For years scientists have been touting the potential of CRISPR, a gene editing tool that allows you to target a specific mutation and either cut it out or replace it with the corrected form of the gene. But like all new tools it had its limitations. One important one was the difficult in delivering the corrected gene to mature cells in large numbers.
Scientists at the Gladstone Institutes and U.C. San Francisco say they think they have found a way around that. And the implications for using this technique to develop new therapies for deadly diseases are profound.
In the past scientists used inactivated viruses as a way to deliver corrected copies of the gene to patients. We have blogged about UCLA’s Dr. Don Kohn using this approach to treat children born with SCID, a deadly immune disorder. But that was both time consuming and expensive.
CRISPR, on the other hand, showed that it could be easier to use and less expensive. But getting it to produce enough cells for an effective therapy proved challenging.
The team at Gladstone and UCSF found a way around that by switching from using CRISPR to deliver a double-stranded DNA to correct the gene (which is toxic to cells in large quantities), and instead using CRISPR to deliver a single stranded DNA (you can read the full, very technical description of their approach in the study they published in the journal Nature Biotechnology).
Alex Marson, MD, PhD, director of the Gladstone-UCSF Institute of Genomic Immunology and the senior author of the study, said this more than doubled the efficiency of the process. “One of our goals for many years has been to put lengthy DNA instructions into a targeted site in the genome in a way that doesn’t depend on viral vectors. This is a huge step toward the next generation of safe and effective cell therapies.”
It has another advantage too, according to Gladstone’s Dr. Jonathan Esensten, an author of the study. “This technology has the potential to make new cell and gene therapies faster, better, and less expensive.”
The team has already used this method to generate more than one billion CAR-T cells – specialized immune system cells that can target cancers such as multiple myeloma – and says it could also prove effective in targeting some rare genetic immune diseases.
The news that a stem cell transplant at City of Hope helped a man with HIV go into long-term remission made banner headlines around the world. As it should. It’s a huge achievement, particularly as the 66-year-old man had been living with HIV since 1988.
First the news. In addition to living with HIV the man was diagnosed with acute leukemia. Doctors at City of Hope found a donor who was not only a perfect match to help battle the patient’s leukemia, but the donor also had a rare genetic mutation that meant they were resistant to most strains of HIV.
In transplanting blood stem cells from the donor to the patient they were able to send both his leukemia and HIV into remission. The patient stopped taking all his antiretroviral medications 17 months ago and today has no detectable levels of HIV.
“This patient had a high risk for relapsing from AML [acute myeloid leukemia], making his remission even more remarkable and highlighting how City of Hope provides excellent care treating complicated cases of AML and other blood cancers.”
It’s a remarkable achievement and is only the fifth time that a patient with both HIV and leukemia has been put into remission after a transplant from an HIV-resistant donor.
So, what does that have to do with CIRM? Well, CIRM’s Alpha Clinics Network helped City of Hope get this case approved by an Institutional Review Board (IRB) and also helped in collecting and shipping the donor blood. In addition, part of the Alpha Clinics team at University of California San Diego helped with the reservoir analysis of blood and gut biopsies to check for any remaining signs of HIV.
It’s a reminder that this kind of achievement is a team effort and CIRM is very good at creating and supporting teams. The Alpha Clinics Network is a perfect example. We created it because there was a need for a network of world-class medical facilities with the experience and expertise to deliver a whole new kind of therapy. The Network has been remarkably successful in doing that with more than 200 clinical trials, taking care of more than 1,000 patients, and treating more than 40 different diseases.
This year our Board approved expanding the number of these clinics to better serve the people of California.
While the role of the Alpha Clinics Network in helping this one patient may seem relatively small, it was also an important one. And we are certainly not stopping here. We have invested more than $79 million in 19 different projects targeting HIV/AIDS, include four clinical trials.
We are in this for the long term and results like the man who had HIV and is now in remission are a sign we are heading in the right direction.
While stem cell and gene therapy research has advanced dramatically in recent years, there are still many unknowns and many questions remaining about how best to use these approaches in developing therapies. That’s why the governing Board of the California Institute for Regenerative Medicine (CIRM) today approved investing almost $25 million in 19 projects in early stage or Discovery research.
The awards are from CIRM’s DISC2 Quest program, which supports the discovery of promising new stem cell-based and gene therapy technologies that could be translated to enable broad use and ultimately, improve patient care.
“Every therapy that helps save lives or change lives begins with a researcher asking a simple question, “What if?”, says Dr. Maria T. Millan, the President and CEO of CIRM. “Our Quest awards reflect the need to keep supporting early stage research, to gain a deeper understanding of stem cells work and how we can best tap into that potential to advance the field.”
Dr. Judy Shizuru at Stanford University was awarded $1.34 million to develop a safer, less-toxic form of bone marrow or hematopoietic stem cell transplant (HCT). HCT is the only proven cure for many forms of blood disorders that affect people of all ages, sexes, and races worldwide. However, current methods involve the use of chemotherapy or radiation to destroy the patient’s own unhealthy blood stem cells and make room for the new, healthy ones. This approach is toxic and complex and can only be performed by specialized teams in major medical centers, making access particularly difficult for poor and underserved communities.
Dr. Shizuru proposes developing an antibody that can direct the patient’s own immune cells to kill diseased blood stem cells. This would make stem cell transplant safer and more effective for the treatment of many life-threatening blood disorders, and more accessible for people in rural or remote parts of the country.
Dr. Lili Yang at UCLA was awarded $1.4 million to develop an off-the-shelf cell therapy for ovarian cancer, which causes more deaths than any other cancer of the female reproductive system.
Dr. Yang is using immune system cells, called invariant natural killer T cells (iNKT) to attack cancer cells. However, these iNKT cells are only found in small numbers in the blood so current approaches involve taking those cells from the patient and, in the lab, modifying them to increase their numbers and strength before transplanting them back into the patient. This is both time consuming and expensive, and the patient’s own iNKT cells may have been damaged by the cancer, reducing the likelihood of success.
In this new study Dr. Yang will use healthy donor cord blood cells and, through genetic engineering, turn them into the specific form of iNKT cell therapy targeting ovarian cancer. This DISC2 award will support the development of these cells and do the necessary testing and studies to advance it to the translational stage.
Timothy Hoey and Tenaya Therapeutics Inc. have been awarded $1.2 million to test a gene therapy approach to replace heart cells damaged by a heart attack.
Heart disease is the leading cause of death in the U.S. with the highest incidence among African Americans. It’s caused by damage or death of functional heart muscle cells, usually due to heart attack. Because these heart muscle cells are unable to regenerate the damage is permanent. Dr. Hoey’s team is developing a gene therapy that can be injected into patients and turn their cardiac fibroblasts, cells that can contribute to scar tissue, into functioning heart muscle cells, replacing those damaged by the heart attack.
It is estimated that as many as 90 percent of people in industrialized countries who die every day, die from diseases of aging such as heart disease, stroke, and cancer. Of those still alive the numbers aren’t much more reassuring. More than 80 percent of people over the age of 65 have a chronic medical condition, while 68 percent have two or more.
Current medications can help keep some of those conditions, such as high blood pressure, under control but regenerative medicine wants to do a lot more than that. We want to turn back the clock and restore function to damaged organs and tissues and limbs. That research is already underway and we are inviting you to a public event to hear all about that work and the promise it holds.
On June 16th from 3p – 4.30p PST we are holding a panel discussion exploring the impact of regenerative medicine on aging. We’ll hear from experts on heart disease and stroke; we will look at other ground breaking research into aging; and we’ll discuss the vital role patients and patient advocates play in helping advance this work.
The discussion is taking place in San Francisco at the annual conference of the International Society for Stem Cell Research. But you can watch it from the comfort of your own home. That’s because we are going to live stream the event.
At the California Institute for Regenerative Medicine (CIRM) we are fortunate in having enough money to fund the most promising research to be tested in a clinical trial. Those are expensive projects, often costing tens of millions of dollars. But sometimes the projects that come to our Board start out years before in much more humble circumstances, raising money through patient advocates, tapping into the commitment and ingenuity of those affected by a disease, to help advance the search for a treatment.
That was definitely the case with a program the CIRM Board voted to approve yesterday, investing more than $11 million dollars to fund a Phase 2 clinical trial testing a cell therapy for dysphagia. That’s a debilitating condition that affects many people treated for head and neck cancer.
Patients with head and neck cancer often undergo surgery and/or radiation to remove the tumors. As a result, they may develop problems swallowing and this can lead to serious complications such as malnutrition, dehydration, social isolation, or a dependence on using a feeding tube. Patients may also inhale food or liquids into their lungs causing infections, pneumonia and death. The only effective therapy is a total laryngectomy where the larynx or voice box is removed, leaving the person unable to speak.
Dr. Peter Belafsky and his team at the University of California at Davis are developing a therapeutic approach using Autologous Muscle Derived Progenitor Cells (AMDC), cells derived from a biopsy of the patient’s own muscle, elsewhere in the body. Those AMDCs are injected into the tongue of the patient, where they fuse with existing muscle fibers to increase tongue strength and ability to swallow.
The $11,015,936 that Dr. Belafsky is getting from CIRM will enable them to test this approach in patients. But without grass roots support the program might never have made it this far.
Ed Steger is a long-term survivor of head and neck cancer, he’s also the President of the National Foundation of Swallowing Disorders (NFOSD). In 2007, after being treated for his cancer, Ed developed a severe swallowing disorder. It helped motivate him to push for better treatment options.
In 2013, a dozen swallowing disorder patients visited UC Davis to learn how stem cells might help people with dysphagia. (You can read about that visit here). Ed says: “We were beyond thrilled with the possibilities and drawing on patients and other UCD contacts our foundation raised enough funds to support a small UCD clinical trial under the guidance of Dr. Belafsky in mouse models that demonstrated these possibilities.”
A few years later that small funding by patients and their family members grew into a well-funded Phase I/II human clinical trial. Ed says the data that trial produced is helping advance the search for treatments.
“Skipping forward to the present, this has now blossomed into an additional $11 million grant, from CIRM, to continue the work that could be a game changer for millions of Americans who suffer annually from oral phase dysphagia. My hat is off to all those that have made this possible… the donors, patient advocates, and the dedicated committed researchers and physicians who are performing this promising and innovative research.”
Our hats are off to them too. Their efforts are making what once might have seemed impossible, a real possibility.
The American Cancer Society estimates that this year in the United States, there will be 268,490 new cases of prostate cancer. It also estimates that 34,500 men will die from the cancer in 2022. Other than skin cancer, prostate cancer is the most common cancer in American men.
“We have a homegrown USC technology which shows a lot of promise. If the path that we are on ultimately proves successful, it could revolutionize the treatment of not only prostate cancer but also other cancers,” said principal investigator Dr. Preet M. Chaudhary, a professor of medicine at the Keck School of Medicine of USC.
A new approach to immunotherapy
CAR-T cell therapy—which is now approved by the U.S. Food and Drug Administration (FDA) to treat several blood cancers—has been revolutionary for certain patients. In CAR-T therapy, a patient’s T-cells—a key part of their immune system—are extracted and genetically engineered to express the chimeric antigen receptor (CAR). The modified T-cells are then reinjected into the patient, where CAR enables them to selectively seek out, bind to, and kill cancer cells.
But its success in treating blood cancers has not translated into effectiveness against solid tumor cancers, such as prostate, breast, brain, gastrointestinal, skin and lung cancer.
“The bottom line is that people have tried to replicate the success of CAR-T cell therapy with solid tumor cancers, and have been mostly unsuccessful,” Chaudhary said.
SIR-T therapy, in contrast, uses different receptors that more closely resemble the body’s natural T-cells. Chaudhary and his team tested thousands of prototypes over an eight-year period to develop receptors that are effective and safe for solid tumors, including prostate cancer. An initial round of tests in mice yielded very promising results, prompting Chaudhary to apply for funding from CIRM.
With CIRM funding, Chaudhary and his team can now begin conducting preclinical trials of SIR-T therapy. Their research over the next two and a half years will culminate in an application for FDA approval to begin clinical trials in humans.
Chaudhary’s lab is also testing SIR-T therapy for other types of cancer, including melanoma, kidney cancer, lymphoma and a different molecule involved in prostate cancer.
“This technology has a lot of different applications, so we are working to ensure the platform works across disease types,” Chaudhary said. “The series of grants we’ve received reflects a lot of excitement about the SIR-T platform.”
While there have been some encouraging advances in treating cancer in recent decades, there are still many cancers that either resist treatment or recur after treatment. Today the governing Board of the California Institute for Regenerative Medicine (CIRM) approved investing in a therapy targeting some of these hard-to-treat tumors.
BioEclipse Therapeutics Inc. was awarded nearly $8M to test a therapy using immune cells loaded with a cancer-killing virus that targets cancer tissue but spares healthy tissue.
BioEclipse combines two approaches—an immune cell called a cytokine-induced killer (CIK) cell and a virus engineered to kill cancer cells called an oncolytic virus (OV)—to create what they call “a multi-mechanistic, targeted treatment.”
They will use the patient’s own immune cells and, in the lab, combine them with the OV. The cell/virus combination will then be administered back to the patient. The job of the CIK cells is to carry the virus to the tumors. The virus is designed to specifically attack and kill tumors and stimulate the patient’s immune system to attack the tumor cells. The goal is to eradicate the primary tumor and prevent relapse and recurrence.
“With the intent to develop this treatment for chemotherapy-resistant or refractory solid tumors—including colorectal cancer, triple negative breast cancer, ovarian cancer, gastric cancer, hepatocellular carcinoma, and osteosarcoma—it addresses a significant unmet medical need in fatal conditions for which there are limited treatment options,” says Dr. Maria T. Millan, President and CEO of CIRM.
The CIRM Board also approved more than $18 million in funding four projects under the Translation Projects program. The goal of this program is to support promising regenerative medicine (stem cell-based or gene therapy) projects that accelerate completion of translational stage activities necessary for advancement to clinical study or broad end use.
The awards went to:
Optogenetic therapy for treating retinitis pigmentosa and other inherited retinal diseases
Paul Bresge Ray Therapeutics Inc.
Living Synthetic Vascular Grafts with Renewable Endothelium
Aijun Wang UC Davis
Next generation affinity-tuned CAR for prostate cancer
Preet Chaudhary University of Southern California
Autologous MPO Knock-Out Hematopoietic Stem and Progenitor Cells for Pulmonary Arterial Hypertension
Venous skin ulcers are open sores on the legs that can take weeks, sometimes even years, to heal and that can cause serious complications if not treated. Around 1% of Americans have venous skin ulcers. They are usually caused by insufficient blood flow from the veins of the legs back to the heart. The resulting increased blood pressure and swelling in the legs can cause an open wound to form that is painful and difficult to heal, seriously impacting quality of life. Those most at risk of developing venous leg ulcers are older people, women and non-white populations.
There are no drugs approved by the US Food and Drug Administration (FDA) for this condition and sometimes these ulcers can lead to serious skin and bone infections and, in rare cases, even skin cancer.
In a news release from UCLA, Dr. Ribas describes how his team were testing a drug called vemurafenib on patients with melanoma. Vemurafenib falls into a category of targeted cancer drugs called BRAF inhibitors, which can shrink or slow the growth of metastatic melanoma in people whose tumors have a mutation to the BRAF gene.
“We noticed that in the first two months of taking this BRAF inhibitor, patients would begin showing a thickening or overgrowth of the skin. It was somewhat of a paradox – the drug stopped the growth of skin cancer cells with the BRAF mutation, but it stimulated the growth of healthy skin cells.”
That’s when the team realized that the drug’s skin stimulating effect could be put to good use for a whole other group of patients – those with chronic wounds.
“Aside from a few famous cases, discovering a side effect that becomes a therapeutic isn’t that common,” Ribas said. “For this reason, I had to work hard to convince somebody in my lab to follow my crazy idea and take time away from immunotherapy research and do wound healing experiments.”
Thanks to that “crazy idea” Dr. Ribas and his team are now testing a gel called LUT017 that stimulates skin stem cells to proliferate and produce more keratinocytes, a kind of cell essential for repairing skin and accelerating wound healing.
The CLIN1 grant of $5,005,126 will help them manufacture and test LUT017 in pre-clinical models and apply to the FDA for permission to study it in a clinical trial in people.
Maria T. Millan, CIRM’s President and CEO says “This program adds to CIRM’s diverse portfolio of regenerative medicine approaches to tackle chronic, debilitating that lead to downstream complications, hospitalization, and a poor quality of life.”
People often complain about how long it can take to turn a scientific discovery into an approved therapy for patients. And they’re right. It can take years, decades even. But for Immune-Onc Therapeutics the path to FDA approval may just have been shortened.
Back in April of 2021 the California Institute for Regenerative Medicine (CIRM) approved investing $6 million in Immune-Onc to conduct a clinical trial for patients with acute myeloid leukemia (AML) and chronic myelomonocytic leukemia (CMML). AML and CMML are both types of blood cancer. AML affects approximately 20,000 people in the United States each year and has a 5-year survival rate of about 25 percent. Anywhere from 15-30 percent of CMML cases eventually progress into AML.
Dr. Paul Woodard and his team are treating patients with an antibody therapy called IO-202 that targets leukemic stem cells. The antibody works by blocking a signal named LILRB4 which is associated with decreased rates of survival in AML patients. The goal is to attain complete cancer remissions and prolonged survival.
Well, they must be doing something right because they just received Fast Track designation from the US Food and Drug Administration (FDA) for IO-202. Getting this designation is a big deal because its goal is to speed up the development and review of drugs to treat serious conditions and fill an unmet medical need to get important new medicines to patients earlier.
Getting a Fast Track designation means the team at Immune-Onc may be:
Eligible for more written communications and even face-to-face meetings with the FDA to discuss the development plan of IO-202
Eligible for Accelerated Approval and Priority Review if relevant criteria are met, which may result in faster approval.
In a press release Dr. Woodard said this was great news. “We are pleased that the FDA has granted IO-202 Fast Track designation in recognition of its potential to improve outcomes for people with relapsed or refractory AML. We look forward to working closely with the FDA to accelerate the clinical development of IO-202, which is currently being evaluated as a monotherapy and in combination with other agents in a Phase 1 dose escalation and expansion trial in patients with AML with monocytic differentiation and in chronic myelomonocytic leukemia (CMML).”
The FDA also granted IO-202 Orphan Drug Designation for treatment of AML in 2020. That’s defined as a therapy that’s intended for the treatment, prevention or diagnosis of a rare disease or condition, affecting less than 200,000 persons in the US.
Getting Orphan Drug Designation qualifies Immune-Onc for incentives including tax credits for clinical trials and the potential for seven years of market exclusivity if and when it is fully approved by the FDA.
A recent discovery by stem cell scientists at Cedars-Sinai may help make cancer treatment more efficient and shorten the time it takes for people to recover from radiation and chemotherapy.
Published in the journal Nature Communications, the study by Dr. John Chute and his team (and co-funded by CIRM) revealed a mechanism through which the blood vessels in the bone marrow respond to injury, such as from chemotherapy or radiation.
When people receive radiation or chemotherapy as part of their cancer treatment, their blood counts plummet. It typically takes several weeks for these counts to return to normal levels. During this period patients are at risk for developing infections that may lead to hospitalization, disruptions in chemotherapy schedules, and even death.
Chute and his colleagues found that when mice receive radiation treatment, the cells that line the inner walls of the blood vessels in the bone marrow produce a protein called semaphorin 3A. This protein tells another protein, called neuropilin 1, to kill damaged blood vessels in the bone marrow.
When the investigators blocked the ability of these blood vessel cells to produce neuropilin 1 or semaphorin 3A, or injected an antibody that blocks semaphorin 3A communication with neuropilin 1, the veins and arteries in the bone marrow regenerated faster following irradiation. In addition, blood counts increased dramatically after one week.
“We’ve discovered a mechanism that appears to control how blood vessels regenerate following injury,” said Chute, senior author of the paper. “Inhibiting this mechanism causes rapid recovery of the blood vessels and blood cells in bone marrow following chemotherapy or irradiation.”
In principle, Chute said, targeting this mechanism could allow patients to recover following chemotherapy in one to two weeks, instead of three or four weeks as currently experienced.
Christina M. Termini, a post-doctoral scientist at the David Geffen School of Medicine at UCLA, was the first author of this study. Read the source press release here.