast enough to help her.

A previous ALS stem cell trial shows the ups and downs faced by advocates for this stubborn fast-progressing and ultimately fatal disease. Largely conducted at the University of Michigan and Emory University that trial had provided one of the early hints of success with a potential stem cell therapy. But a subsequent larger trial did not achieve the results it was hoped it would produce.

Svendsen argues that trial has provided valuable insights, proven that you can put stem cells in the spinal cord and provides some rational as to why his team may have greater success. The Cedars team uses a different type of cell and boosts those cells’ performance with an added copy of a gene that makes a protein known to protect the type of nerves destroyed in ALS.

The earlier trial used cells from the spinal cord; Svendsen’s team uses cells from the brain’s cortex. In both cases the cells were recovered from discarded fetal tissue, but the cells from the cortex migrate better after transplantation and are more likely to spread out and have an impact on a greater area. Both teams transplant middleman cells that are part way down the path between stem cells and mature adult cells. But those stem/progenitor cells from the two teams mature into different adult nerve tissue. The ones from the spinal cord mostly become nerve cells called interneurons, while those from the cortex being used at Cedars all transform into astrocytes, the cells that protect nerves. Astrocytes have been shown to go bad in ALS and it is their malfunction that puts the body on a deadly path to paralysis.

In addition to potentially replacing the nerves’ valuable damaged support cells Svendsen hopes to boost the chances for therapeutic success by making the cells a drug delivery vehicle. The drug of choice: a growth factor called GDNF known to enhance the survival of many types of nerves. Both of the cell types used in ALS so far produce small quantities of GDNF, but the Cedars team wants to crank up that production.

That’s where the gene therapy comes into play. The Cedars team uses a modified lentivirus as a delivery vehicle to carry the GDNF gene into the stem cells. They have shown that half of the stem cells end up having copies of the gene and make the protective elixir. Once transplanted, the cells continue to pump out GDNF into the damaged area—helping the patient’s own neurons survive and function.

As Svendsen and his colleagues complete the last tests needed to get permission to test their one-two-punch cells in humans, they are already working on a key refinement. They would like to be able to regulate when and for how long the therapeutic gene is turned on—to actually make the protective protein on demand. This could be key if any side effects develop. Using a trick that other gene therapy experts have used, they plan to further modify the genetic manipulation so that the gene is only turned on in the presence of the antibiotic doxycycline. So, taking a pill could activate the gene.

After 15 years of intense effort, you can hear the excitement in Svendsen’s voice when he talks about the possibility of beginning a clinical trial later this year. He has all the additional processes in place and says, “we will begin recruiting patients the first week we have approval.”

[May is ALS Awareness month if you want to find out more about how you can help fight the disease visit the ALS Goldenwest chapter website]

Thrust into ALS Advocacy

A publicist for big-name stars, Nanci Ryder found herself thrust into ALS advocacy after her diagnosis last summer.

A publicist for big-name stars, Nanci Ryder found herself thrust into ALS advocacy after her diagnosis last summer.

I have always had a fascination for medicine, and thanks to the Internet, I’ve become a tireless researcher. Having already faced breast cancer a decade ago, the only power I have ever felt over the adversity of a life-threatening illness is knowledge. When I was diagnosed in August 2014 with bulbar ALS, I had to know the specifics of the disease. But more importantly, I had to know who was at the forefront fighting it.

Having spent my entire professional career providing public relations counsel to hundreds of actors and entertainers, I was no stranger to the value of their influence in bringing attention to far-ranging issues, and ALS would be no exception. I had seen what my longtime client Michael J. Fox was able to do for Parkinson’s research and I was determined to follow his example. With the support of clients past and present, Renee Zellweger, Reese Witherspoon, Emmy Rossum and many others, I immediately decided I would commit my energies to support awareness efforts that would translate into additional funding for research.

I met Clive Svendsen through the Cedar Sinai ALS program. I had read about his research in gene therapy and later toured his lab with my friend and ALS advocate, Courteney Cox. We were both very excited by the promise of his research. While there are no cures, I was admittedly daunted when I discovered I was not a candidate for any of the gene therapy clinical trials since my ALS (bulbar) began in the brain, and not in the spine as in 99% of cases.

We cannot always derive the benefits of our efforts for ourselves, but we can help others. That is my life’s path.

Nanci Ryder

Genes + Cells: Stem Cells Deliver Genetic Punch

Bad luck stalked the early years of gene therapy. The pioneering research revealed it is difficult to manipulate a patient’s genes both efficiently and safely. Today, after more than two decades of tireless labor in the lab, nearly 2,000 gene therapy trials have been conducted or are approved, with many of the most promising using stem cells to carry the genetic tricks.

CIRM is providing $110 million in funds for nine projects that have made it into the clinic—or hope to get there soon—by marrying the power of gene manipulation and stem cells. We have several other projects combing the two therapy tools in earlier stages of development.

The first gene therapy trial in the U.S. in 1990 sought to cure Severe Combined Immune Deficiency (SCID), or ‘bubble-baby disease,” and produced modest success. But it did not last. The gene-modified cells did not stick around. Much tinkering ensued to create better ways of getting the desired therapeutic gene into cells, but one of those new tools resulted in the death of a patient in a clinical trial in 1999. That death of Jesse Gelsinger led the Food and Drug Administration to suspend several ongoing clinical trials. Then the 2003 death of a SCID patient from leukemia, believed to have been caused by another gene delivery approach, further dampened the field.

But researchers who see great potential for treating unmet medical needs are not easily dissuaded. The pioneers of gene therapy studied why the deaths occurred and found gene delivery tools that would not go down those same unsafe paths. They discovered ways to get the genes expressed by cells efficiently and longterm. CIRM grantee at the University of California, Los Angeles (UCLA), Don Kohn was helping lead the charge in the early days; despite setbacks he stuck with it, and last year announced that 18 kids had been cured of SCID using stem cells modified to produce the protein missing in the disease. He has just launched a clinical trial hoping to vanquish sickle cell anemia in the same way.

CIRM clinical projects combining stem cells and gene manipulation fall into three categories:

    1. Genetic fix when someone is born with a mutated copy of a gene.
    2. Gene modification to alter stem cells to give them a desired trait.
    3. Gene insertion as drug delivery to give cells a boost of a naturally occurring protein.

Both of the CIRM genetic fix projects seek to rectify errors in the gene for hemoglobin, the protein that our red blood cells use to carry oxygen. Kohn explains his work to provide a working copy of a hemoglobin gene in sickle cell patient’s blood-forming stem cells in our “Stem Cells in Your Face” video series.

Sangamo’s clinical trial won’t be correcting the defective hemoglobin gene in Beta Thalassemia patients directly, but instead will edit the patient’s genes to turn on the gene for fetal hemoglobin that is not normally active as an adult. The company’s team has shown that this gene can produce enough of the protein to end the patients’ need for constant blood transfusions, which up until now has been the only way for them to get healthy red blood cells.

Genetically modifying stem cells to give them desired traits comes in many forms. The two HIV/AIDS projects both seek to alter patients’ blood-forming stem cells so that they produce T cells that are immune to infection by the virus. City of Hope scientists, working with Sangamo, devised a way to alter a protein on the surface of T cells, called a receptor that the virus uses like a door to gain entry into the cells. It is like taking away the key so the virus can’t get in. The Calimmune team doubled down on door security. They are altering two different receptors the virus uses for entry.

Both of the cancer projects seek to alter blood-forming stem cells so that they produce immune system cells that are better targeted to killing a patient’s specific tumor.

Gene insertion to act as a “drug” delivery system also has diverse applications. The Huntington’s disease project uses a type of stem cell found in bone marrow called a mesenchymal stem cell (MSC) to deliver a nerve growth factor that has been shown to be protective of nerves facing the type of damage seen in Huntington’s.

The ALS project starts with cells called neural progenitors, “teenaged” cells that are only part way along the path of maturity between a nerve stem cell and the final adult brain cells. Once transplanted the cells should have a two-pronged benefit. They mature specifically into astrocytes, the initial brain cell to go bad in ALS, and the added gene will produce a growth factor that has been shown to be protective of the damage seen in ALS—a different growth factor than the one used in the Huntington’s research.

In limb ischemia, poor blood circulation and severe pain results from clogged blood vessels, so therapies that stimulate growth of new vessels make sense. A growth factor called VEGF has long been known to do this, but when doctors tried injecting it into aching legs it didn’t stick around long enough to do any good. MSCs are also known to stimulate blood vessel growth and have shown some benefit when transplanted into patients with limb ischemia. If that benefit could be ratcheted up patients could gain significant pain relief. The UC Davis team hopes to transplant MSCs that have an extra copy of the VEGF gene so they stimulate vessel growth through two paths.

The marriage of gene therapy and stem cell therapy seems likely to produce a number of live-happily-ever-after therapies.