Category Archives: Stem Cells

Understanding the genetic causes of rare diseases supports drug development. Credit: Shutterstock.

Developing drugs to treat rare diseases is fraught with challenges; these range from trying to recruit from tiny patient populations to fill much-need clinical trials to the complex reimbursement landscape for these innovative, and often bespoke, therapies. However, as scientists improve their understanding of the genetic causes of many rare conditions and regulators explore new reimbursement options, pharma companies and smaller biotech firms are increasingly being empowered to address more of these tricky indications.

In this context, could 2020 be a breakthrough year for patients with rare diseases? Here are three case studies of companies on the verge of having treatments for rare diseases approved Rocket and Fanconi anaemia, PTC Therapeutics and aromatic l-amino acid decarboxylase (AADC) deficiency and, finally, Amryt and epidermolysis bullosa.

Fanconi anaemia (FA) is a rare paediatric inherited diseasecharacterised by bone marrow failure and predisposition to cancer, in the words of Rocket Pharmas CEO Gaurav Shah. Caused by a mutation in the FANC genes, patients with Fanconi experience bone marrow failure as they are unable to create new blood cells.

The current standard of care for Fanconi is a stem cell transplant, but Shah explains the risks involved with these pioneering procedures.

While these transplants do prolong patients lives, the procedure is incredibly difficult and is associated with a high potential for graft-versus-host disease, he says. Stem cell transplants can also lead to an even higher risk of head and neck cancer risk for Fanconi patients; almost everyone with FA who undergoes this procedure dies in their 30s.

Rocket wants to change this situation with its lentiviral vector gene therapy, RP-L102. It is specifically for Fanconi-A, which Shah explains is the most common form of the disease. He adds that the therapy contains patient-derived haematopoietic stem cells that have been generally modified to contain a functional copy of FANCA gene, a mutation which causes Fanconi-A.

RP-L102 is currently in a global registrational Phase IIA study, which has been efficacious and safe in patients so far. The data demonstrate that a single dose of RP-L102 leads to both genetic and functional correction as measured by a progressive increase in corrected peripheral blood and bone marrow cells, says Shah. Most importantly, this treatment can be administered without a conditioning regimen [of chemotherapy and radiation]. [This] means we may be able to treat patients as a preventative measure before bone marrow failure occurs, like a vaccine, with a single dose administration early in life.

Based on these promising signals, RP-L102 has received all accelerated regulatory tools from the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). The company is hoping to complete its biologics license applications and marketing authorisation applications (MAA) to the two regulators within the next few years.

To overcome challenges facing Rocket in the development of RP-L102, Shah explains the company worked to improve upon its own expertise in rare diseases by working with world-class research and development partners, as well immersing itself within patient communities to learn more about their treatment needs.

Slightly further along the drug approval journey is PTC Therapeutics AADC deficiency drug, PTC-AADC, for which the company recently submitted an MAA to the EMA. The company expects full EMA approval towards the end of 2020 and to treat the first patients either in the first or second quarter of 2021.

PTC acquired PTC-AADC, alongside other gene therapy assets, when it bought rare central nervous system-focused Agilis Biotherapeutics in July 2018, PTCs EMEA and Asia Pacific senior vice-president and general manager Adrian Haigh explains.

AADC deficiency is a rare condition caused by a mutation in the DDC gene, which leads to issues with the AADC enzyme and subsequent reductions in the production of dopamine. Children suffering with AADC deficiency fail to reach neurological and development milestones and have a high risk of death early in life. The only current approach to treating the condition is through dopamine agonists, which Haigh notes are largely ineffective.

The particular approach developed by Agilis, [which is] unlike other forms of gene therapy, involves delivering a very small dose of gene therapy directly into the affected, post-mitotic cells, Haigh says. The rationale is that once youve delivered the drug to post-mitotic cells, which are not dividing, it is going to stay there for a long time.

Other advantages include a reduced chance of significant immune reaction and since the dose is smaller, the treatment could overcome some of the manufacturing issues facing other gene therapies. PTC has decided to bring PTC-AADCs manufacturing in house so they are not reliant on third parties schedules and capacities.

PTCs MAA for its AADC deficiency gene therapy is based on two clinical trials of 26 patients in total. Haigh explains the company has mapped motor milestones, and he noted that in advisory boards with payers theyve been incredibly impressed by our videos showing children progressing from lying flat on their backs to walking around.

He notes that in this case, it is certainly not ethical to drill a hole in a patients head and inject a virus containing a placebo and instead PTC has successfully completed a single-arm trial by comparing with patients natural history. Regulators need to be open to novel clinical trial design, particularly in rare diseases where you have ethical problems, Haigh argues.

The company had to abandon a previous drug in development because they could not agree an economic and deliverable clinical trial design with the FDA.

One of the main challenges that faced PTC in the development of PTC-AADC was diagnosis. Haigh explains they found a lot of patients have been misdiagnosed with either cerebral palsy or epilepsy so the company launched a free genetic testing programme. This also allowed them to find patients to recruit into the trial and estimate the number of patients with AADC deficiency who might be able to benefit from this gene therapy.

Epidermolysis bullosa (EB) is a group of rare skin conditions caused by genetic mutations in the genes that encode for the proteins of the skin, particularly in collagen VII.

There are currently no approved treatments for this condition, EB charity DEBRAs UK branch director of research Caroline Collins notes the condition is managed by regular changing of dressings and the lancing of blisters.

EB is characterised by blisters and wounds on the skin; these wounds are extremely painful and can cover huge areas of the patients body, such as their whole back or entire legs. However, Collins explains these are not like the kinds of wounds you get with ulcers or burns, and they move continuously.

As well as making it incredibly challenging for patients to deal with these never-healing wounds, it also makes it difficult for drug developers to find and establish accepted clinical trial endpoints centred on wound healing. DEBRA is therefore advocating for natural history to be considered in clinical trial designs, Collins explains.

Despite these challenges, UK drug company Amryt is hoping to submit authorisation applications to the FDA and EMA by the end of 2021 for its EB drug, AP101. The company has repurposed the topical gel created for burns wounds to treat EB. It is made from a combination of an extract from the bark of the birch tree and pure sunflower oil, the companys chief medical officer Dr Mark Sumeray explains.

AP101 is currently being studied in a Phase III study Amryt claim this is the biggest global EB trial ever undertaken and has been granted rare paediatric disease designation from the FDA.

Although the current results are blinded, Sumeray explains a recent analysis by an independent data monitoring board found that the firm only needed to increase the number of patients slightly, suggesting that at this point in time, the data would have looked encouraging. Too small a patient population makes it hard for efficacy to be statistically significant.

Since Amryts AP101 may be the first drug approved for EB, Collins emphasises it is important that the company has productive conversations with regulators about the specific challenges of EB. This will help to set the ground for others to follow and further transform the lives of EB patients.

It is clear that Amryt is committed to EB because the company in-licensed a second EB candidate, a topical gene therapy called AP103 in 2018.

Sumeray explains: We have invested a lot of time and effort in the development, not only of the lead product, but also of relationships with physicians and scientists working in EB. If we can figure out how to successfully bring products to the market and have them reimbursed, then all of that knowledge can applied again.

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Rare disease outlook 2020: three therapies set to make waves this year - pharmaceutical-technology.com

Neuroplast is a company based in Maastricht (the Netherlands) developing autologous stem cell therapies for patients suffering from neurodegenerative diseases such as spinal cord injury (SCI), amyotrophic lateral sclerosis (ALS) and traumatic brain injury.

Recently, the company has raised 4 million from Dutch-based Brightlands Venture Partners and LIOF and from an existing shareholder and informal investor Lumana Invest BV.

CEO Johannes de Munter said:

The financing and support of the investors will enable us to perform multicenter clinical trials in the Netherlands, Denmark, Germany, and Spain and bring the product to market.

This Dutch startup will use the fund to perform a phase II/III clinical trial with the aim of obtaining conditional market approval for the treatment of patients suffering from Spinal Cord Injury.

Founded by physician Hans de Munter and neurologist Erik Wolters in 2014, Neuroplast has expanded with Juliette van den Dolder, who was appointed as COO and management team member.

In the case of SCI, isolating, manufacturing, and reinserting patients own cells, very promising preclinical outcomes have resulted in an Orphan Drug Designation from European regulatory authorities, allowing a fast-track procedure for the clinical trials. These trials are expected to start in March 2020.

Marcel Kloosterman Director at Brightlands Venture Partners:

Neuroplast combines breakthrough science with a solid management team. In a sizable market characterised by major unmet need, successful treatment of (accident caused) paralysed patients would make life so much easier for them and their families while lowering the burden and costs for the society.

Yearly, 24,500 people in Europe and the USA are diagnosed with Spinal Cord Injury, usually caused by accident. Its worth mentioning that for Europe and the US, the medical cost associated with Spinal Cord Injury is over 13 bn per year.

CEO Johannes de Munter adds:

Neuroplast is becoming an ATMP player in the region and wants to contribute to our beautiful eco-system.

Main image credits:Neuroplast

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Dutch startup Neuroplast raises 4M for its stem cell-based technology to treat patients with Spinal Cord Injury - Silicon Canals

The road into Batlow is littered with the dead.

In the smoky, gray haze of the morning, it's hard to make out exactly what Matt Roberts' camera is capturing. Roberts, a photojournalist with the Australian Broadcasting Corporation, keeps his lens focused on the road as he rolls into the fire-ravaged town 55 miles west of Canberra, Australia's capital. At the asphalt's edge, blackened livestock carcasses lie motionless.

The grim scene, widely shared on social media, is emblematic of the impact the 2019-20 bushfire season has had on Australia's animal life. Some estimates suggest "many, many billions" of animals have been killed, populations of endemic insects could be crippled and, as ash washes into riverways, marine life will be severely impacted. The scale of the bushfires is so massive, scientists are unlikely to know the impact on wildlife for many years.

But even before bushfires roared across the country, Australia's unique native animals were in a dire fight for survival. Habitat destruction, invasive species, hunting and climate change have conspired against them. Populations of native fauna are plummeting or disappearing altogether, leaving Australia with an unenviable record: It has the highest rate of mammal extinctions in the world.

A large share of Australia's extinctions have involved marsupials -- the class of mammals that includes the nation's iconic kangaroos, wallabies, koalas and wombats. A century ago, the Tasmanian tiger still padded quietly through Australia's forests. The desert rat-kangaroo hopped across the clay pans of the outback, sheltering from the sun in dug-out nests.

Now they're gone.

Australia's 2019-20 bushfire season has been devastating for wildlife.

In a search for answers to the extinction crisis, researchers are turning to one lesser-known species, small enough to fit in the palm of your hand: the fat-tailed dunnart. The carnivorous mouse-like marsupial, no bigger than a golf ball and about as heavy as a toothbrush, has a tiny snout, dark, bulbous eyes and, unsurprisingly, a fat tail. It's Baby Yoda levels of adorable -- and it may be just as influential.

Mapping the dunnart's genome could help this little animal become the marsupial equivalent of the lab mouse -- a model organism scientists use to better understand biological processes, manipulate genes and test new approaches to treating disease. The ambitious project, driven by marsupial geneticist Andrew Pask and his team at the University of Melbourne over the last two years, will see scientists take advantage of incredible feats of genetic engineering, reprogramming cells at will.

It could even aid the creation of a frozen Noah's Ark of samples: a doomsday vault of marsupial cells, suspended in time, to preserve genetic diversity and help prevent further decline, bringing species back from the brink of extinction.

If that sounds far-fetched, it isn't. In fact, it's already happening.

Creating a reliable marsupial model organism is a long-held dream for Australian geneticists, stretching back to research pioneered by famed statistician Ronald Fisher in the mid-20th century. To understand why the model is so important, we need to look at the lab mouse, a staple of science laboratories for centuries.

"A lot of what we know about how genes work, and how genes work with each other, comes from the mouse," says Jenny Graves, a geneticist at La Trobe University in Victoria, Australia, who has worked with marsupials for five decades.

The mouse is an indispensable model organism that shares many genetic similarities with humans. It has been key in understanding basic human biology, testing new medicines and unraveling the mysteries of how our brains work. Mice form such a critical part of the scientific endeavor because they breed quickly, have large litters, and are cheap to house, feed and maintain.

The lab mouse has been indispensable in understanding physiology, biology and genetics.

In the 1970s, scientists developed a method to insert new genes into mice. After a decade of refinement, these genetically modified mice (known as "transgenic mice") provided novel ways to study how genes function. You could add a gene, turning its expression up to 11, or delete a gene entirely, shutting it off. Scientists had a powerful tool to discover which genes performed the critical work in reproduction, development and maturation.

The same capability does not exist for marsupials. "At the moment, we don't have any way of manipulating genes in a devil or a kangaroo or a possum," says Graves. Without this capability, it's difficult to answer more pointed questions about marsupial genes and how they compare with mammal genes, like those of mice and humans.

So far, two marsupial species -- the Tammar wallaby and the American opossum -- have been front and center of research efforts to create a reliable model organism, but they both pose problems. The wallaby breeds slowly, with only one baby every 18 months, and it requires vast swaths of land to maintain.

The short-tailed opossum might prove an even more complicated case. Pask, the marsupial geneticist, says the small South American marsupial is prone to eating its young, and breeding requires researchers to sift through hours of video footage, looking for who impregnated whom. Pask also makes a patriotic jab ("they're American so we don't like them") and says their differences from Australian marsupials make them less useful for the problems Australian species face.

But the dunnart boasts all the features that make the mouse such an attractive organism for study: It is small and easy to house, breeds well in captivity and has large litters.

"Our little guys are just like having a mouse basically, except they have a pouch," Pask says.

Pask (front) and Frankenberg inspect some of their dunnarts at the University of Melbourne.

A stern warning precedes my first meeting with Pask's colony of fat-tailed dunnarts.

"It smells like shit," he says. "They shit everywhere."

I quickly discover he's right. Upon entering the colony's dwellings on the third floor of the University of Melbourne's utilitarian BioSciences building, you're punched in the face by a musty, fecal smell.

Pask, a laid-back researcher whose face is almost permanently fixed with a smile, and one of his colleagues, researcher Stephen Frankenberg, appear unfazed by the odor. They've adapted to it. Inside the small room that houses the colony, storage-box-cages are stacked three shelves high. They're filled with upturned egg cartons and empty buckets, which work as makeshift nests for the critters to hide in.

Andrew Pask

Frankenberg reaches in without hesitation and plucks one from a cage -- nameless but numbered "29" -- and it hides in his enclosed fist before peeking out of the gap between his thumb and forefinger, snout pulsing. As I watch Frankenberg cradle it, the dunnart seems curious, and Pask warns me it's more than agile enough to manufacture a great escape.

In the wild, fat-tailed dunnarts are just as inquisitive and fleet-footed. Their range extends across most of southern and central Australia, and the most recent assessment of their population numbers shows they aren't suffering population declines in the same way many of Australia's bigger marsupial species are.

Move over, Baby Yoda.

As I watch 29 scamper up Frankenberg's arm, the physical similarities between it and a mouse are obvious. Pask explains that the dunnart's DNA is much more closely related to the Tasmanian devil, an endangered cat-sized carnivore native to Australia, than the mouse. But from a research perspective, Pask notes the similarities between mouse and dunnart run deep -- and that's why it's such an important critter.

"The dunnart is going to be our marsupial workhorse like the mouse is for placental mammals," Pask says.

For that to happen, Pask's team has to perfect an incredible feat of genetic engineering: They have to learn how to reprogram its cells.

To do so, they collect skin cells from the dunnart's ear or footpad and drop them in a flask where scientists can introduce new genes into the skin cell. The introduced genes are able to trick the adult cell, convincing it to become a "younger," specialized cell with almost unlimited potential.

The reprogrammed cells are known as "induced pluripotent stem cells," or iPS cells, and since Japanese scientists unraveled how to perform this incredible feat in 2006, they have proven to be indispensable for researchers because they can become any cell in the body.

"You can grow them in culture and put different sorts of differentiation factors on them and see if they can turn into nerve cells, muscle cells, brain cells, blood vessels," Pask explains. That means these special cells could even be programmed to become a sperm or an egg, in turn allowing embryos to be made.

Implanting the embryo in a surrogate mother could create a whole animal.

It took about 15 minutes to get this dunnart to sit still.

Although such a technological leap has been made in mice, it's still a long way from fruition for marsupials. At present, only the Tasmanian devil has had iPS cells created from skin, and no sperm or egg cells were produced.

Pask's team has been able to dupe the dunnart's cells into reverting to stem cells -- and they've even made some slight genetic tweaks in the lab. But that's just the first step.

He believes there are likely to be small differences between species, but if the methodology remains consistent and reproducible in other marsupials, scientists could begin to create iPS cells from Australia's array of unique fauna. They could even sample skin cells from wild marsupials and reprogram those.

Doing so would be indispensable in the creation of a biobank, where the cells would be frozen down to -196 degrees Celsius (-273F) and stored until they're needed. It would act as a safeguard -- a backup copy of genetic material that could, in some distant future, be used to bring species back from the edge of oblivion, helping repopulate them and restoring their genetic diversity.

Underneath San Diego Zoo's Beckman Center for Conservation Research lies the Frozen Zoo, a repository of test tubes containing the genetic material of over 10,000 species. Stacked in towers and chilled inside giant metal vats, the tubes contain the DNA of threatened species from around the world, suspended in time.

It's the largest wildlife biobank in the world.

"Our goal is to opportunistically collect cells ... on multiple individuals of as many species as we can, to provide a vast genetic resource for research and conservation efforts," explains Marlys Houck, curator at the Frozen Zoo.

The Zoo's efforts to save the northern white rhino from extinction have been well publicized. Other research groups have been able to create a northern white rhino embryo in the lab, combining eggs of the last two remaining females with frozen sperm from departed males. Scientists propose implanting those embryos in a surrogate mother of a closely related species, the southern white rhino, to help drag the species back from the edge of oblivion.

For the better part of a decade, conservationists have been focused on this goal, and now their work is paying off: In the "coming months," the lab-created northern white rhino embryo will be implanted in a surrogate.

Sudan, the last male northern white rhinoceros, was euthanized in 2018.

Marisa Korody, a conservation geneticist at the Frozen Zoo, stresses that this type of intervention was really the last hope for the rhino, a species whose population had already diminished to just eight individuals a decade ago.

"We only turn to these methods when more traditional conservation methods have failed," she says.

In Australia, researchers are telling whoever will listen that traditional conservation methods are failing.

"We've been saying for decades and decades, many of our species are on a slippery slope," says John Rodger, a marsupial conservationist at the University of Newcastle, Australia, and CEO of the Fauna Research Alliance, which has long advocated for the banking of genetic material of species in Australia and New Zealand.

In October, 240 of Australia's top scientists delivered a letter to the government detailing the country's woeful record on protecting species, citing the 1,800 plants and animals in danger of extinction, and the "weak" environmental laws which have been ineffective at keeping Australian fauna alive.

Institutions around Australia, such as Taronga Zoo and Monash University, have been biobanking samples since the '90s, reliant on philanthropic donations to stay online, but researchers say this is not enough. For at least a decade, they've been calling for the establishment of a national biobank to support Australia's threatened species.

John Rodger

"Our real problem in Australia ... is underinvestment," Rodger says. "You've got to accept this is not a short-term investment."

The current government installed a threatened-species commissioner in 2017 and committed $255 million ($171 million in US dollars) in funding to improve the prospects of 20 mammal species by 2020. In the most recent progress report, released in 2019, only eight of those 20 were identified as having an "improved trajectory," meaning populations were either increasing faster or declining slower compared to 2015.

A spokesperson for the commissioner outlined the $50 million investment to support immediate work to protect wildlife following the bushfires, speaking to monitoring programs, establishment of "insurance populations" and feral cat traps. No future strategies regarding biobanking were referenced.

Researchers believe we need to act now to preserve iconic Australian species like the koala.

In the wake of the catastrophic bushfire season and the challenges posed by climate change, Australia's extinction crisis is again in the spotlight. Koalas are plastered over social media with charred noses and bandaged skin. On the front page of newspapers, kangaroos bound in front of towering walls of flame.

Houck notes that San Diego's Frozen Zoo currently stores cell lines "from nearly 30 marsupial species, including koala, Tasmanian devil and kangaroo," but that's only one-tenth of the known marsupial species living in Australia today.

"Nobody in the world is seriously working on marsupials but us," Rodger says. "We've got a huge interest in maintaining these guys for tourism, national icons... you name it."

There's a creeping sense of dread in the researchers I talk to that perhaps we've passed a tipping point, not just in Australia, but across the world. "We are losing species at an alarming rate," says Korody from the Frozen Zoo. "Some species are going extinct before we even know they are there."

With such high stakes, Pask and his dunnarts are in a race against time. Perfecting the techniques to genetically engineer the tiny marsupial's cells will help enable the preservation of all marsupial species for generations to come, future-proofing them against natural disasters, disease, land-clearing and threats we may not even be able to predict right now.

Pask reasons "we owe it" to marsupials to develop these tools and, at the very least, biobank their cells if we can't prevent extinction. "We really should be investing in this stuff now," he says. He's optimistic.

In some distant future, years from now, a bundle of frozen stem cells might just bring the koala or the kangaroo back from the brink of extinction.

And for that, we'll have the dunnart to thank.

Originally published Feb. 18, 5 a.m. PT.

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Building a 'doomsday vault' to save the kangaroo and koala from extinction - CNET

- First conditional approval of ZYNTEGLOTM (autologous CD34+ cells encoding A-T87Q-globin gene) gene therapy for patients 12 years and older with transfusion-dependent -thalassemia who do not have 0/0 genotype in Europe achieved in 2019; Germany launch underway

- Announced positive top-line data from pivotal Phase 2 KarMMa study of ide-cel in relapsed and refractory multiple myeloma

- Presented clinical data across studies of LentiGlobin gene therapy for -thalassemia (betibeglogene autotemcel) and LentiGlobin gene therapy for sickle cell disease (SCD) and bb21217 in multiple myeloma at American Society of Hematology (ASH) Annual Meeting

- Ended quarter with $1.24 billion in cash, cash equivalents and marketable securities

bluebird bio, Inc. (NASDAQ: BLUE) today reported financial results and business highlights for the fourth quarter and full year ended December 31, 2019.

"2019 was truly a transformative year for bluebird, with our first commercial product now launched in Europe and exciting progress across our first four clinical programs and pipeline," said Nick Leschly, chief bluebird. "Notably, our data in SCD continues to build, and at the ASH annual meeting in December we presented data that showed a 99% reduction in the annualized rate of vaso-occlusive crises (VOC) and acute chest syndrome (ACS) in HGB-206 Group C patients with history of VOCs and ACS who had at least six months follow-up. In -thalassemia, the consistency with which patients who do not have a 0/0 genotype in our Northstar-2 (HGB-207) study are achieving transfusion independence is very encouraging and were starting to see indications that we may be able to see similar outcomes with many patients with 0/0 genotypes as well in our Northstar-3 (HGB-212 study). These data put us in a strong position as we progress our European launch, currently underway in Germany. At the end of 2019, we also announced positive top-line data from the pivotal KarMMa study of ide-cel. We and our partners at BMS look forward to submitting these data to the FDA in the first half of this year. Amidst all of our progress in 2019, our birds demonstrated time and again their dedication to patients and ability to meet and learn from the many challenges we have faced along the way. I look forward to facing the challenges of 2020 with this amazing flock."

Recent Highlights:

TRANSFUSION-DEPENDENT -THALASSEMIA

SICKLE CELL DISEASE (SCD)

MULTIPLE MYELOMA

COMPANY

Upcoming Anticipated Milestones:

Fourth Quarter and Full Year 2019 Financial Results

LentiGlobin for -thalassemia Safety

Non-serious adverse events (AEs) observed during the HGB-204, HGB-207 and HGB-212 clinical studies that were attributed to LentiGlobin for -thalassemia were hot flush, dyspnoea, abdominal pain, pain in extremities, thrombocytopenia, leukopenia, neutropenia and non-cardiac chest pain. One serious adverse event (SAE) of thrombocytopenia was considered possibly related to LentiGlobin for -thalassemia for TDT.

Additional AEs observed in clinical studies were consistent with the known side effects of HSC collection and bone marrow ablation with busulfan, including SAEs of veno-occlusive disease.

With more than five years of follow-up to date, there have been no new unexpected safety events, no deaths, no graft failure and no cases of vector-mediated replication competent lentivirus or clonal dominance. In addition, there have been no new reports of veno-occlusive liver disease (VOD) as of the data cutoff presented at ASH.

About LentiGlobin for -Thalassemia (betibeglogene autotemcel)

The European Commission granted conditional marketing authorization for LentiGlobin for -thalassemia, to be marketed as ZYNTEGLO (autologous CD34+ cells encoding A-T87Q-globin gene) gene therapy, for patients 12 years and older with TDT who do not have a 0/0 genotype, for whom hematopoietic stem cell (HSC) transplantation is appropriate, but a human leukocyte antigen (HLA)-matched related HSC donor is not available.

TDT is a severe genetic disease caused by mutations in the -globin gene that result in reduced or significantly reduced hemoglobin (Hb). In order to survive, people with TDT maintain Hb levels through lifelong chronic blood transfusions. These transfusions carry the risk of progressive multi-organ damage due to unavoidable iron overload.

Story continues

LentiGlobin for -thalassemia adds functional copies of a modified form of the -globin gene (A-T87Q-globin gene) into a patients own hematopoietic (blood) stem cells (HSCs). Once a patient has the A-T87Q-globin gene, they have the potential to produce HbAT87Q, which is gene therapy-derived hemoglobin, at levels that may eliminate or significantly reduce the need for transfusions.

The conditional marketing authorization for ZYNTEGLO is only valid in the 28 member states of the EU as well as Iceland, Liechtenstein and Norway. For details, please see the Summary of Product Characteristics (SmPC).

The U.S. Food and Drug Administration granted LentiGlobin for -thalassemia Orphan Drug status and Breakthrough Therapy designation for the treatment of TDT.

bluebird bio has initiated its rolling BLA submission of LentiGlobin for -thalassemia for approval in the U.S. and is engaged with the FDA in discussions regarding the requirements and timing of certain information to be provided in the BLA, including information regarding various release assays for LentiGlobin for -thalassemia. Subject to these ongoing discussions, the company is currently planning to complete the BLA submission in the second half of 2020.

LentiGlobin for -thalassemia continues to be evaluated in the ongoing Phase 3 Northstar-2 and Northstar-3 studies. For more information about the ongoing clinical studies, visit http://www.northstarclinicalstudies.com or clinicaltrials.gov and use identifier NCT02906202 for Northstar-2 (HGB-207), NCT03207009 for Northstar-3 (HGB-212).

bluebird bio is conducting a long-term safety and efficacy follow-up study (LTF-303) for people who have participated in bluebird bio-sponsored clinical studies of LentiGlobin for -thalassemia. For more information visit: https://www.bluebirdbio.com/our-science/clinical-trials or clinicaltrials.gov and use identifier NCT02633943 for LTF-303.

About bluebird bio, Inc.

bluebird bio is pioneering gene therapy with purpose. From our Cambridge, Mass., headquarters, were developing gene therapies for severe genetic diseases and cancer, with the goal that people facing potentially fatal conditions with limited treatment options can live their lives fully. Beyond our labs, were working to positively disrupt the healthcare system to create access, transparency and education so that gene therapy can become available to all those who can benefit.

bluebird bio is a human company powered by human stories. Were putting our care and expertise to work across a spectrum of disorders including cerebral adrenoleukodystrophy, sickle cell disease, -thalassemia and multiple myeloma, using three gene therapy technologies: gene addition, cell therapy and (megaTAL-enabled) gene editing.

bluebird bio has additional nests in Seattle, Wash.; Durham, N.C.; and Zug, Switzerland. For more information, visit bluebirdbio.com.

Follow bluebird bio on social media: @bluebirdbio, LinkedIn, Instagram and YouTube.

ZYNTEGLO, LentiGlobin, and bluebird bio are trademarks of bluebird bio, Inc.

The full common name for ZYNTEGLO: A genetically modified autologous CD34+ cell enriched population that contains hematopoietic stem cells transduced with lentiviral vector encoding the A-T87Q-globin gene.

Forward-Looking Statements

This release contains "forward-looking statements" within the meaning of the Private Securities Litigation Reform Act of 1995, including statements regarding the companys financial condition, results of operations, as well as statements regarding the plans for regulatory submissions and commercialization for ZYNTEGLO and the companys product candidates, including anticipated regulatory milestones, the execution of the companys commercial launch plans, planned clinical studies, as well as the companys intentions regarding the timing for providing further updates on the development and commercialization of ZYNTEGLO and the companys product candidates. Any forward-looking statements are based on managements current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. These risks and uncertainties include, but are not limited to, the risks that the preliminary positive efficacy and safety results from our prior and ongoing clinical trials will not continue or be repeated in our ongoing or future clinical trials; the risk of cessation or delay of any of the ongoing or planned clinical studies and/or our development of our product candidates; the risk that the current or planned clinical trials of our product candidates will be insufficient to support regulatory submissions or marketing approval in the United States and European Union; the risk that regulatory authorities will require additional information regarding our product candidates, resulting in delay to our anticipated timelines for regulatory submissions, including our applications for marketing approval; the risk that we will encounter challenges in the commercial launch of ZYNTEGLO in the European Union, including in managing our complex supply chain for the delivery of drug product, in the adoption of value-based payment models, or in obtaining sufficient coverage or reimbursement for our products; the risk that our collaborations, including the collaborations with Bristol-Myers Squibb and Forty Seven, will not continue or will not be successful; and the risk that any one or more of our product candidates, will not be successfully developed, approved or commercialized. For a discussion of other risks and uncertainties, and other important factors, any of which could cause our actual results to differ from those contained in the forward-looking statements, see the section entitled "Risk Factors" in our most recent Form 10-K, as well as discussions of potential risks, uncertainties, and other important factors in our subsequent filings with the Securities and Exchange Commission. All information in this press release is as of the date of the release, and bluebird bio undertakes no duty to update this information unless required by law.

bluebird bio, Inc.Condensed Consolidated Statements of Operations and Comprehensive Loss(in thousands, except per share data)(unaudited)

For the three months endedDecember 31,

For the year endedDecember 31,

2019

2018

2019

2018

Revenue:

Collaboration revenue

$ 7,159

$ 18,382

$ 36,469

$ 52,353

License and royalty revenue

2,838

861

8,205

2,226

Total revenues

9,997

19,243

44,674

54,579

Operating expenses:

Research and development

161,821

119,722

582,413

448,589

Selling, general and administrative

76,202

53,508

271,362

174,129

Cost of license and royalty revenue

1,073

818

2,978

885

Change in fair value of contingent consideration

1,435

2,156

2,747

2,999

Total operating expenses

240,531

176,204

859,500

626,602

Loss from operations

(230,534)

(156,961)

(814,826)

(572,023)

Interest income, net

6,855

6,209

34,761

14,624

Other (expense) income, net

535

1,916

(10,088)

1,961

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bluebird bio Reports Fourth Quarter and Full Year 2019 Financial Results and Highlights Operational Progress - Yahoo Finance

The Stem Cells market is an intrinsic study of the current status of this business vertical and encompasses a brief synopsis about its segmentation. The report is inclusive of a nearly accurate prediction of the market scenario over the forecast period market size with respect to valuation as sales volume. The study lends focus to the top magnates comprising the competitive landscape of Stem Cells market, as well as the geographical areas where the industry extends its horizons, in magnanimous detail.

The market report, titled Global Stem Cells Market Research Report 2019 By Manufacturers, Product Type, Applications, Region and Forecast to 2025, recently added to the market research repository of details in-depth past and present analytical and statistical data about the global Stem Cells market. The report describes the Stem Cells market in detail in terms of the economic and regulatory factors that are currently shaping the markets growth trajectory, the regional segmentation of the global Stem Cells market, and an analysis of the markets downstream and upstream value and supply chains.

Request Sample Report @https://www.mrrse.com/sample/11510?source=atm

The report offers the market growth rate, size, and forecasts at the global level in addition as for the geographic areas: Latin America, Europe, Asia Pacific, North America, and Middle East & Africa. Also, it analyses, roadways and provides the global market size of the main players in each region. Moreover, the report provides knowledge of the leading market players within the Stem Cells market. The industry-changing factors for the market segments are explored in this report. This analysis report covers the growth factors of the worldwide market based on end-users.

The key manufacturers covered in this Stem Cells market report:

companies profiled in the global stem cells market are STEMCELL Technologies Inc., Astellas Pharma Inc., Cellular Engineering Technologies Inc., BioTime Inc., Takara Bio Inc., U.S. Stem Cell, Inc., BrainStorm Cell Therapeutics Inc., Cytori Therapeutics, Inc., Osiris Therapeutics, Inc., Caladrius Biosciences, Inc. and others.

The global stem cells market has been segmented as follows:

Global Stem Cells Market, by Product Type

Global Stem Cells Market, by Source

Global Stem Cells Market, by Application

Global Stem Cells Market, by End Users

Global Stem Cells Market, by Geography

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In accordance with a competitive prospect, this Stem Cells report dispenses a broad array of features essential for measuring the current Stem Cells market performance along with technological advancements, business abstract, strengths and weaknesses of market position and hurdles crossed by the leading Stem Cells market players to gain leading position. Other aspects such as customer base, sales reach, local coverage, production price trends, and production cost layout are also analyzed to bestow accurate rivalry perspective.

Pivotal highlights of Stem Cells market:

The Stem Cells market report includes a brief about the cost analysis, key raw material used, as well as the fluctuating price trends of the war material.

The suppliers of the raw material and their market concentration rate have also been enlisted.

The manufacturing cost structures, encompassing details about the raw material, manufacturing process analysis, as well as labor costs have been enumerated in the study.

Substantial details about the industry chain analysis, downstream buyers, and sourcing strategies have been elucidated.

A separate section has been designated for the analysis of the marketing strategy adopted, as well details about the distributors that are a part of the supply chain.

The report is inclusive of information regarding the channels adopted for the product marketing, marketing channel development trends, pricing and brand strategies, as well as target clientele.

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Tags: Stem Cells InduStem Cells Market Definitions and OverviewStem Cells Market DynamicsStem Cells Market IndicatorsStem Cells Market Segmentation and ScopeStem Cells Market Trends Analysis

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Stem Cells Augmented Expansion to be Registered by 2019-2027 - TechNews.mobi

news

Researchers have identified that in leukaemia, mutated receptors allow blood stem cells to activate one another without the proper signal and suggest this discovery could lead to targeted novel therapies.

Research into cell signalling has shown that in leukaemia, mutations in the cytokine receptors of blood stem cells triggers an overproduction of blood cells, causing the condition. The scientists hope this discovery will pave the way for targeted novel therapeutics in future.

In the study, published in Science, the research team discovered that while blood stem cells are normally regulated by cytokines, mutations can allow them to be activated without the correct signals, prompting the development of blood cells to spiral out of control.

The researchers used super-resolution fluorescent microscopy to study the way blood stem cells communicate with each other in real time. They observed cytokines binding to designated cell surface receptors, pairing the blood stem cells up and causing the production of blood cells. But when cells with mutations affecting these receptors were introduced, the cells paired up without cytokines and produced an imbalance of healthy platelets, white and red blood cells.

Professor Ian Hitchcock from the York Biomedical Research Institute and the Department of Biology at the University of York, UK, explained: Our bodies produce billions of blood cells every day via a process of cells signalling between each other. Cytokines act like a factory supervisor, tightly regulating this process and controlling the development and proliferation of the different blood cell types.

Our observations led us to a previously unknown mechanism for how individual mutations trigger blood stem cells to start signalling independently of cytokines, causing the normal system to become out of control and leading to diseases like leukaemia. Understanding this mechanism may enable the identification of targets for the development of new drugs.

Professor Ilpo Vattulainen from the University of Helsinki, Finland, added: Our biomolecular simulations unveiled surprising features concerning the orientation of active receptor pairs at the plasma membrane, explaining how mutations render activation possible without a ligand (eg, cytokine). These predictions were subsequently confirmed experimentally.

See the article here:
Mutated blood stem cell receptors could be therapeutic targets for leukaemia - Drug Target Review

Research into alternative stem cell sources has identified urine derived renal progenitor cells (UdRPCs) as a possible option for use in regenerative kidney therapies in the future.

Scientists have demonstrated their protocol for the reproducible isolation of kidney stem cells from human urine. These urine derived renal progenitor cells (UdRPCs) could be used to provide easier access to stem cells for regenerative kidney therapies and modelling diseases for R&D.

A shortage of donor organs and the risks and pain associated with bone marrow stem cell extractions and third trimester amniotic fluid collection have encouraged researchers to find alternative sources of stem cells. According to scientists, several laboratories have indicated urine could be an alternative source, at least for kidney stem cells, so the researchers from Heinrich Heine University-Duesseldorf (HHU) Germany,set out to complete a comprehensive molecular and cellular analysis of these cells.

UdRPCs should be considered as the choice of renal stem cells for facilitating the study of nephrogenesis, nephrotoxicity, disease modelling and drug development

Their study, published in Scientific Reports, revealed that UdRPCs isolated from ten individuals express both markers typically seen in bone marrow-derived mesenchymal stem cells (MSCs) and renal stem cells. The renal stem cell markers, according to the paper, allow UdRPCs to be differentiated into cell types present in the kidney, eg, podocytes and the proximal and distal tubules. The study also showed that these progenitor cells have similar properties to amniotic fluid-derived stem cells (AFCs).

Wasco Wruck, bioinformatician and co-author of the study, said: It is amazing that these valuable cells can be isolated from urine and comparing all the genes expressed in UdRPCs with that derived from kidney biopies we could confirm their renal and renal progenitor cell properties and origin.

According to Martina Bohndorf, a study co-author, UdRPCs can also be easily and efficiently reprogrammed into induced pluripotent stem cells using a non-viral integration-free and safe method.

Dr James Adjaye, study senior author and professor at the Institute for Stem Cell Research and Regenerative Medicine (ISRM) in the medical faculty of HHU, revealed that one of the most promising options in the near future is the use of transplantable renal stem cells (UdRPCs) for treatment of kidney diseases as a complementary option to kidney organs. He concluded that human UdRPCs should be considered as the choice of renal stem cells for facilitating the study of nephrogenesis, nephrotoxicity, disease modelling and drug development.

Excerpt from:
Kidney stem cells isolated from urine could be regenerative therapies - Drug Target Review

The external fund manager backed by Berkshire Hathaways Charlie Munger, Li Lu, makes no bones about it when he says The biggest investment risk is not the volatility of prices, but whether you will suffer a permanent loss of capital. Its only natural to consider a companys balance sheet when you examine how risky it is, since debt is often involved when a business collapses. We can see that Public Joint-Stock Company Human Stem Cells Institute (MCX:ISKJ) does use debt in its business. But should shareholders be worried about its use of debt?

Generally speaking, debt only becomes a real problem when a company cant easily pay it off, either by raising capital or with its own cash flow. In the worst case scenario, a company can go bankrupt if it cannot pay its creditors. However, a more usual (but still expensive) situation is where a company must dilute shareholders at a cheap share price simply to get debt under control. By replacing dilution, though, debt can be an extremely good tool for businesses that need capital to invest in growth at high rates of return. The first step when considering a companys debt levels is to consider its cash and debt together.

See our latest analysis for Human Stem Cells Institute

As you can see below, Human Stem Cells Institute had 377.6m of debt at June 2019, down from 401.9m a year prior. However, because it has a cash reserve of 177.9m, its net debt is less, at about 199.7m.

Zooming in on the latest balance sheet data, we can see that Human Stem Cells Institute had liabilities of 411.1m due within 12 months and liabilities of 756.6m due beyond that. On the other hand, it had cash of 177.9m and 79.7m worth of receivables due within a year. So its liabilities total 910.1m more than the combination of its cash and short-term receivables.

This deficit is considerable relative to its market capitalization of 1.04b, so it does suggest shareholders should keep an eye on Human Stem Cells Institutes use of debt. This suggests shareholders would heavily diluted if the company needed to shore up its balance sheet in a hurry.

We measure a companys debt load relative to its earnings power by looking at its net debt divided by its earnings before interest, tax, depreciation, and amortization (EBITDA) and by calculating how easily its earnings before interest and tax (EBIT) cover its interest expense (interest cover). This way, we consider both the absolute quantum of the debt, as well as the interest rates paid on it.

While Human Stem Cells Institutes low debt to EBITDA ratio of 0.88 suggests only modest use of debt, the fact that EBIT only covered the interest expense by 5.9 times last year does give us pause. So wed recommend keeping a close eye on the impact financing costs are having on the business. It was also good to see that despite losing money on the EBIT line last year, Human Stem Cells Institute turned things around in the last 12 months, delivering and EBIT of 193m. The balance sheet is clearly the area to focus on when you are analysing debt. But you cant view debt in total isolation; since Human Stem Cells Institute will need earnings to service that debt. So if youre keen to discover more about its earnings, it might be worth checking out this graph of its long term earnings trend.

Finally, a business needs free cash flow to pay off debt; accounting profits just dont cut it. So it is important to check how much of its earnings before interest and tax (EBIT) converts to actual free cash flow. Over the last year, Human Stem Cells Institute reported free cash flow worth 2.0% of its EBIT, which is really quite low. For us, cash conversion that low sparks a little paranoia about is ability to extinguish debt.

On the face of it, Human Stem Cells Institutes level of total liabilities left us tentative about the stock, and its conversion of EBIT to free cash flow was no more enticing than the one empty restaurant on the busiest night of the year. But at least its pretty decent at managing its debt, based on its EBITDA,; thats encouraging. Once we consider all the factors above, together, it seems to us that Human Stem Cells Institutes debt is making it a bit risky. Thats not necessarily a bad thing, but wed generally feel more comfortable with less leverage. The balance sheet is clearly the area to focus on when you are analysing debt. However, not all investment risk resides within the balance sheet far from it. Consider for instance, the ever-present spectre of investment risk. Weve identified 2 warning signs with Human Stem Cells Institute (at least 1 which shouldnt be ignored) , and understanding them should be part of your investment process.

Of course, if youre the type of investor who prefers buying stocks without the burden of debt, then dont hesitate to discover our exclusive list of net cash growth stocks, today.

If you spot an error that warrants correction, please contact the editor at editorial-team@simplywallst.com. This article by Simply Wall St is general in nature. It does not constitute a recommendation to buy or sell any stock, and does not take account of your objectives, or your financial situation. Simply Wall St has no position in the stocks mentioned.

We aim to bring you long-term focused research analysis driven by fundamental data. Note that our analysis may not factor in the latest price-sensitive company announcements or qualitative material. Thank you for reading.

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We Think Human Stem Cells Institute (MCX:ISKJ) Is Taking Some Risk With Its Debt - Simply Wall St

A new study on how and when the precursors to eggs and sperm are formed during development could help pave the way for generating egg and sperm cells in the lab to treat infertility.

The study, publishedin the journal Cell Reports, describes the way in which human stem cells evolve into germ cells, the precursors for egg and sperm cells.

Right now, if your body doesnt make germ cells then theres no option for having a child thats biologically related to you, said Amander Clark, the studys lead author, a member of theEli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. What we want to do is use stem cells to be able to generate germ cells outside the human body so that this kind of infertility can be overcome.

It is estimated that infertility affects 10% of the U.S. population, and infertility rates have increased over the past several decades because more people are waiting longer to have children. Many forms of infertility can be treated using procedures that join egg and sperm together outside the body, such as in vitro fertilization and intracytoplasmic sperm injection. But for people whose bodies dont produce eggs or sperm because of chemotherapy, radiation, genetics or other unexplained causes those treatments arent an option unless a donor provides the eggs or sperm.

With donated eggs and sperm, the child is not genetically related to one or both parents, said Clark, who also is a UCLA professor and chair of molecular cell and developmental biology. To treat patients who want a child who is genetically related, we need to understand how to make germ cells from stem cells, and then how to coax those germ cells into eggs or sperm.

In developing male and female embryos, a subset of pluripotent stem cells cells that have the potential to become nearly every type of cell in the body become germ cells that will later generate eggs or sperm. Researchers previously demonstrated the ability to make similar stem cells in a laboratory, called induced pluripotent stem cells, or iPS cells, from a persons own skin or blood cells.

Clark and her colleagues used technology that enables them to measure the active genes in more than 100,000 embryonic stem cells and iPS cells as they generated germ cells. Collaborators at the Massachusetts Institute of Technology developed new algorithms to analyze the massive amounts of data.

The experiments revealed a detailed timeline for when germ cells form: They first become distinct from other cells of the body between 24 and 48 hours after stem cells start differentiating into cell types that will ultimately make up all the specialized cells in the adult body.

Clark said that information would help scientists focus their efforts on that particular timeframe in future studies, in order to maximize the number of germ cells they can create.

The study also revealed that the germ cells come from two different populations of stem cells amnion cells, which are located in the fluid and membrane that surrounds the embryo during pregnancy, as well as gastrulating cells from the embryo itself.

When the researchers compared the germ cells derived from embryonic stem cells with those derived from iPS cells in the lab, they found that the patterns by which genes were activated were nearly identical.

This tells us that the approach were using to begin the process of making germ cells is on the right track, Clark said. Now were poised to take the next step of combining these cells with ovary or testis cells.

That next step is critical because molecular signals from ovary or testis tissue are what signal germ cells to mature into eggs and sperm.

If the approach were to be incorporated into a future treatment for infertility, scientists might eventually be able to use a patients own skin cells to form stem cells that can be coaxed into both germ cells and ovarian or testis tissue and those cell types might be able to be used to generate a persons own eggs or sperm in the lab.

Were going in the right direction but it will take a lot of new innovations to solve infertility related to the loss of germ cells, Clark said.

The techniques described above were used in laboratory tests only and have not been tested in humans or approved by the Food and Drug Administration as safe and effective for use in humans.

The research was supported by the National Institutes of Health and a Broad Stem Cell Research Center Innovation Award.

Media Contact

Mirabai Vogt-James310-983-1163mvogt@mednet.ucla.edu

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Research could be step toward lab-grown eggs and sperm to treat... - ScienceBlog.com

SAN ANTONIO, Feb. 3, 2020 /PRNewswire/ -- SASpine is now offering cutting edge Stem Cell Treatments to patients. For the past several years Dr. Steven Cyr, Mayo Clinic Trained Spine Surgeon, has been researching the benefits of stem cells in the treatment of multiple medical conditions including spinal disorders, specifically, conditions which involve spinal cord injury, degenerative disc disease, herniated discs, and as a supplement to enhance the success of Spinal fusions when treating instability, deformity, and fractures of the spine.

Steven J. Cyr, M.D., is a spine surgeon who has gained a reputation for surgical excellence in Texas, throughout the nation, and abroad.

Dr. Steven Cyr has been treating patients using growth factors and stem cells contained in amniotic tissue and bone marrow aspirate to provide a potential for improved success with fusion procedures, when treating herniated discs, and for arthritic or damaged joints, with remarkable success. "The goal of any medical intervention is to yield improved outcomes with the ideal result of returning a patient to normal function, when possible," states Dr Cyr. He went on to elaborate that there are times when only a structural solution can solve problems related to spinal disorders, but even in that scenario, the use of stem cells or growth factors derived from stem cell products can possibly improve the success of surgical procedures. "I have patients previously unable to jog or run return to normal function and athletic ability after injections of growth factors and stem cell products into the knee joints, hip joints, and shoulder joints," he said. "This includes high-level athletes, professional dancers, and the average weekend warrior."

There may be promise in treating patients with spinal cord injury as well. SASpine CEO, LeAnn Cyr, states, "There are reports of patients gaining significant neurological improvement after being treated with stem cells." Dr Cyr continues, "Most patients with spinal cord injuries resulting from trauma also have mechanical pressure on the nerves that result either from bone fragments or disc material compressing the spinal cord that needs to be removed along with surgical stabilization of the spinal bones. There's significant potential that stem cells bring to the equation when treating these types of patients, and I am excited about the potential that these products offer to the host of treatments to address spinal conditions and arthritic joints."

For more information about SASpine's Stem Cell Treatment Program, visit http://www.saspine.com or call (210) 487-7463 in San Antonio or (832) 919-7990 in Houston.

Related Linkswww.facebook.com/saspinewww.instagram.com/surgical.associates.in.spine

If you've been living with back pain, you're not alone. Here at SASpine, we have experienced spine specialists who are committed to improving your quality of life. (PRNewsfoto/SASpine)

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SOURCE SASpine

Excerpt from:
SASpine to offer Stem Cell Therapy - Yahoo Finance