Stem Cell Clinic

Study tests whether stem cells heal arthritis in large dogs – Los Angeles Times

About a year ago, Cheryl Timmons was worried her dog Baxter would soon need to retire from being a therapy dog due to arthritis in his hips.

The 99-pound German shepherds physical health was wearing down after years of bringing joy to childrens hospitals, senior homes and courtrooms, where he served as the first and only service dog providing comfort to child trafficking victims in Orange County.

Timmons, who rescued Baxter from the streets of San Bernardino, worried that she may even have to put him down.

To combat the worsening arthritis, Timmons took him to therapy sessions. A GoFundMe campaign to help pay for the therapy reached a goal of $4,500.

But the arthritis was still taking hold, affecting how Baxter functioned during long workdays.

Then in late August, he was given stem cell injections as part of a new study at the Anaheim Hills Pet Clinic. The effort, headed by San Diego-based Animal Cell Therapies, is testing whether stem cells can help alleviate arthritis in dogs weighing 70 pounds or more.

Baxter, now 11 years old, has been feeling better since he received his injection.

His arthritis is greatly improved, Timmons said. I swear by the stem cell treatment. It has made such a huge difference.

Everybody in the court would notice that he wasnt having a good day. Now hes looking great again. Hes running through the courtroom. He is one happy boy.

Baxter was one of about 10 dogs that was tested at the Anaheim clinic. Animal Cell Therapies is conducting the testing at a dozen clinics throughout the country.

There are about 35 dogs currently enrolled in the study. Researchers are hoping to test between 60 and 80 dogs.

Kathy Petrucci, chief executive of Animal Cell Therapies, said its too early to tell whether the treatment is successful in treating arthritis in large dogs, but the early results are promising.

The company conducted a similar study a year ago, which showed benefits for arthritis in dogs under 70 pounds. However, the results were mixed for bigger dogs.

Petrucci said they increased the dosage for the current study.

We dont know every single mechanism that is involved ... it helps decrease inflammation in the joints, Petrucci said of the treatment. We think that the cells secrete a lot of positive beneficial growth factors that help decrease inflammation, help make the environment a better, more friendly place for more normal cells to come in and help repair the joints.

Whatever the cause, Timmons just hopes the treatment allows Baxter to keep doing what he does best.

With the stem cells, he acts like hes invincible, Timmons said, laughing. I really hope he is.

To enroll in the study, visit dogstemcellstudy.com.

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Study tests whether stem cells heal arthritis in large dogs - Los Angeles Times

Stem cells and the heartthe road ahead – Science Magazine

Heart disease is the primary cause of death worldwide, principally because the heart has minimal ability to regenerate muscle tissue. Myocardial infarction (heart attack) caused by coronary artery disease leads to heart muscle loss and replacement with scar tissue, and the heart's pumping ability is permanently reduced. Breakthroughs in stem cell biology in the 1990s and 2000s led to the hypothesis that heart muscle cells (cardiomyocytes) could be regenerated by transplanting stem cells or their derivatives. It has been 18 years since the first clinical trials of stem cell therapy for heart repair were initiated (1), mostly using adult cells. Although cell therapy is feasible and largely safe, randomized, controlled trials in patients show little consistent benefit from any of the treatments with adult-derived cells (2). In the meantime, pluripotent stem cells have produced bona fide heart muscle regeneration in animal studies and are emerging as leading candidates for human heart regeneration.

In retrospect, the lack of efficacy in these adult cell trials might have been predicted. The most common cell type delivered has been bone marrow mononuclear cells, but other transplanted cell types include bone marrow mesenchymal stromal cells and skeletal muscle myoblasts, and a few studies have used putative progenitors isolated from the adult heart itself. Although each of these adult cell types was originally postulated to differentiate directly into cardiomyocytes, none of them actually do. Indeed, with the exception of skeletal muscle myoblasts, none of these cell types survive more than a few days in the injured heart (see the figure). Unfortunately, the studies using bone marrow and adult resident cardiac progenitor cells were based on a large body of fraudulent work (3), which has led to the retraction of >30 publications. This has left clinical investigators wondering whether their trials should continue, given the lack of scientific foundation and the low but measurable risk of bleeding, stroke, and infection.

Additionally, investigators have struggled to explain the beneficial effects of adult cell therapy in preclinical animal models. Because none of these injected cell types survive and engraft in meaningful numbers or directly generate new myocardium, the mechanism has always been somewhat mysterious. Most research has focused on paracrine-mediated activation of endogenous repair mechanisms or preventing additional death of cardiomyocytes. Multiple protein factors, exosomes (small extracellular vesicles), and microRNAs have been proposed as the paracrine effectors, and an acute immunomodulatory effect has recently been suggested to underlie the benefits of adult cell therapy (4). Regardless, if cell engraftment or survival is not required, the durability of the therapy and need for actual cells versus their paracrine effectors is unclear.

Of particular importance to clinical translation is whether cell therapy is additive to optimal medical therapy. This remains unclear because almost all preclinical studies do not use standard medical treatment for myocardial infarction. Given the uncertainties about efficacy and concerns over the veracity of much of the underlying data, whether agencies should continue funding clinical trials using adult cells to treat heart disease should be assessed. Perhaps it is time for proponents of adult cardiac cell therapy to reconsider the approach.

Pluripotent stem cells (PSCs) include embryonic stem cells (ESCs) and their reprogrammed cousins, induced pluripotent stem cells (iPSCs). In contrast to adult cells, PSCs can divide indefinitely and differentiate into virtually every cell type in the human body, including cardiomyocytes. These remarkable attributes also make ESCs and iPSCs more challenging to control. Through painstaking development, cell expansion and differentiation protocols have advanced such that batches of 1 billion to 10 billion pharmaceutical-grade cardiomyocytes, at >90% purity, can be generated.

Preclinical studies indicate that PSC-cardiomyocytes can remuscularize infarcted regions of the heart (see the figure). The new myocardium persists for at least 3 months (the longest time studied), and physiological studies indicate that it beats in synchrony with host myocardium. The new myocardium results in substantial improvement in cardiac function in multiple animal models, including nonhuman primates (5). Although the mechanism of action is still under study, there is evidence that these cells directly support the heart's pumping function, in addition to providing paracrine factors. These findings are in line with the original hope for stem cell therapyto regenerate lost tissue and restore organ function. Additional effects, such as mechanically buttressing the injured heart wall, may also contribute.

Breakthroughs in cancer immunotherapy have led to the adoption of cell therapies using patient-derived (autologous) T cells that are genetically modified to express chimeric antigen receptors (CARs) that recognize cancer cell antigens. CAR T cells are the first U.S. Food and Drug Administration (FDA)approved, gene-modified cellular pharmaceutical (6). The clinical and commercial success of autologous CAR T cell transplant to treat B cell malignancies has opened doors for other complex cell therapies, including PSC derivatives. There is now a regulatory path to the clinic, private-sector funding is attracted to this field, and clinical investigators in other areas are encouraged to embrace this technology. Indeed, the first transplants of human ESC-derived cardiac progenitors, surgically delivered as a patch onto the heart's surface, have been carried out (7). In the coming years, multiple attempts to use PSC-derived cardiomyocytes to repair the human heart are likely.

What might the first human trials look like? These studies will probably employ an allogeneic (non-self), off-the-shelf, cryopreserved cell product. Although the discovery of iPSCs raised hopes for widespread use of autologous stem cell therapies, the current technology and regulatory requirements likely make this approach too costly for something as common as heart disease, although this could change as technology and regulations evolve. Given that it would take at least 6 months to generate a therapeutic dose of iPSC-derived cardiomyocytes, such cells could only be applied to patients whose infarcts are in the chronic phase where scarring (fibrosis) and ventricular remodeling are complete. Preclinical data indicate that chronic infarcts benefit less from cardiomyocyte transplantation than do those with active wound-healing processes.

Adult cells from bone marrow or the adult heart secrete beneficial paracrine factors but do not engraft in the infarcted heart. Pluripotent stem cells give rise to cardiomyocytes that engraft long term in animal models, beat in synchrony with the heart, and secrete beneficial paracrine factors. Long-term cardiomyocyte engraftment partially regenerates injured heart, which is hypothesized to bring clinical benefits.

The need for allogeneic cells raises the question of how to prevent immune rejection, both from innate immune responses in the acute phase of transplantation or from adaptive immune responses that develop more slowly through the detection of non-self antigens presented by major histocompatibility complexes (MHCs). A current strategy is the collection of iPSCs from patients who have homozygous MHC loci, which results in exponentially more MHC matches with the general population. However, studies in macaque monkeys suggest that MHC matching will be insufficient. In a macaque model of brain injury, immunosuppression was required to prevent rejection of MHC-matched iPSC-derived neurons (8). Similarly, MHC matching reduced the immunogenicity of iPSC-derived cardiomyocytes transplanted subcutaneously or into the hearts of rhesus macaques, but immunosuppressive drugs were still required to prevent rejection (9).

Numerous immune gene editing approaches have been proposed to circumvent rejection, including preventing MHC class I and II molecule expression, overexpressing immunomodulatory cell-surface factors, such CD47 and human leukocyte antigen E (HLA-E) and HLA-G (two human MHC molecules that promote maternal-fetal immune tolerance), or engineering cells to produce immunosuppressants such as programmed cell death ligand 1 (PDL1) and cytotoxic T lymphocyteassociated antigen 4 (CTLA4) (10). These approaches singly or in combination seem to reduce adaptive immune responses in vitro and in mouse models. Overexpressing HLA-G or CD47 also blunts the innate natural killer cellmediated response that results from deleting MHC class I genes (11). However, these manipulations are not without theoretical risks. It could be difficult to clear viral infections from an immunostealthy patch of tissue, and possible tumors resulting from engraftment of PSCs might be difficult to clear immunologically.

Ventricular arrhythmias have emerged as the major toxicity of cardiomyocyte cell therapy. Initial studies in small animals showed no arrhythmic complications (probably because their heart rates are too fast), but in large animals with human-like heart rates, arrhythmias were consistently observed (5, 12). Stereotypically, these arrhythmias arise a few days after transplantation, peak within a few weeks, and subside after 4 to 6 weeks. The arrhythmias were well tolerated in macaques (5) but were lethal in a subset of pigs (12). Electrophysiological studies indicate that these arrhythmias originate in graft regions from a source that behaves like an ectopic pacemaker. Understanding the mechanism of these arrhythmias and developing solutions are major areas of research. There is particular interest in the hypothesis that the immaturity of PSC-cardiomyocytes contributes to these arrhythmias, and that their maturation in situ caused arrhythmias to subside.

A successful therapy for heart regeneration also requires understanding the host side of the equation. PSC-derived cardiomyocytes engraft despite transplantation into injured myocardium that is ischemic with poor blood flow. Although vessels eventually grow in from the host tissue, normal perfusion is not restored. Achieving a robust arterial input will be key to restoring function, which may require cotransplanting other cell populations or tissue engineering approaches (13, 14). Most PSC-mediated cardiac cell therapy studies have been performed in the subacute window, equivalent to 2 to 4 weeks after myocardial infarction in humans. At this point, there has been insufficient time for a substantial fibrotic response. Fibrosis has multiple deleterious features, including mechanically stiffening the tissue and creating zones of electrical insulation that can cause arrhythmias. Extending this therapy to other clinical situations, such as chronic heart failure, will require additional approaches that address the preexisting fibrosis. Cell therapy may again provide an answer because CAR T cells targeted to cardiac fibroblasts reduced fibrosis (15).

Developing a human cardiomyocyte therapy for heart regeneration will push the limits of cell manufacturing. Each patient will likely require a dose of 1 billion to 10 billion cells. Given the widespread nature of ischemic heart disease, 105 to 106 patients a year are likely to need treatment, which translates to 1014 to 1016 cardiomyocytes per year. Growing cells at this scale will require introduction of next generation bioreactors, development of lower-cost media, construction of large-scale cryopreservation and banking systems, and establishment of a robust supply chain compatible with clinical-grade manufacturing practices.

Beyond PSC-cardiomyocytes, other promising approaches include reactivating cardiomyocyte division and reprogramming fibroblasts to form new cardiomyocytes. However, these approaches are at an earlier stage of development, and currently, PSC-derived cardiomyocyte therapy is the only approach that results in large and lasting new muscle grafts. The hurdles to this treatment are known, and likely addressable, thus multiple clinical trials are anticipated.

Acknowledgments: C.E.M. and W.R.M. are scientific founders of and equity holders in Sana Biotechnology. C.E.M. is an employee of Sana Biotechnology. W.R.M. is a consultant for Sana Biotechnology. C.E.M. and W.R.M. hold issued and pending patents in the field of stem cell and regenerative biology.

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Stem cells and the heartthe road ahead - Science Magazine

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

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