First patient dosed in clinical trial for a drug-resistant form of epilepsy

Tablet BM47753. Neo-Babylonian Period. Courtesy of the British Museum, London.

Epilepsy seems to have been a problem for people for as long as people have been around. The first recorded mention of it is on a 4000-year-old Akkadian tablet found in Mesopotamia (modern day Iraq). The tablet includes a description of a person with “his neck turning left, hands and feet are tense, and his eyes wide open, and from his mouth froth is flowing without him having any consciousness.”

Despite that long history, effective treatments for epilepsy were a long time coming. It wasn’t till the middle of the 19th century that physicians started using bromides to help people with the condition, but they also came with some nasty side effects, including depression, weakness, fatigue, lethargy, and coma.

Fast forward 150 years or so and we are now, hopefully, entering a new era. This week, Neurona Therapeutics announced they had dosed the first patient in their first-in-human clinical trial formesial temporal lobe epilepsy (MTLE), the most common form of focal epilepsy in adults. The trial specifically targets people who have a drug-resistant form of MTLE.

Neurona has developed a therapy called NRTX-1001, consisting of a specialized type of neuronal or brain cell derived from embryonic stem cells.  These cells are injected into the brain in the area affected by the seizures where they release a neurotransmitter or chemical messenger that will block the signals in the brain causing the epileptic seizures. Pre-clinical testing suggests a single dose of NRTX-1001 may have a long-lasting ability to suppress seizures.

A new approach is very much needed because current therapies for drug-resistant epilepsy are only partially effective and have serious drawbacks. One treatment that can significantly reduce seizure frequency is the removal of the affected part of the brain, however this can cause serious, irreversible damage, such as impacting memory, mood and vision.

CIRM has a vested interest in seeing this therapy succeed. We have invested more than $14 million over four different awards, in helping this research progress from a basic or Discovery level through to the current clinical trial.

In a news release, two key figures in administering the first dose to a patient said this was an important step forward. 

Harish Babu, M.D., Ph.D., assistant professor of neurosurgery at SUNY Upstate Medical University said: “Neurona’s regenerative cell therapy approach has the potential to provide a single-administration, non-destructive alternative for the treatment of drug-resistant focal epilepsy. Currently, people with mesial temporal lobe epilepsy who are not responsive to anti-seizure medications have few options, such as an invasive surgery that removes or destroys the affected brain tissue.”

Robert Beach, M.D., Ph.D. professor of neurology at SUNY Upstate Medical University added: “The objective of NRTX-1001 is to add cells that have the potential to repair the circuits that are damaged in epilepsy and thus reduce seizure activity.”

There is a huge unmet medical need for an effective, long-term therapy. Right now, it’s estimated that three million Americans have epilepsy, and 25 to 35 percent live with ongoing seizures despite dozens of approved drugs on the market.

If this therapy works it might mean that 4,000 year old tablet will become a medical footnote, rather than a reminder that we still have work to do.

Can regenerative medicine turn back the clock on aging?

One of my favorite phrases is “standing room only”. I got a chance to use it last week when we held a panel discussion on whether regenerative medicine could turn back the clock on aging. The event was at the annual conference of the International Society for Stem Cell Research (ISSCR) and more than 150 people packed into a conference room to hear the debate (so far more than 800 also watched a live stream of the event.)

It’s not surprising the place was jammed. The speakers included:

  • Dr. Deepak Srivastava, the President of the Gladstone Institutes, an expert on heart disease and the former President of ISSCR.
  • Dr. Stanley “Tom” Carmichael, Chair of the Department of Neurology at UCLA and an expert on strokes and other forms of brain injury.
  • Adrienne Shapiro, the mother of a daughter with sickle cell disease, a tireless patient advocate and supporter of regenerative medicine research, and the co-founder of Axis Advocacy, a family support organization for people with sickle cell.
  • Jonathan Tomas, PhD, JD, the Chair of the CIRM Board.

And the topic is a timely one. It is estimated that as many as 90 percent of the people who die every day, die from diseases of aging such as heart disease, stroke, and cancer. So, what can be done to change that, to not just slow down or stop these diseases, but to turn back the clock, to repair the damage already done and replace cells and tissues already destroyed.

The conversation was enlightening, hopeful and encouraging, but also cautionary.

You can watch the whole event on our Youtube channel.

I think you are going to enjoy it.

Two reasons to remember June 19th

Today marks two significant events for the Black community. June 19th is celebrated as Juneteenth, the day when federal troops arrived in Galveston, Texas to ensure that the enslaved people there were free. That moment came two and a half years after President Abraham Lincoln signed the Emancipation Proclamation into law.

June 19th is also marked as World Sickle Cell Awareness Day. It’s an opportunity to raise awareness about a disease that affects around 100,000 Americans, most of them Black, and the impact it has on the whole family and entire communities.

Sickle cell disease (SCD) is an inherited blood disorder that is caused by a genetic mutation. Instead of red blood cells being smooth and round and flowing easily through arteries and veins, the cells are sickle shaped and brittle. They can clog up arteries and veins, cutting off blood to vital organs, causing intense pain, organ damage and leading to premature death.

SCD can be cured with a bone marrow transplant, but that’s a risky procedure and most people with SCD don’t have a good match. Medications can help keep it under control but cannot cure it. People with SCD live, on average, 30 years less than a healthy adult.

CIRM has invested almost $60 million in 13 different projects, including five clinical trials, to try and develop a cure for SCD. There are encouraging signs of progress. For example, in July of 2020, Evie Junior took part in a CIRM-funded clinical trial where his own blood stem cells were removed then, in the laboratory, were genetically modified to repair the genetic mutation that causes the disease. Those cells were returned to him, and the hope is they’ll create a sickle cell-free blood supply. Evie hasn’t had any crippling bouts of pain or had to go to the hospital since his treatment.

Evie Junior: Photo by Jaquell Chandler

CIRM has also entered into a unique partnership with the National Heart, Lung and Blood Institute (NHLBI) to co-fund cell and gene therapy programs under the NIH “Cure Sickle Cell” initiative.  The goal is to markedly accelerate the development of cell and gene therapies for SCD.

“There is a real need for a new approach to treating SCD and making life easier for people with SCD and their families,” says Adrienne Shapiro, the mother of a daughter with SCD and the co-founder of Axis Advocacy, a sickle cell advocacy and education organization. “Finding a cure for Sickle Cell would mean that people like my daughter would no longer have to live their life in short spurts, constantly having their hopes and dreams derailed by ER visits and hospital stays.  It would mean they get a chance to live a long life, a healthy life, a normal life.”

We will all keep working together to advance this research and develop a cure. Until then Juneteenth will be a reminder of the work that still lies ahead.

Creating a ‘bespoke’ approach to rare diseases

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Up until recently the word “bespoke” meant just one thing to me, a hand-made suit, customized and fitted to you. There’s a street in London, Saville Row, that specializes in these suits. They’re gorgeous. They’re also very expensive and so I thought I’d never have a bespoke anything.

I was wrong. Because CIRM is now part of a bespoke arrangement. It has nothing to do with suits, it’s far more important than that. This bespoke group is aiming to create tailor-made gene therapies for rare diseases.

It’s called the Bespoke Gene Therapy Consortium (BGTC). Before we go any further I should warn you there’s a lot of acronyms heading your way. The BGTC is part of the Accelerating Medicines Partnership® (AMP®) program. This is a public-private partnership between the National Institutes of Health (NIH), the U.S. Food and Drug Administration (FDA), and multiple public and private organizations, such as CIRM.

The program is managed by the Foundation for the NIH (FNIH) and it aims to develop platforms and standards that will speed the development and delivery of customized or ‘bespoke’ gene therapies that could treat the millions of people affected by rare diseases.

Why is it necessary? Well, it’s estimated that there are around 7,000 rare diseases and these affect between 25-30 million Americans. Some of these diseases affect only a few hundred, or even a few dozen people. With so few people they almost always struggle to raise the funds needed to do research to find an effective therapy. However, many of these rare diseases are linked to a mutation or defect in a single gene, which means they could potentially be treated by highly customizable, “bespoke” gene therapy approaches.

Right now, individual disease programs tend to try individual approaches to developing a treatment. That’s time consuming and expensive. The newly formed BGTC believes that if we create a standardized approach, we could develop a template that can be widely used to develop bespoke gene therapies quickly, more efficiently and less expensively for a wide array of rare diseases.

“At CIRM we have funded several projects using gene therapy to help treat, and even cure, people with rare diseases such as severe combined immunodeficiency,” says Dr. Maria T. Millan, the President and CEO of CIRM. “But even an agency with our resources can only do so much. This agreement with the Bespoke Gene Therapy Consortium will enable us to be part of a bigger partnership, one that can advance the field, overcome obstacles and lead to breakthroughs for many rare diseases.”

With gene therapy the goal is to identify the genetic defect that is causing the disease and then deliver a normal copy of the gene to the right tissues and organs in the body, replacing or correcting the mutation that caused the problem. But what is the best way to deliver that gene? 

The BGTC’s is focusing on using an adeno-associated virus (AAV) as a delivery vehicle. This approach has already proven effective in Leber congenital amaurosis (LCA), retinitis pigmentosa (RP), and spinal muscular atrophy. The consortium will test several different approaches using AAV gene therapies starting with basic research and supporting those all the way to clinical trials. The knowledge gained from this collaborative approach, including developing ways to manufacture these AAVs and creating a standard regulatory approach, will help build a template that can then be used for other rare diseases to copy.

As part of the consortium CIRM will identify specific rare disease gene therapy research programs in California that are eligible to be part of the AMP BGTC. CIRM funding can then support the IND-enabling research, manufacturing and clinical trial activities of these programs.

“This knowledge network/consortium model fits in perfectly with our mission of accelerating transformative regenerative medicine treatments to a diverse California and world,” says Dr. Millan. “It is impossible for small, often isolated, groups of patients around the world to fund research that will help them. But pooling our resources, our skills and knowledge with the consortium means the work we support here may ultimately benefit people everywhere.”

Join us to hear how stem cell and gene therapy are taking on diseases of aging

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.

Here’s where you can see the livestream: https://www.youtube.com/watch?v=CaUgsc5alDI

And if you have any questions you would like the panel to answer feel free to send them to us at info@cirm.ca.gov

The long road to developing a therapy for epilepsy

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Good science takes time. That’s an important guiding phrase for researchers looking to develop new therapies. But it’s also a frustrating reality for patients who are waiting for something to help them now.

That point was driven home last week when the governing board of the California Institute for Regenerative Medicine (CIRM) voted to invest almost $8 million to test a new approach to treating a drug-resistant form of epilepsy. This approach holds a lot of promise but getting to this point has not been easy or quick.

Epilepsy is one of the most common neurological disorders in the US, affecting more than three million people. More than one third of those people have a form of epilepsy that doesn’t respond to current medications, so the only options are surgery or using lasers (LITT) to remove the affected part of the brain. Not surprisingly this can cause serious, irreversible damage, such as effects on memory, mood and vision. Equally unsurprising, because of those impacts many people are reluctant to go that route.

Now a company called Neurona Therapeutics has developed a new approach called NRTX-1001. This consists of a specialized type of neuronal or brain cell that is derived from embryonic stem cells (hESCs).  These neuronal cells are injected into the brain in the area affected by the seizures where they release a neurotransmitter or chemical messenger that will block the signals in the brain causing the epileptic seizures. Pre-clinical testing suggests a single dose of NRTX-1001 may have a long-lasting ability to suppress seizures.

Cory Nicholas, PhD, the Co-Founder and CEO of Neurona says this approach will be tested on people with drug-resistant temporal lobe epilepsy, the most common form of epilepsy.

“To our knowledge, NRTX-1001 is the first human cell therapy to enter clinical trials for epilepsy. This cell therapy has the potential to provide a less invasive, non-tissue destructive, regenerative alternative for people with chronic focal seizures.” 

“Epilepsy patient advocates and clinicians have said that such a regenerative cell therapy could represent a first option that, if successful, could obviate the need for lobectomy/LITT. And for those not eligible for lobectomy/LITT, cell therapy could provide the only option to potentially achieve seizure-freedom.”

Nicholas says this work didn’t happen overnight. “This effort to develop regenerative cell therapy for epilepsy officially began in the early 2000’s from the laboratories of John Rubenstein, MD, PhD, Arturo Alvarez-Buylla, PhD, and Arnold Kriegstein, MD, PhD, at UC San Francisco. They were among the first to understand how specialized inhibitory nerve cells, called interneurons, develop from neural stem cells in our forebrain before birth. Subsequently, they pioneered the extraction and use of these cells as a cell therapy in preclinical models.”

Over the years the group working on this approach expanded, later becoming Neurona Therapeutics, and CIRM supported that work with several awards.

“CIRM provided the necessary funds and expertise to help translate our discoveries toward the clinic using human embryonic stem cell (hESC) technology to generate a sustainable supply of interneuron cells for further evaluation. Truly, CIRM has been the essential catalyst in accelerating this important research from bench to bedside.”

Nicholas says its immensely gratifying to be part of this work, and to know that if it succeeds it will be life-altering, even life-saving, for so many people.

“It is difficult to reflect back with all the work that is happening at present on the first-in-human trial, but it is always emotional for me to think about our amazing team: Neurona employees, CIRM staff, clinicians, professors, trainees, collaborators, and investors; who have worked tirelessly in contributing to the advancement of this therapeutic mission. I am deeply humbled by the opportunity to be part of this innovative, rigorous, and compassionate effort, and by the responsibility to the brave patients participating in the study. We remain steadfast in our commitment to patient safety and cautiously optimistic that NRTX-1001 cell therapy will improve quality of life for people living with chronic focal epilepsy. Moreover, we are sincerely thankful to Californians for their commitment to CIRM’s vision, and we are proud to be a part of this groundbreaking initiative that has put our state at the forefront, dedicated to fulfilling the promise of regenerative medicine.”

The power of the patient advocate: how a quick visit led to an $11M grant to fund a clinical trial

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Members of NFOSD visiting UC Davis in 2013

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.

Google eases ban on ads for stem cell therapies

What started out as an effort by Google to crack down on predatory stem cell clinics advertising bogus therapies seems to be getting diluted. Now the concern is whether that will make it easier for these clinics to lure unsuspecting patients to pay good money for bad treatments?

A little background might help here. For years Google placed no restrictions on ads by clinics that claimed their stem cell “therapies” could cure or treat all manner of ailments. Then in September of 2019 Google changed its policy and announced it was going to restrict advertisements for stem cell clinics offering unproven, cellular and gene therapies.

This new policy was welcomed by people like Dr. Paul Knoepfler, a stem cell scientist at UC Davis and longtime critic of these clinics. In his blog, The Niche, he said it was great news:

“Google Ads for stem cell clinics have definitely driven hundreds if not thousands of customers to unproven stem cell clinics. It’s very likely that many of the patients who have ended up in the hospital due to bad outcomes from clinic injections first went to those firms because of Google ads. These ads and certain particularly risky clinics also are a real threat to the legitimate stem cell and gene therapy fields.”

Now the search-engine giant seems to be adjusting that policy. Google says that starting July 11 it will permit ads for stem cell therapies approved by the US Food and Drug Administration (FDA). That’s fine. Anything that has gone through the FDA’s rigorous approval process deserves to be allowed to advertise.

The real concern lies with another adjustment to the policy where Google says it will allow companies to post ads as long as they are “exclusively educational or informational in nature, regardless of regulatory approval status.” The problem is, Google doesn’t define what constitutes “educational or informational”. That leaves the door open for these clinics to say pretty much anything they want and claim it meets the new guidelines.

To highlight that point Gizmodo did a quick search on Google using the phrase “stem cells for neuropathy” and quickly came up with a series of ads that are offering “therapies” clearly not approved by the FDA. One ad claimed it was “FDA registered”, a meaningless phrase but one clearly designed to add an air of authenticity to whatever remedy they were peddling.

The intent behind Google’s change of policy is clearly good, to allow companies offering FDA-approved therapies to advertise. However, the outcome may not be quite so worthy, and might once again put patients at risk of being tricked into trying “therapies” that will almost certainly not do them any good, and might even put them in harm’s way.

The bootcamp helping in the fight against rare diseases

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Dr. Emil Kakkis at the Rare Entrepreneur Bootcamp

Imagine you or someone you love is diagnosed with a rare disease and then told, “There is no cure, there are no treatments and because it’s so rare no one is even doing any research into developing a treatment.” Sadly for millions of people that’s an all-too-common occurrence.

There are around 7,000 rare diseases affecting some 25-30 million Americans. Some of these are ultra-rare conditions where worldwide there may be only a few hundred people, or even a few dozen, diagnosed with it. And of all these rare diseases, only 5% have an approved therapy.

For the people struggling with a rare disease, finding a sense of hope in the face of all this can be challenging. Some say it feels as if they have been abandoned by the health care system. Others fight back, working to raise both awareness about the disease and funds to help support research to develop a treatment. But doing that without experience in the world of fund raising and drug development can pose a whole new series of challenges.

That’s where Ultragenyx comes into the picture. The company has a simple commitment to patients. “We aim to develop safe and effective treatments for many serious rare diseases as fast as we can, and we are committed to helping the whole rare disease community move forward by sharing our science and expertise to advance future development, whether by us or others.”

They live up to that commitment by hosting a Rare Entrepreneur Bootcamp. Every year they bring together a dozen or so patient or family organizations that are actively raising funds for a potential treatment approach and give them a 3-day crash course in what they’ll need to know to have a chance to succeed in rare disease drug development.

A panel discussion at the Rare Entrepreneur Bootcamp

Dr. Emil Kakkis, the founder of Ultragenyx, calls these advocates “warriors” because of all the battles they are going to face. He told them, “Get used to hearing no, because you are going to hear that a lot. But keep fighting because that’s the only way you get to ‘yes’.”

The bootcamp brings in experts to coach and advise the advocates on everything from presentation skills when pitching a potential investor, to how to collaborate with academic researchers, how to design a clinical trial, what they need to understand about manufacturing or intellectual property rights.

In a blog about the event, Arjun Natesan, vice president of Translational Research at Ultragenyx, wrote, “We are in a position to share what we’ve learned from bringing multiple drugs to market – and making the process easier for these organizations aligns with our goal of treating as many rare disease patients as possible. Our aim is to empower these organizations with guidance and tools and help facilitate their development of life-changing rare disease treatments.”

For the advocates it’s not just a chance to gain an understanding of the obstacles ahead and how to overcome them, it’s also a chance to create a sense of community. Meeting others who are fighting the same fight helps them realize they are not alone, that they are part of a bigger, albeit often invisible, community, working tirelessly to save the lives of their children or loved ones.  

CIRM also has a commitment to supporting the search for treatments for rare diseases. We are funding more than two dozen clinical trials, in addition to many earlier stage research projects, targeting rare conditions.

Stem cell-derived retinal patch continues to show promising results two years post-implantation

Earlier this year we wrote about the promising results of a phase 1 clinical trial aimed at replacing the deteriorating cells in the retinas of people suffering from age-related macular degeneration- one of the leading causes of blindness worldwide for people over 50. Now there’s even more good news! Highlighted in a news story on the UC Santa Barbara (UCSB) website, researchers are continuing to make progress in their bid to secure approval from the Food and Drug Administration for the life-changing treatment.

Through the collaborative efforts of researchers at UCSB, University of Southern California and California Institute of Technology, a stem cell-derived implant using cells from a healthy donor was developed. The bioengineered implant, described as a scaffold, was then implanted under the retina of 16 participants. If the implant was to work, the new cells would then take up the functions of the old ones, and slow down or prevent further deterioration. In the best-case scenario, they could restore some lost vision.

The first sets of trials, funded by the California Institute for Regenerative Medicine (CIRM), concentrated on establishing the safety of the patch and collecting data on its effectiveness. Parting ways with old practices, the participants in the trial were given just two months of immunosuppressants whereas in the past, using donor cells meant that patients often had to be given long-term immunosuppression to stop their body’s immune system attacking and destroying the implanted cells. The team found that after two years, the presence of the patch hadn’t triggered other conditions associated with implantation, such as the formation of new blood vessels or scar tissue that could cause a detachment of the retina.

Even more importantly, they found no sign of inflammation that indicated an immune response to the foreign cells even after the patient was taken off immunosuppressants two months post-implantation. “What really makes us excited is that there is some strong evidence to show that the cells are still there two years after implantation and they’re still functional,” said Mohamed Faynus, a graduate student researcher in the lab of stem cell biologist Dennis O. Clegg at UCSB.

Having passed the initial phase, the team of researchers now hopes to begin phase 2 of the trial. This time, they are aiming to more specifically assesses the effectiveness of the patch in participants. Looking even farther ahead, the Clegg Lab and colleagues are also exploring combining multiple cell types on the patch to treat patients at varying stages of the disease.

In addition, there have also been improvements made to extend the shelf life of the patch. “Cryopreservation of the therapy significantly extends the product’s shelf-life and allows us to ship the implant on demand all over the world, thus making it more accessible to patients across the globe,” said Britney Pennington, a research scientist in the Clegg Lab.