San Diego research centers receive $15 million to train next generation of scientists

San Diego Community News Group

Three San Diego research institutions have been awarded nearly $15 million from the California Institute of Regenerative Medicine (CIRM) to train the next generation of scientists in regenerative medicine, a field of research that holds great promise for generating transformative medicines.

Scripps Research, University of California San Diego, and Sanford Burnham Prebys each received grants of around $5 million from CIRM to support the training of graduate students, postdoctoral trainees, and clinical trainees.

The CIRM awards will also foster interdisciplinary regenerative medicine collaborations among the three San Diego recipient institutions and support outreach science activities in the broader San Diego community. The funding also will support educational programs for K-12 students and undergraduates on topics related to regenerative medicine that are intended to reduce disparities and disproportionate access to science.

"CIRM has provided critical leadership spearheading regenerative medicine and stem cell research," says Peter Schultz, president and CEO of Scripps Research. "This forward-looking investment in training the next generation of scientists will help ensure continued progress toward realizing the tremendous promise of regenerative medicine."

Schultz will head the Scripps Research program which received $4,931,353 to train scientists in disciplines and techniques central to stem cell biology and regenerative medicine. These include cellular processes involved in human embryonic and adult stem cell self-renewal and differentiation and the development of novel drugs to target related pathways.

University of California San Diego received $4,992,446 to train the next generation of stem cell biologists, driving advances ranging from the unraveling of fundamental mechanisms of cell function to the development of new therapies. The UC San Diego training program will be led by Alysson R. Muotri, PhD, professor of pediatrics and cellular and molecular medicine at UC San Diego School of Medicine, and Sheldon Morris, MD, primary care physician at UC San Diego Health.

This grant comes at a time when stem cell research in San Diego has matured, thanks to strong support over the years from visionaries such as CIRM and philanthropist T. Denny Sanford, Muotri said. The only way to keep up this momentum is to have professionals that understand how to use and apply stem cell and gene therapies. We are building the next generation of researchers and clinicians to do this.

Sanford Burnham Prebys received $4,931,353 to launch a multidisciplinary stem cell training program. The grant will provide funds for competitive awards for PhD students, postdocs and clinical fellows in stem cell, gene therapy and regenerative medicine fields at the institute. The training program will be led by Evan Snyder, MD, PhD, professor and director of the Center for Stem Cells & Regenerative Medicine, as well as professors/directors Pier Lorenzo Puri, MD, and Alessandra Sacco, PhD, in the Development, Aging and Regeneration Program Center at Sanford Burnham Prebys.

Sacco says stem cell research holds tremendous promise for medical treatments, and that CIRMs support will allows scientists to learn more about the process through which science becomes medicine.

We are exceptionally grateful that CIRM is supporting this important program, says Sacco. This award helps the next generation of stem cell and regenerative medicine scientists who will work across boundaries and between disciplines to become capable of translating basic discovery science into clinical research for patient benefit.

This years awards build on an earlier Research Training program through which CIRM supported training in regenerative medicines from 2006-2016 and trained 940 CIRM Scholars including 321 doctoral students, 453 postdocs and 166 MDs.

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San Diego research centers receive $15 million to train next generation of scientists - Three San Diego research institutions have been awarded nearly...

Kawasaki disease (KD) is rare, with fewer than 6,000 diagnosed cases per year in the United States. It is most common in infants and young children and causes inflammation in the walls of some blood vessels in the body. KD is a common cause of acquired heart disease in children around the world, causing coronary artery aneurysms in a quarter of untreated children.

Multisystem inflammatory syndrome in children (MIS-C) is also rare, a life-threatening illness that follows exposure to severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2). MIS-C is characterized by the acute onset of fever and variable symptoms, including rash, cardiovascular complications, shock and gastrointestinal symptoms, including abdominal pain, diarrhea and vomiting.

KD and MIS-C share several clinical features and immune responses. Both conditions are treated with intravenous immunoglobulin (IVIG), a therapeutic containing antibodies purified from blood products. Antibodies in the blood protect us from a number of viral, bacterial and fungal pathogens, but when administered as IVIG, can also suppress excessive inflammation. How it does this is an ongoing area of research worldwide.

In a pair of new studies, published online October 26 and August 31, 2021, two collaborating teams of researchers at University of California San Diego School of Medicine examined the use of IVIG in two groups; one group used a second dose of IVIG in children with KD who do not respond to the first dose of the drug, and the other group used IVIG as an effective treatment for MIS-C.

Our research teams looked further into KD to improve treatment, and then used what we know about that disease to advance science in another illness, said senior author Jane C. Burns, MD, professor and director of the Kawasaki Disease Research Center at UC San Diego School of Medicine and Rady Childrens Hospital-San Diego.

In a paper published in the October 26, 2021 online edition of the Lancet: Child and Adolescent Health, researchers found treating IVIG-resistant KD patients with infliximab, a targeted anti-inflammatory drug, was more effective than a second dose of IVIG.

In an earlier paper, published in the August 31, 2021 online edition of The Journal of Clinical Investigation, researchers found why IVIG is a successful treatment for MIS-C.

IVIG is the standard of care for KD and can alleviate symptoms and stabilize patients within hours of administration. However, 10 to 20 percent of children have recurrence of fever after initial therapy and are at an increased risk of coronary artery aneurysms. Historically, a second dose of IVIG has been advocated for treatment of IVIG-resistant KD.

In a national, randomized clinical trial, known as KIDCARE, involving 30 clinical sites and 103 children, researchers looked at a second dose of IVIG versus infliximab in children with KD who did not respond to the first dose of IVIG. They found those treated with infliximab had shorter duration of fever, reduced need for additional therapy, less severe anemia and shorter hospitalizations.

Jane C. Burns, MD, is a professor and director of the Kawasaki Disease Research Center at UC San Diego School of Medicine and Rady Childrens Hospital-San Diego.

Researchers in this field have been trying to answer the question of what we should use when the first dose of IVIG does not work since the 1980s, said Burns.

This clinical trial was designed to find out the safest and most effective way to stop the fever and get these children out of the hospital. Our results show that infliximab is the best treatment that does the job safely and quickly.

Additionally, IVIG administration can take up to 12 hours while infliximab requires two.

Trials of infliximab for KD treatment began in the early 2000s in San Diego. Researchers found that the target of infliximab, a pro-inflammatory molecule called TNF, was markedly elevated in the bloodstream of KD patients. This suggested that infliximab, a monoclonal antibody that neutralizes TNF, might be an effective treatment.

We are on the forefront of advances in treatment for KD patients and this finding is another example of how our team moves innovative research from the lab to the patient bedside, said Burns.

Next steps include clinical trials to determine the best treatment for children with KD who come to the hospital already showing damage to the coronary arteries.

MIS-C was first identified in children in April 2020 and is a rare complication of the coronavirus SARS-CoV-2, which causes COVID-19. The inflammation caused by the condition affects several organs and progresses over time. Symptoms are usually seen between two and six weeks after initial infection, which may in fact not cause any symptoms at all.

Both KD and MIS-C share a robust activation of the innate immune system, termed the first responder arm of the immune system. In contrast to KD, however, additional anti-inflammatory therapies, such as steroids or biologic therapies are often needed to further reduce inflammation with MIS-C.

In a recent study, researchers examined what IVIG does to white blood cells (WBC) in MIS-C and KD. Neutrophils are a type of WBC that prevent serious infections by killing invading bacteria and fungi.

Using cell samples from children with MIS-C or KD, researchers found that neutrophils laden with IL-1b, a key mediator of the inflammatory response, are generated in large numbers and play an active role in inflammation in patients. Exposing these patient cells to IVIG in the laboratory, researchers showed that IVIG targets and kills those neutrophils, thus, reducing inflammation.

Ben Croker, PhD, is an associate professor in the Department of Pediatrics at UC San Diego School of Medicine.

This finding is important because it shows how and why IVIG is successful in rapidly reducing inflammation in kids. It targets a different part of the immune response to steroids, which can also suppress inflammation, said Ben Croker, PhD, associate professor in the Department of Pediatrics at UC San Diego School of Medicine.

Initially, we borrowed from the KD playbook to treat MIS-C because of the similarities between the two diseases. We were challenged to treat a severe reaction (MIS-C) to a novel virus no one on the planet had seen two years ago. Our studies now support an important role for IVIG as a therapy for these patients, said Burns.

Croker noted that these findings pave the way for the next discovery, which will be understanding the mechanism by which IVIG accomplishes its killing mission so that it could be replaced with a less expensive, more readily available treatment.

Co-authors include: Samantha Roberts, Adriana Tremoulet, Feng He, Beth Printz and Sonia Jain, all with UC San Diego; Negar Ashouri with CHOC Childrens Hopsital; Supriya Jain, Maria Fareri Children's Hospital; David Michalik, Miller Children's Hospital Long Beach; Kavita Sharma, Children's Health, University of Texas Southwestern Medical Center; Dongngan Truong, University of Utah/Primary Childrens Hospital; James Wood, Indiana University School of Medicine; Katherine Kim, University of California Davis; and the KIDCARE Multicenter Study Group.

Funding for the KIDCARE study came from Patient Centered Outcomes Research Institute (PCORI).

Co-authors include: Yanfang Peipei Zhu, Isaac Shamie, Jamie Casey Lee, Weiqi Peng, Shiela Angulo, Linh Le, Yushan Liu, Huilai Miao, Hainan Xiong, Cathleen Pena, Elizabeth Moreno, Eric Griffis, Stephanie Labou, Alessandra Franco, Lori Broderick, Hal Hoffman, Chisato Shimizu, Nathan Lewis, John Kanegaye, Adriana Tremoulet, and the Pediatric Emergency Medicine Kawasaki Disease Research Group, all with UC San Diego; and Cameron Nowell with Monash Institute of Pharmaceutical Sciences in Australia.

Funding for this research came, in part, from the National Institutes of Health (grants R61HD105590, RO1HL124209, RO1HL140898-03S1), Patient Centered Outcomes Research Institute (CER1602-3447), the American Asthma Foundation, the American Heart Association, the Novo Nordisk Foundation provided to the Technical University of Denmark (NNF20SA0066621), NIGMS (R35 GM119850) and the American Academy of Allergy, Asthma and Immunology Foundation.

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Same Treatment Tested for Kids with Kawasaki Disease and Rare COVID-19 Reaction - UC San Diego Health

In this companion article, Dr. Jared Weiss provides key insights into recent advancements in the standard of care for extensive-stage small cell lung cancer and examines challenges affecting treatment.

While patients with small cell lung cancer can be responsive to initial treatment with chemotherapy, relapse is an important consideration for clinicians. Many patients will also present with advanced disease at diagnosis, so it is essential that clinicians continue to optimize the management of extensive-stage small cell lung cancer (ES-SCLC).

The treatment of ES-SCLC has included the use of platinum chemotherapy (cisplatin, carboplatin) in combination with etoposide. However, in 2019, the IMpower133 clinical trial led to the approval of atezolizumab in combination with etoposide and carboplatin in the first-line setting. Combination therapy with durvalumab, etoposide, and platinum chemotherapy was also approved in the first-line setting with the CASPIAN clinical trial in 2020. Although these new treatment approaches have advanced the standard of care in ES-SCLC, there continue to be challenges affecting optimal patient management and important areas of unmet need that must be addressed.

In this new Precision Medicine Perspectives in Small Cell Lung Cancer series, experts in the management of ES-SCLC reflect on the current therapeutic landscape and highlight some challenges affecting optimal treatment. In the first interview of the series, Jared Weiss, MD, from the University of North Carolina Lineberger Comprehensive Cancer Center in Chapel Hill, North Carolina provides an overview of recent advancements in the standard of care and underscores the importance of utilizing effective therapeutic approaches while also mitigating and managing the toxicity associated with treatment.

TARGETED ONCOLOGY: What do you consider the biggest challenges in treating ES-SCLC?

WEISS: In my opinion, the unambiguously greatest challenge in treating extensive-stage small cell lung cancer is the lack of therapeutic efficacy. I've been frustrated with extensive-stage small cell lung cancer treatment for some time, as I think many have. It's very frequent that we get these rapid, dramatic, and even complete responses. You have a high log cell kill, you're close to cure, and then you don't get there. This was true even in the era before modern therapeutics. Even back in the era of CAV (cyclophosphamide, doxorubicin, vincristine), we would get complete responses that were not curative. For a long time, we've recognized that, in terms of cell count number, we're getting close to a cure, yet we just about never get there. We're so close, yet for decades have never crossed that finish line.

Even if you step back and say that we don't cure most stage 4 cancers and that we should be a little more realistic, even still, the duration of control that we get is grossly inadequate, and our survival is grossly inadequate. Along the way, our patients suffer not just from the adverse effects of what we do to themalthough I would list that as another really important unmet needthey also suffer from the effects of our therapy, so we need therapies that are more effective. Ideally, curing some or really all patients, we need treatments that are less toxic.

TARGETED ONCOLOGY: How do these challenges affect a patient's treatment plan?

WEISS: When thinking about how to treat a patient, we have to recognize that small cell lung cancer tends to present very symptomatically. It likes to grow in the central area of the chest with a lot of lymphadenopathy, so you get central chest syndromes. You get pain, and you get trouble breathing from clipping off the central airways and the central vessels, so there's often an urgency to treat small cell lung cancer. Of the solid tumors, it is the one that I treat the most inpatient. This is probably true for most consultative physicians.

The good part of this, though, is that the chemotherapy works. If you have a patient in the hospital, even in an extreme situation like on a ventilator, when you give them a cycle of chemotherapy, days later, they're doing much better. The major treatment consideration is efficacy. Fortunately, in the short run, efficacy is quite good.

Then of course, another consideration is toxicity minimization. If you look at the historic evolution of cytotoxic chemotherapy in the preimmunotherapy era and look at the front-line evolution from CAV to platinum and etoposide and the second-line evolution from CAV to topotecan, we really don't have an improvement in survival. What we have is an improvement in toxicity profile and patient convenience profile; this matters, even if we wanted more out of it. Then of course, as we entered the immunotherapy era, there is finally an advantage in survival. Not as much as we'd like, but real.

These historic considerations are the same that we face in clinic every day. What do we need to address our patients immediate needs? What's the best regimen to give them long-term control? And of course, how can we minimize the adverse effects of therapy? Small cell treatment is toxic; the most common toxicities are myelosuppression and their downstream sequalae, like fatigue. There is need for supportive care interventions because our patients are very much suffering from the treatment in addition to suffering from the disease.

TARGETED ONCOLOGY: Regarding recent approvals, first line use of atezolizumab, carboplatin, and etoposide gained approval in 2019, and then durvalumab, carboplatin or cisplatin, and etoposide gained approval in 2020. How have these approvals changed decision-making for first-line therapy for ES-SCLC?

WEISS: First-line treatment of extensive-stage small cell lung cancer changed dramatically in 2019 with the approval of atezolizumab. For a very long time until then, the evolution of frontline regimens never improved survival. Enter IMpower-133: This was a randomized study of carboplatin and etoposide, plus either placebo or the PD-L1 inhibitor atezolizumab. We have an improvement in progression-free survival, we have an improvement in overall survival, and there was not much extra toxicity. There were some immune-related adverse events that you see with the addition of atezolizumab, of course, but looking at the safety profile globally, there was not a terribly big increase.

The same was pretty much replicated in 2020 in the CASPIAN study with the addition of the PD-L1 inhibitor durvalumab to platinum and etoposide. This was a 3-arm randomized study; the third arm had the CTLA-inhibitor tremelimumab. That really didn't improve outcomes any further, so I'll focus on what was approved, deservedly: the addition of durvalumab.

If you look at the forbidden but omnipresent cross-trial comparisons, the curves were nearly superimposable from IMpower-133, which to me reflects that the agents are more similar than different and that both companies conducted their trials fairly and appropriately. There were minor differences in inclusion criteria and enrolled patients, but the main meaning of having 2 trials with similar safety, PFS (progression-free survival), and OS (overall survival) is that it is true. In science, we like to have everything confirmed with another case study. The addition of the PD-L1 inhibitor, the approved ones being atezolizumab or durvalumab, to standard platinum and etoposide improved survival in extensive-stage small lung cancer. This, of course, has changed the standard of care. In the US and other countries that can afford it, the absolute unambiguous standard of care for patients eligible for a checkpoint inhibitor is platinum, etoposide, and a checkpoint inhibitor.

TARGETED ONCOLOGY: What do you consider the most significant unmet needs in the management of ES-SCLC?

WEISS: We've spoken already about the unmet need of actually curing people, and even if we can't do that, of having more durable control with the drugs. We have spoken about the unacceptable toxicity profile of our current standards of care. The 1 additional theme that I might mention for unmet needs is dealing with the patient and their systems as a whole.

While I love my smokers and non-smokers the same and have no desire to stigmatize anybody, we do need to recognize that smoking brings with it smoking-associated comorbidities. In addition to decreased socioeconomic resources, the patients bodies come to their cancer more beaten up with things like COPD (chronic obstructive pulmonary disease) and more limited blood counts. They're less able to tolerate and benefit from the standard of care in addition to the greater difficulty in traveling to academic centers and getting trials. Optimal care of the patient with extensive-stage small cell lung cancer involves not only less toxic therapy, better supportive care, and therapies that work better, but it also requires an extensive network to support the patient to be able to get those more advanced standards of care applied to them.

Additionally, lung cancer is a heavily stigmatized cancer that disproportionately affects patients with fewer financial resources and social capital to bring to their treatment. If you contrast this, for example, with a patient with estrogen receptor positive breast cancer, or a patient with HPV (human papillomavirus)-positive head and neck cancer, these are patients who can afford to travel for trials, who can get many opinions. In contrast, many of my patients with small cell lung cancer have trouble paying for the tank of gas to get to the doctor's visit.

TARGETED ONCOLOGY: Chemotherapy-induced myelosuppression (CIM) can result from some treatment regimens. How significant of an issue is CIM and to what extent does it affect a patients treatment course?

WEISS: The problem is actually quite common if you look at the toxicity tables of the regimens that have defined our standard of care. If you look at IMpower-133, if you look at CASPIAN, if you look at the phase I basket results of lurbinectedin, and if you look at any of the dozen or so topotecan trials, what you can see is that the majority of patients are experiencing adverse events. The most common of these are myelosuppressive events, which until very recently we couldn't do a whole lot about.

Chemotherapy-induced myelosuppression is a major harm to treatment. While dose density doesn't have a great impact on survival in small cell lung cancer the way it does in breast cancer or some lymphomas, there are meaningful harms to needing to delay and reduce doses. It is inconvenient for patients. It's inconvenient for providers. It causes substantial anxiety.

Further, neutropenia very much hurts people. Febrile neutropenia can be a fatal event, it can delay chemotherapy, and it results in the need for drugs like pegfilgrastim that have adverse effects like bone pain. When you get to anemia, which causes fatigue, fatigue is the quality-of-life issue that perhaps we have the most trouble controlling in clinic, and for many patients, this affects them the most.

I think myelosuppression deserves a renewed focus. For years, we haven't thought that much about myelosuppression other than maybe neutropenia because we had a bit of a learned helplessness. This was the cost of business for giving cytotoxic drugs, and we started to say, "Well, of course, you get tired. Of course you get anemic." The introduction of effective drugs to protect neutrophils has changed this. Trilaciclib, which can help with the myelosuppression, now means that we can actually do something about it.

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EP. 2B: Challenges Affecting the Management of Extensive-Stage Small Cell Lung Cancer - Targeted Oncology

1. Intracranial response rate of 55% was reported in patients receiving cabozantinib with progressing brain metastases with no concomitant brain-directed local therapy

2. Cabozantinib was well-tolerated with common adverse events such as fatigue, diarrhea and palmar-plantar erythrodysesthesia

Evidence Rating Level: 2 (Good)

Study Rundown: Patients with metastatic renal cell carcinoma (RCC) may develop brain metastases, increasing their morbidity and mortality. Currently, the standard treatment of care includes local therapies targeting metastases (e.g., stereotactic radiosurgery, whole-brain radiotherapy). RCC patients with brain metastases were poorly represented in other clinical trials and the aim of this study was to characterize cabozantinib monotherapy in the treatment of progressive brain metastases. This study aimed to evaluate the efficacy and safety of cabozantinib for the treatment of brain metastases in patients with metastatic RCC. Patients were divided into two cohorts. Cohort A comprised of patients with progressing brain metastases who did not receive brain-directed local therapy concomitantly. Cohort B comprised of patients with stable brain metastases who received brain-directed local therapy concomitantly. Cabozantinib showed a notable intracranial response rate of 55% and 47% in cohorts A and B, respectively. Commonly reported adverse events included fatigue, diarrhea and palmar-plantar erythrodysesthesia. Limitations to the study include having a low number of patients in each cohort and the lack of information regarding other concomitant medications that the patients may be on, which could influence the safety profile of cabozantinib. Overall, this study demonstrated that cabozantinib could be an effective treatment for patients with brain metastases from RCC, particularly patients with progressive brain metastases. However, further investigation is required to confirm the findings and establish a more comprehensive efficacy and safety profile of cabozantinib in patients with brain metastases, including in combination with other therapies.

Click to read the study in JAMA Oncology

Relevant Reading: Cabozantinib in Renal Cell Carcinoma With Brain Metastases: Safety and Efficacy in a Real-World Population

In-Depth [retrospective cohort]: This was a multicenter, international, retrospective cohort study of 88 patients at 15 academic centers in the United States, Belgium, France, and Spain. Patients were eligible if they had brain metastases from RCC and received cabozantinib between January 2014 and October 2020. The patients were divided into 2 cohorts. Cohort A included patients with progressing brain metastases at the start of cabozantinib who were not receiving concomitant brain-directed local therapy. Cohort B included patients with stable brain metastases at the start of cabozantinib who were receiving brain-directed local therapy concomitantly. The study examined the intracranial and extracranial objective response rates (ORRs) as well as the safety profile of cabozantinib. The intracranial ORR for Cohort A and B were 55% (95% confidence interval [CI]: 36%-73%) and 47% (95% CI: 33%-61%), respectively. 32% of the patients in Cohort A experienced stable disease compared to 42% of patients in Cohort B. 13% of the patients in Cohort A and 11% of patients in Cohort B experienced progressive disease. The extracranial ORR for Cohort A and B were 48% (95% CI: 31%-66%) and 38% (95% CI: 25%-52%), respectively. The median overall survival was 16.0 months (95%CI, 12.0-21.9months). Commonly reported adverse events included fatigue (77%), diarrhea (46%) and palmar-plantar erythrodysesthesia (32%). There were no reported deaths and neurological toxic effects (e.g., seizure, brain hemorrhage, stroke).

Image: PD

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Cabozantinib is associated with an intracranial response in the treatment of brain metastases from renal cell carcinoma - 2 Minute Medicine

CARLSBAD, Calif.--(BUSINESS WIRE)--Lineage Cell Therapeutics, Inc. (NYSE American and TASE: LCTX), a clinical-stage biotechnology company developing allogeneic cell therapies for unmet medical needs, reported today that updated interim results from a Phase 1/2a clinical study of its lead product candidate, OpRegen, an investigational retinal pigment epithelium cell transplant therapy currently in development for the treatment of dry age-related macular degeneration (AMD), will be featured in a presentation at the 2021 American Academy of Ophthalmology (AAO) 125th Annual Meeting, to be held at the Ernest N. Morial Convention Center, New Orleans, LA (November 12 15, 2021). The presentation, OpRegen Trial: Phase 1/2a Dose Escalation Study of Human Embryonic Stem-Cell Derived Retinal Pigment Epithelium Cells Transplanted Subretinally in Patients with Advanced AMD, will be presented on November 13, 2021 at 2:38 pm EDT as part of the Gene and Cell-Based Therapies Session, by Michael S. Ip, M.D., Professor, Department of Ophthalmology at the David Geffen School of Medicine at the University of California - Los Angeles.

In addition to Dr. Ips presentation, Lineage also intends to announce updated interim results from the Phase 1/2a study next month, which will include a minimum of 12 months of follow-up in all 24 patients treated with OpRegen, including all 12 patients treated in Cohort 4, which had better baseline vision and smaller areas of GA at baseline than earlier cohorts. OpRegen is well-positioned among product candidates in development for dry AMD as the only experimental therapy that has demonstrated an ability to halt or reverse the expansion of geographic atrophy as well as restore layers of retinal tissue in three patients to date. Specifically, outer retinal layer restoration was observed via optical coherence tomography (OCT) and was evidenced by the presence of new areas of retinal pigment epithelium (RPE) monolayer with overlying ellipsoid zone, external limiting membrane, and outer nuclear layer, all of which were not present at the time of baseline assessment. These findings are suggestive of integration of the new RPE cells with functional photoreceptors in areas that previously showed no presence of any of these cells.

The American Academy of Ophthalmology is the worlds largest association of eye physicians and surgeons. The mission of the American Academy of Ophthalmology is to protect sight and empower lives by serving as an advocate for patients and the public, leading ophthalmic education, and advancing the profession of ophthalmology. For more information, please visit https://www.aao.org/ or follow the association on Twitter @aao_ophth.

About OpRegen

OpRegen is currently being evaluated in a Phase 1/2a open-label, dose escalation safety and efficacy study of a single injection of human retinal pigment epithelium cells derived from an established pluripotent cell line and transplanted subretinally in patients with advanced dry AMD with geographic atrophy (GA). The study enrolled 24 patients into 4 cohorts. The first 3 cohorts enrolled only legally blind patients with Best Corrected Visual Acuity (BCVA) of 20/200 or worse. The fourth cohort enrolled 12 better vision patients (BCVA from 20/65 to 20/250 with smaller mean areas of GA). Cohort 4 also included patients treated with a new thaw-and-inject formulation of OpRegen, which can be shipped directly to sites and used immediately upon thawing, removing the complications and logistics of having to use a dose preparation facility. The primary objective of the study is to evaluate the safety and tolerability of OpRegen as assessed by the incidence and frequency of treatment emergent adverse events. Secondary objectives are to evaluate the preliminary efficacy of OpRegen treatment by assessing the changes in ophthalmological parameters measured by various methods of primary clinical relevance. OpRegen is a registered trademark of Cell Cure Neurosciences Ltd., a majority-owned subsidiary of Lineage Cell Therapeutics, Inc.

About Age-Related Macular Degeneration

AMD is an eye disease that can blur the sharp, central vision in patients and is the leading cause of vision loss in people over the age of 60. There are two forms of AMD: dry (atrophic) AMD and wet (neovascular) AMD. Dry (atrophic) AMD is the more common of the two forms, accounting for approximately 85-90% of all cases. In atrophic AMD, parts of the macula get thinner with age and accumulations of extracellular material between Bruch's membrane and the retinal pigmented epithelium, known as drusen, increase in number and volume, leading to a progressive loss of central vision, typically in both eyes. Global sales of the two leading wet AMD therapies were in excess of $10 billion in 2019. Nearly all cases of wet AMD eventually will develop the underlying atrophic AMD if the newly formed blood vessels are treated correctly. There are currently no U.S. Food and Drug Administration, or European Medicines Agency, approved treatment options available for patients with atrophic AMD.

About Lineage Cell Therapeutics, Inc.

Lineage Cell Therapeutics is a clinical-stage biotechnology company developing novel cell therapies for unmet medical needs. Lineages programs are based on its robust proprietary cell-based therapy platform and associated in-house development and manufacturing capabilities. With this platform Lineage develops and manufactures specialized, terminally differentiated human cells from its pluripotent and progenitor cell starting materials. These differentiated cells are developed to either replace or support cells that are dysfunctional or absent due to degenerative disease or traumatic injury or administered as a means of helping the body mount an effective immune response to cancer. Lineages clinical programs are in markets with billion dollar opportunities and include three allogeneic (off-the-shelf) product candidates: (i) OpRegen, a retinal pigment epithelium transplant therapy in Phase 1/2a development for the treatment of dry age-related macular degeneration, a leading cause of blindness in the developed world; (ii) OPC1, an oligodendrocyte progenitor cell therapy in Phase 1/2a development for the treatment of acute spinal cord injuries; and (iii) VAC2, an allogeneic dendritic cell therapy produced from Lineages VAC technology platform for immuno-oncology and infectious disease, currently in Phase 1 clinical development for the treatment of non-small cell lung cancer. For more information, please visit http://www.lineagecell.com or follow the Company on Twitter @LineageCell.

Forward-Looking Statements

Lineage cautions you that all statements, other than statements of historical facts, contained in this press release, are forward-looking statements. Forward-looking statements, in some cases, can be identified by terms such as believe, may, will, estimate, continue, anticipate, design, intend, expect, could, can, plan, potential, predict, seek, should, would, contemplate, project, target, tend to, suggest, or the negative version of these words and similar expressions. Such statements include, but are not limited to, statements relating to the projected timing of future announcements or presentations of updated or additional data from the Phase 1/2a clinical study of OpRegen, the potential benefits of treatment with OpRegen in dry AMD patients with GA, the significance of clinical data reported to date from the ongoing Phase 1/2a study of OpRegen, including the findings of retinal tissue restoration, Lineages plans to meet with the FDA to discuss OpRegens clinical development, the potential utilization of OCT imaging to measure efficacy in a pivotal clinical trial of OpRegen for the treatment of dry AMD with GA, and the potential for Lineages investigational allogeneic cell therapies to provide safe and effective treatment for multiple, diverse serious or life threatening conditions. Forward-looking statements involve known and unknown risks, uncertainties and other factors that may cause Lineages actual results, performance or achievements to be materially different from future results, performance or achievements expressed or implied by the forward-looking statements in this press release, including risks and uncertainties inherent in Lineages business and other risks in Lineages filings with the Securities and Exchange Commission (SEC). Lineages forward-looking statements are based upon its current expectations and involve assumptions that may never materialize or may prove to be incorrect. All forward-looking statements are expressly qualified in their entirety by these cautionary statements. Further information regarding these and other risks is included under the heading Risk Factors in Lineages periodic reports with the SEC, including Lineages most recent Annual Report on Form 10-K and Quarterly Report on Form 10-Q filed with the SEC and its other reports, which are available from the SECs website. You are cautioned not to place undue reliance on forward-looking statements, which speak only as of the date on which they were made. Lineage undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made, except as required by law.

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OpRegen Data Update to Be Featured at 2021 American Academy of Ophthalmology Annual Meeting in Presentation by Michael S. Ip, M.D. - Business Wire

Parkinsons disease (PD) is the most common neurodegenerative movement disorder, afflicting more than 10 million people worldwide and more than one million Americans. While there is no cure for PD, current therapies focus on treating motor symptoms and fail to reverse, or even address, the underlying neurological damage. In a new study, researchers at the Medical University of South Carolina (MUSC) have identified a novel role for the regulatory protein Bach1 in PD. Their results, published on Oct. 25 in the Proceedings of the National Academy of Sciences, showed that levels of Bach1 were increased in postmortem PD-affected brains, and that cells without Bach1 were protected from the damages that accumulate in PD. In collaboration with vTv Therapeutics, they identified a potent inhibitor of Bach1, called HPPE, that protected cells from inflammation and the buildup of toxic oxidative stress when administered either before or after the onset of disease symptoms.

This is the first evidence that Bach1 is dysregulated in Parkinsons disease, said Bobby Thomas, Ph.D., professor of Pediatrics in the College of Medicine and the SmartState COEE Endowed Chair in Pediatric Neurotherapeutics.

In PD, brain cells that produce the chemical messenger dopamine begin to die as the disease progresses, resulting in tremors and other disruptions to motor function. Additionally, as we age, neurons accumulate damage through inflammation and the buildup of toxic oxidative stress.

There are many genes that combat these destructive pathways, many of which are controlled by two key proteins: Nrf2 and Bach1. Nrf2 functions to turn on the expression of over 250 genes that are involved in protecting the cell from these stressors. Conversely, Bach1 prevents these genes from being activated.

Thomas lab found that levels of Bach1 are increased in autopsied brains of patients with PD, as well as toxin-based preclinical PD models, suggesting that high levels of Bach1 may contribute to PD pathophysiology. To confirm this, the researchers depleted Bach1 in a PD mouse model and showed that dopamine-producing neurons were protected from some of the destructive stress pathways.

To determine how the loss of Bach1 protected neurons from accumulated stress, they analyzed the entire genome of brains from Bach1-depleted mice and looked at which genes were activated.

What we found was that Bach1 not only represses the expression of protective genes that are under the control of Nrf2, but it also regulates the expression of many other genes not directly regulated by Nrf2, said Thomas. So there are additional advantages to inhibiting Bach1 besides just activating Nrf2. Ideally you would want a drug that inhibits Bach1 and also activates Nrf2.

To that end, Thomas partnered with the North Carolina-based company vTv Therapeutics to develop Bach1 inhibitors. Using its proprietary TTP Translational Technology platform, vTv discovered several potential candidates that were validated by Thomas. The top candidate, HPPE, functioned as a superior Bach1 inhibitor in in vitro models. Importantly, HPPE was also a potent activator of Nrf2.

Therefore, pharmacological intervention using HPPE provided the dual benefit of stabilizing Nrf2 and inhibiting Bach1. But how would HPPE work in a preclinical PD mouse model?

The effectiveness of HPPE was tested in a neurotoxin-based PD mouse model. HPPE alleviated toxin-induced PD symptoms when given either before the induction of disease or after the onset of disease symptoms. Further analyses showed that HPPE protects neurons from destructive pathways by turning on antioxidant genes and turning off pro-inflammatory genes.

Interestingly, HPPE worked better at protecting neurons than current FDA-approved Nrf2 activators, such as Tecfidera (dimethyl fumarate). Current activators function as electrophiles they permanently bind to and modify proteins which can lead to cellular toxicity or activation of the immune system and have many side effects.

The most interesting aspect of the study is that the Bach1 inhibitor is a non-electrophile, so it doesnt work like the FDA-approved Nrf2 activators, said Thomas. As a result of this difference, hopefully, HPPE will not demonstrate as many side effects.

Disruption of Bach1 and the simultaneous activation of Nrf2 clearly provide a strong basis for using HPPE as a potential therapeutic in PD. But several questions remain unanswered. While there were no side effects observed with acute treatment using HPPE in the PD mouse model, one key goal moving forward is to determine what impacts, if any, long-term use of HPPE might have. Another key question centers on the benefits of modulating this pathway in more chronic models of PD, other cell types in the brain and potentially other dementias.

Thispathway may be beneficial whenever you have impairments in anti-inflammatorypathways or mitochondrial dysfunctions, said Thomas. I think any disease thathas these kinds of etiologies would benefit from modulating this pathway.

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Deterioration of brain cells in Parkinson's disease is slowed by blocking the Bach1 protein, preclinical study shows - Medical University of South...

Dr. Michael Kaplitt, a professor of neurological surgery at Weill Cornell Medicine and a longtime leader in developing cutting-edge surgical therapies for movement disorders, leads a team that has been awarded a three-year, $8.9 million grant from the Aligning Science Across Parkinsons (ASAP) initiative. The grant will fund an ambitious and innovative multi-institutional collaborative effort to study how abnormal protein aggregates may spread from the gut to the brain to drive the early stages of Parkinsons disease.

Dr. Michael Kaplitt. Credit: Stephanie Diani

ASAP is a coordinated research initiative to advance targeted basic research for Parkinsons disease. Its mission is to accelerate the pace of discovery and inform the path to a cure through collaboration, research-enabling resources and data sharing. The Michael J. Fox Foundation for Parkinsons Research is ASAPs implementation partner and issued the grant.

I am so grateful to ASAP and The Michael J. Fox Foundation for this exciting opportunity, said Dr. Kaplitt, who is also vice-chair for research in the Department of Neurological Surgery at Weill Cornell Medicine and a neurosurgeon at NewYork-Presbyterian/Weill Cornell Medical Center. Interaction between the body and the brain is a very exciting and important area of research, and it is increasingly clear that, at least in some cases, Parkinsons disease may begin in the gut, with the disease spreading through nerve connections to the brain and eventually throughout the brain.

Parkinsons disease is a progressive neurodegenerative disease that is considered chiefly a movement disorder, although it typically features many other signs and symptoms, from sleep problems and low blood pressure to dementia. Parkinsons affects more than 10 million people worldwide and has no cure.

One clue to the cause of the disorder is the presence of abnormal clumps of protein within brain cells in affected brain regions. These clumps mainly consist of tiny, fiber-like aggregates of the brain-cell protein alpha synuclein. The synuclein fibrils tend to spread through the brain in a characteristic pattern during the course of Parkinsons. There is evidence suggesting that, in many cases, these disease-linked fibrils form initially in nerve cells in the intestines and trigger the classic signs of Parkinsons only after they travel to the brain, via a large gut-to-brain nerve called the vagus nerve.

Dr. Kaplitt and his collaborators will use a recently developed mouse model of this gut-to-brain disease-seeding process to explore in detail how it begins in the intestines, how it relates to early, pre-motor Parkinsons signs including sleep disorders, and whether it differs between maleswho are known to get Parkinsons at a higher rateand pre-menopausal females. Ultimately the researchers will try to develop methods for the early detection of gut alpha-synuclein aggregates and the blocking of their spread to the brain to prevent full-blown Parkinsons. Dr. Kaplitt will draw on his extensive experience in developing and testing experimental gene therapies for Parkinsons.

Bringing our nearly 30 years of experience with gene therapy to this project will allow us to not only understand how this gut-to-brain transmission happens, but also potentially intervene genetically to improve brain function and stop the spread of disease, said Dr. Kaplitt, who is also a professor of neuroscience in the Feil Family Brain and Mind Research Institute, a professor of neurological surgery in neurology and of neurological surgery in otolaryngology at Weill Cornell Medicine.

Dr. Kaplitt will collaborate with co-investigators Dr. Ted Dawson, director of the Johns Hopkins Institute for Cell Engineering and professor of neurology at the Johns Hopkins University School of Medicine, and Dr. Per Svenningsson, a professor of neurology at Karolinska Institutet and Karolinska University Hospital in Sweden, on the research. Co-investigator Dr. Roberta Marongiu, assistant professor of neuroscience research in neurological surgery and assistant professor of research in neuroscience in the Feil Family Brain and Mind Research Institute at Weill Cornell Medicine, will conduct the research examining sex and menopause effects.

It is exciting to be part this fantastic team of international investigators, said Dr. Dawson. There is a growing amount of evidence of the guts role in Parkinsons disease, and we are developing excellent scientific models to study the diseases progression from the start. Our multidisciplinary approach holds tremendous promise in identifying innovative ways to treat Parkinsons disease.

"It is very stimulating to work on this excellent team to increase our understanding of mechanisms underlying the propagation of alpha-synuclein from the gut to the brainstem,"added Dr. Svenningsson.

We are excited to work with our outstanding international team of leading investigators to address different aspects of this question, said Dr. Kaplitt.

It is extremely exciting to work alongside this outstanding team of investigators, said Dr. Marongiu. My group will study how sex and menopause influence the spread of Parkinsons disease pathology from the gut to the brain in the early stages of the disease. This will help us understand more about the intricate relationship between hormones and onset of Parkinsons and has the potential to identify novel precision medicine approaches for men and women.

Other members of Dr. Kaplitts team include Drs. Chris Schaffer and Nozomi Nishimura, associate professors at the Meinig School of Biomedical Engineering at Cornell University, who will use innovative methods they have developed to image vagus-linked gut neurons, to track the spread and the physiological effects of early synuclein pathology. Dr. Babacar Cisse, assistant professor of neurological surgery at Weill Cornell Medicine, a neurosurgeon at NewYork-Presbyterian/Weill Cornell Medical Center and an expert in immune cells in the brain called microglia, will investigate whether microglia are responsible for some of the patterns of spread once the pathology enters the brain from the gut.

"We are so honored that Dr. Kaplitt and his team have been selected for this grant," said Dr. Philip E. Stieg, chair of neurological surgery at Weill Cornell Medicine and neurosurgeon-in-chief of NewYork-Presbyterian/Weill Cornell Medical Center. "There is no neurosurgeon in the world better qualified than he is to do this work. Dr. Kaplitt has been a pioneer in functional neurosurgery, particularly for movement disorders, for many years now and is a true leader in the field.

Bringing together this international team of the most forward-thinking, most innovative researchers in Parkinson's disease holds so much promise for patients, he added. We all look forward to the discoveries that come from this research, which has the potential to create effective new treatments for this debilitating disease."

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$9M Grant Funds Study of Gut-Brain Connection in Parkinson's Disease - Weill Cornell Medicine Newsroom