Age-related macular degeneration (AMD) is the leading cause of vision loss in the elderly. Now, new research using 3D organoid models of the eye has uncovered clues as to what happens in AMD, and how to stop it.
In AMD, a person loses their central vision because the light sensitive cells in the macula, a part of the retina, are damaged or destroyed. This impacts a person’s ability to see fine details, recognize faces or read small print, and means they can no longer drive.
No one is quite sure what causes AMD, but in a study in the journal Nature Communications, German researchers used miniature human retina organoids to get some clues.
Building a better model for research
Organoids are 3D models made from human cells that are grown in the lab. Because they have some of the characteristics of a human organ—in this case the retina—they help researchers better understand what is happening in the AMD-affected eye.
In this study they found that photoreceptors, the light sensitive cells at the back of the retina, were missing but there was no sign of dead cells in the organoid. This led them to suspect that something called cell extrusion was at play.
Cell extrusion is where a cell exports or sends large particles outside the cell. In this case it appeared that something was causing these photoreceptors to be extruded, leading to the impaired visual ability.
In a news release Mark Karl, one of the authors of the study, said, “This was the starting point for our research project: we observed that photoreceptors are lost, but we could not detect any cell death in the retina. Half of all photoreceptors disappeared from the retinal organoid within ten days, but obviously they did not die in the retina. That made us curious.”
Using snakes to fight AMD
Further research identified two proteins that appeared to play a key role in the process, triggering the degeneration of the retinal organoid. They also tested a potential therapy to see if they could stop the process and save the photoreceptors. The therapy they tried, a snake venom, not only stopped the photoreceptors from being ejected, but it also prevented further damage to the retinal cells.
Karl says this is the starting point for the next step in the research. “This gives hope for the development of future preventive and therapeutic treatments for complex neurodegenerative diseases such as AMD.”
CIRM’s fight against blindness
The California Institute for Regenerative Medicine (CIRM) has funded six clinical trials targeting vision loss, including one for AMD. We recently interviewed Dr. Dennis Clegg, one of the team trying to develop a treatment for AMD and he talked about the encouraging results they have seen so far. You can hear that interview on our podcast “Talking ‘Bout (re)Generation.”
Three families battling a life-threatening immune disorder got some great news last week. A clinical trial that could save the life of their child has once again been given the go-ahead by the US Food and Drug Administration (FDA).
The clinical trial is the work of UCLA’s Dr. Don Kohn, and was strongly supported by CIRM. It is targeting ADA-SCID, a condition where the child is born without a functioning immune system so even a simple infection could prove fatal. In the past they were called “bubble babies” because some had been placed inside sterile plastic bubbles to protect them from germs.
Dr. Kohn’s approach – using the patient’s own blood stem cells, modified in the lab to correct the genetic mutation that causes the problem – had shown itself to be amazingly effective. In a study in the prestigious New England Journal of Medicine, the researchers showed that of 50 patients treated all had done well and 97 percent were considered cured.
UCLA licensed the therapy to Orchard Therapeutics, who planned to complete the testing needed to apply for permission to make it more widely available. But Orchard ran into problems and shelved the therapy.
After lengthy negotiations Orchard returned the therapy to UCLA last year and now the FDA has given clearance for UCLA to resume treating patients. That is expected to start early next year using CIRM funds left over when Orchard halted its work.
One of the people who played a big role in helping persuade Orchard to return the therapy to UCLA is Alysia Vaccaro. She is the mother of Evie, a child born with ADA-SCID who was cured by Dr. Kohn and his team and is now a thriving 9 year old.
You can watch an interview we did with Alysia about the impact this research has had on her family, and how important it is for other families with ADA-SCID kids.
Every year California performs around 100 kidney transplants in children but, on average, around 50 of these patients will have their body reject the transplant. These children then have to undergo regular dialysis while waiting for a new organ. Even the successful transplants require a lifetime of immunosuppression medications. These medications can prevent rejection but they also increase the risk of infection, gastrointestinal disease, pancreatitis and cancer.
Dr. Alice Bertaina and her team at Stanford University were awarded $11,998,188 to test an approach that uses combined blood stem cell (HSC) and kidney transplantation with the goal to improve outcomes with kidney transplantation in children. This approach seeks to improve on the blood stem cell preparation through an immune-based purification process.
In this approach, the donor HSC are transplanted into the patient in order to prepare for the acceptance of the donor kidney once transplanted. Donor HSC give rise to cells and conditions that re-train the immune system to accept the kidney. This creates a “tolerance” to the transplanted kidney providing the opportunity to avoid long-term need for medications that suppress the immune system.
Pre-clinical data support the idea that this approach could enable the patient to stop taking any immunosuppression medications within 90 days of the surgery.
Dr. Maria T. Millan, President and CEO of CIRM, a former pediatric transplant surgeon and tolerance researcher states that “developing a way to ensure long-term success of organ transplantation by averting immune rejection while avoiding the side-effects of life-long immunosuppression medications would greatly benefit these children.”
The CIRM Board also awarded $7,141,843 to Dr. Ivan Kingand Tachyon Therapeutics, Inc to test a drug showing promise in blocking the proliferation of cancer stem cells in solid tumors such as colorectal and gastrointestinal cancer.
Patients with late-stage colorectal cancer are typically given chemotherapy to help stop or slow down the progression of the disease. However, even with this intervention survival rates are low, usually not more than two years.
Tachyon’s medication, calledTACH101, is intended to target colorectal cancer (CRC) stem cells as well as the bulk tumor by blocking an enzyme called KDM4, which cancer stem cells need to grow and proliferate.
In the first phase of this trial Dr. King and his team will recruit patients with advanced or metastatic solid tumors to assess the safety of TACH101, and determine what is the safest maximum dose. In the second phase of the trial, patients with gastrointestinal tumors and colorectal cancer will be treated using the dose determined in the first phase, to determine how well the tumors respond to treatment.
The CIRM Board also awarded $5,999,919 to Dr. Natalia Gomez-Ospina and her team at Stanford University for a late-stage preclinical program targeting Severe Mucopolysaccharidosis type 1, also known as Hurler syndrome. This is an inherited condition caused by a faulty gene. Children with Hurler syndrome lack an enzyme that the body needs to digest sugar. As a result, undigested sugar molecules build up in the body, causing progressive damage to the brain, heart, and other organs. There is no effective treatment and life expectancy for many of these children is only around ten years.
Dr. Gomez-Ospina will use the patient’s own blood stem cells that have been genetically edited to restore the missing enzyme. The goal of this preclinical program is to show the team can manufacture the needed cells, to complete safety studies and to apply to the US Food and Drug Administration for an Investigational New Drug (IND), the authorization needed to begin a clinical trial in people.
Finally the Board awarded $20,401,260 to five programs as part of its Translational program. The goal of the Translational program is to support promising stem cell-based or gene projects that accelerate completion of translational stage activities necessary for advancement to clinical study or broad end use. Those can include therapeutic candidates, diagnostic methods or devices and novel tools that address critical bottlenecks in research.
The successful applicants are:
PRINCIPAL INVESTIGATOR – INSTITUTION
Cell Villages and Clinical Trial in a Dish with Pooled iPSC-CMs for Drug Discovery
Nikesh Kotecha — Greenstone Biosciences
Specific Targeting Hypoxia Metastatic Breast Tumor with Allogeneic Off-the-Shelf Anti-EGFR CAR NK Cells Expressing an ODD domain of HIF-1α
Jianhua Yu — Beckman Research Institute of City of Hope
CRISPR/Cas9-mediated gene editing of Hematopoietic stem and progenitor cells for Friedreich’s ataxia
Stephanie Cherqui — University of California, San Diego
Development of a Gene Therapy for the Treatment of Pitt Hopkins Syndrome (PHS) – Translating from Animal Proof of Concept to Support Pre-IND Meeting
Allyson Berent — Mahzi Therapeutics
Overcoming resistance to standard CD19-targeted CAR T using a novel triple antigen targeted vector
William J Murphy — University of California, Davis
We at the California Institute for Regenerative Medicine have a lot to be thankful for this Thanksgiving. We get to work with some extraordinary colleagues, we get to know some remarkable patient advocates who are pioneers in volunteering for stem cell and gene therapies, and we have a front row seat in a movement that is changing the face of medicine.
We also get to work with some brilliant scientists and help support their research. As if we needed any reminders of how important that funding is, we thought we would share this video with you. It’s from the talented post docs and researchers at the University of California San Diego. It’s a delightful parody of the Cyndi Lauper classic “Girls Just Wanna Have Fun”. Only in this case it’s “Nerds Just Wanna Have Funds.”
The world of stem cell research is advancing rapidly, with new findings and discoveries seemingly every week. And yet some things that we knew years ago are still every bit as relevant today as they were then.
Take for example a TEDx talk by Dr. Daniel Kota, a stem cell researcher and the Director, Cellular Therapy – Research and Development at Houston Methodist.
Dr. Kota’s talk is entitled: “Promises and Dangers of Stem Cell Therapies”. In it he talks about the tremendous potential of stem cells to reverse the course of disease and help people battle previously untreatable conditions.
But he also warns about the gap between what the science can do, and what people believe it can do. He says too many people have unrealistic expectations of what is available right now, fueled by many unscrupulous snake oil salesmen who open clinics and offer “treatments” that are both unproven and unapproved by the Food and Drug Administration.
He says we need to “bridge the gap between stem cell science and society” so that people have a more realistic appreciation of what stem cells can do.
Sadly, as the number of clinics peddling these unproven therapies grows in the US, Dr. Kota’s message remains all too timely.
Let’s back up a little. Children born with SCID have no functioning immune system, so even a simple infection can prove life threatening. Left untreated, children with SCID often die in the first few years of life. Several of the approaches CIRM has funded use the child’s own blood stem cells to help fix the problem. But at Jasper Therapeutics they are using another approach. They use a bone marrow or hematopoietic stem cell transplant (HCT). This replaces the child’s own blood supply with one that is free of the SCID mutation, which helps restore their immune system.
However, there’s a problem. Most bone marrow transplants use chemotherapy or radiation to destroy the patient’s own unhealthy blood stem cells and make room for the new, healthy ones. It can be effective, but it is also toxic and complex and can only be performed by specialized teams in major medical centers, making access particularly difficult for poor and underserved communities.
To get around that problem Jasper Therapeutics is using an antibody called JSP191 – developed with CIRM funding – that directs the patient’s own immune cells to kill diseased blood stem cells, creating room to transplant new, healthy cells. To date the therapy has already been tested in 16 SCID patients.
In addition to treating 16 patients treated without any apparent problems, Jasper has also been granted Fast Track Designation by the US Food and Drug Administration. This can help speed up the review of treatments that target serious unmet conditions. They’ve also been granted both Orphan and Rare Pediatric Disease designations. Orphan drug designation qualifies sponsors for incentives such as tax credits for clinical trials. Rare Pediatric Disease designation means that if the FDA does eventually approve JSP191, then Jasper can apply to receive a priority review of an application to use the product for a different disease, such as someone who is getting a bone marrow transplant for sickle cell disease or severe auto immune diseases.
In a news release, Ronald Martell, President and CEO of Jasper Therapeutics said:
“The FDA’s Fast Track designation granted for JSP191 in Severe Combined Immunodeficiency (SCID) reinforces the large unmet medical need for patients with this serious disease. Along with its previous designations of Orphan and Rare Pediatric Disease for JSP191, the FDA’s Fast Track recognizes JSP191’s potential role in improving clinical outcomes for SCID patients, many of whom are too fragile to tolerate the toxic chemotherapy doses typically used in a transplant.”
The headline in the journal Nature was intended to grab attention and it definitely did that. It read: ‘The scandal of researchers paid less than a living wage’ The rest of the article built on that saying “The cost-of-living crisis is a fundamental threat for PhD scholars and early-career researchers. They need to be paid properly.”
So, just how poorly are these researchers – PhD candidates and postdoctoral students – paid? Well, according to one survey salaries for PhD students in the biological sciences are below the cost of living at almost every institution in the United States. And imagine trying to live on a sub-standard income in a state as expensive as California?
The outrage is fueled by a survey of more than 3,200 students, three quarters of whom are PhD candidates. Around 85% of the students said inflation is making things even worse and almost half said it was making it hard to complete their courses.
The situation isn’t any better in other countries. In the UK, PhD students often get the equivalent of just $20,400, and that’s after getting a recent big boost of more than $2,000 per year. It’s no wonder English students organized protests calling for better funding. Students in Ireland also staged protests, saying the money they get simply isn’t enough.
The Nature Editorial said this isn’t just a matter of inconvenience for the students, it’s a threat to the future of science: “If students don’t have the resources to support themselves, they can’t put their full efforts into their training and development. And if their stipends aren’t keeping pace with rising rents and the cost of groceries and fuel, any gaps will only grow with time — with devastating results for the ability of research to attract the best talent.”
That’s one of the reasons the California Institute for Regenerative Medicine (CIRM) tries to make sure all the students in its internship programs have enough money to live on. We know it’s hard to focus on work if you are hungry or worried that you don’t have enough money to pay your bills.
When our Board approved a new internship program, called COMPASS (Creating Opportunities through Mentorship and Partnership Across Stem Cell Science) they made sure that enough money was included to cover students living expenses, course fees and even travel to scientific conferences. The Board allocated more than $58,000 a year to support each students, many of whom will come from poor or low-income communities and might not otherwise be able to afford to stay in school.
For our Bridges students, many of whom are also from low-income communities or are the first in their family to attend college, the Board allocated each one around $72,000 worth of support per year.
We know that the future of regenerative medicine in California depends on having a skilled, well-trained, diverse workforce. That doesn’t just mean PhDs doing the research, it also means the technicians and support staff that can help with manufacturing etc. Without a living wage that makes this possible many students will drop out and the field as a whole will struggle. Those most affected will be students from poor backgrounds or from disadvantaged and historically marginalized communities.
We need to support these students in every way we can. If we don’t provide enough financial support for these students to succeed, the field as a whole will be a lot poorer.
It’s always nice to be told you are doing a good job. It’s even nicer when it’s unexpected. That’s certainly the case when we, the Communications Team at the California Institute for Regenerative Medicine, found out we’d been named as a finalist for the Patient Advocacy Award (non-profit category) as part of the Phacilitate Advanced Therapies Awards.
To be honest, we didn’t even know we’d been nominated. But who cares. We are now in the final. And we are in good company. Our friends at Americans for Cures, were also nominated. They are advocates for stem cell research in California and were hugely instrumental in getting Proposition 14 passed in 2020, that’s the voter initiative that refunded CIRM with $5.5 billion.
While we may focus on different areas we all share a common goal, a desire to ensure that the voice of the patient is front and center in all that we do. At CIRM we have patient advocates on our Board and on the panel of experts who review applications for our funding. We have patient advocates helping guide the clinical trials we fund. And now, as we expand our efforts to reach out in every community in California, we have patients and patient advocates guiding that work as well.
We do this work because it’s important and because, without the support of the patient advocacy community, we wouldn’t be here.
It’s an old cliché that when you are in this position you say, “it’s an honor just to be nominated.” But in this case, it’s true.
Doctor Dennis Clegg, a researcher and scientist at UC Santa Barbara, is fascinated by the eye. He thinks it’s one of the most beautiful objects in nature and wonders how something as complex and elegant developed and is able to connect with our brains to make vision possible. That’s why he has spent his career trying to understand that question and develop answers, to help reverse vision loss and blindness in people.
The good news is that Dennis and his colleagues have made encouraging progress in answering some of those questions. In one early-stage CIRM-funded clinical trial they were able to reverse the effects of macular degeneration, the leading cause of vision loss in the elderly.
So we sat down with Dennis to talk about his research, his love of dogs (he has six!) and his work as a volunteer firefighter. That’s all in the latest episode of our podcast, ‘Talking ‘Bout (re)Generation’.
This brings the total number of CIRM funded clinical trials to 83.
$11,999,984 was awarded to Dr. Jana Portnow at the Beckman Research Institute of City of Hope. They are using Neural stem cells (NSCs) as a form of delivery vehicle to carry a cancer-killing virus that specifically targets brain tumor cells.
Glioblastoma is the most common malignant primary brain tumor in adults and each year about 12,000 Americans are diagnosed. The 5-year survival rate is only about 10%.
The current standard of care involves surgically removing the tumor followed by radiation, chemotherapy, and alternating electric field therapy. Despite these treatments, survival remains low.
The award to Dr. Portnow will fund a clinical trial to assess the safety and effectiveness of this stem cell-based treatment for Glioblastoma.
The Board also awarded $3,111,467 to Dr. Boris Minev of Calidi Biotherapeutics. This award is in the form of a CLIN1 grant, with the goal of completing the testing needed to apply to the Food and Drug Administration (FDA) for permission to start a clinical trial in people.
This project uses donor fat-derived mesenchymal stem cells that have been loaded with oncolytic virus to target metastatic melanoma, triple negative breast cancer, and advanced head & neck squamous cell carcinoma.
“There are few options for patients with advanced solid tumor cancers such as glioblastoma, melanoma, breast cancer, and head & neck cancer,” says Maria T. Millan, M.D., President and CEO of CIRM. “Surgical resection, chemotherapy and radiation are largely ineffective in advanced cases and survival typically is measured in months. These new awards will support novel approaches to address the unmet medical needs of patients with these devastating cancers.”
The CIRM Board also voted to approve awarding $71,949,539 to expand the CIRM Alpha Clinics Network. The current network consists of six sites and the Board approved continued funding for those and added an additional three sites. The funding is to last five years.
The goal of the Alpha Clinics award is to expand existing capacities for delivering stem cell, gene therapies and other advanced treatment to patients. They also serve as a competency hub for regenerative medicine training, clinical research, and the delivery of approved treatments.
Each applicant was required to submit a plan for Diversity, Equity and Inclusion to support and facilitate outreach and study participation by underserved and disproportionately affected populations in the clinical trials they serve.
The successful applicants are:
The Stanford Alpha Stem Cell Clinic
Stanford University – Matthew Porteus
UCSF Alpha Stem Cell Clinic
U.C. San Francisco – Mark Walters
A comprehensive stem cell and gene therapy clinic to advance new therapies for a diverse patient population in California
Cedars-Sinai Medical Center – Michael Lewis
The City of Hope Alpha Clinic: A roadmap for equitable and inclusive access to regenerative medicine therapies for all Californians
City of Hope – Leo Wang
Alpha Stem Cell Clinic for Northern and Central California
U.C. Davis – Mehrdad Abedi
Expansion of the Alpha Stem Cell and Gene Therapy Clinic at UCLA
U.C. Los Angeles – Noah Federman
Alpha Clinic Network Expansion for Cell and Gene Therapies
University of Southern California – Thomas Buchanan
A hub and spoke community model to equitably deliver regenerative medicine therapies to diverse populations across four California counties
U.C. Irvine – Daniela Bota
UC San Diego Health CIRM Alpha Stem Cell Clinic
U.C. San Diego – Catriona Jamieson
The Board also unanimously, and enthusiastically, approved the election of Maria Gonzalez Bonneville to be the next Vice Chair of the Board. Ms. Bonneville, the current Vice President of Public Outreach and Board Governance at CIRM, was nominated by all four constitutional officers: the Governor, the Lieutenant Governor, the Treasurer and the Controller.
In supporting the nomination, Board member Ysabel Duron said: “I don’t think we could do better than taking on Maria Gonzalez Bonneville as the Vice Chair. She is well educated as far as CIRM goes. She has a great track record; she is empathetic and caring and will be a good steward for the taxpayers to ensure the work we do serves them well.”
In her letter to the Board applying for the position, Ms. Bonneville said: “CIRM is a unique agency with a large board and a long history. With my institutional knowledge and my understanding of CIRM’s internal workings and processes, I can serve as a resource for the new Chair. I have worked hand-in-hand with both the Chair and Vice Chair in setting agendas, prioritizing work, driving policy, and advising accordingly. I have worked hard to build trusted relationships with all of you so that I could learn and understand what areas were of the most interest and where I could help shed light on those particular programs or initiatives. I have also worked closely with Maria Millan for the last decade, and greatly enjoy our working relationship. In short, I believe I provide a level of continuity and expertise that benefits the board and helps in times of transition.”
In accepting the position Ms. Bonneville said: “I am truly honored to be elected as the Vice Chair for the CIRM Board. I have been a part of CIRM for 11 years and am deeply committed to the mission and this new role gives me an opportunity to help support and advance that work at an exciting time in the Agency’s life. There are many challenges ahead of us but knowing the Board and the CIRM team I feel confident we will be able to meet them, and I look forward to helping us reach our goals.”
Ms. Bonneville will officially take office in January 2023.
The vote for the new Chair of CIRM will take place at the Board meeting on December 15th.