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Stem Cells: Creating Spare Human Body Parts (2)

The Californian company, Viacyte, is trialing a ‘teabag’ about the size and shape of a credit card. Made of surgical-grade polymer, the capsule encases immature beta cells (they’re more robust if they mature inside the body), and is inserted just under the patient’s skin.

The key challenge, so far, is providing intimate contact with surrounding blood vessels so that the transplanted cells increase in number and survive. Overall, they said there was a low rate of survival, but when cells did survive they produced insulin.

The company is now evaluating a second device that allows the patient’s blood vessels to grow through the walls of the capsule.

More than 20 years ago, a few different research groups around the world gave it a try. Using human foetal tissue, they dissected out the dopamine-producing cells, and surgically implanted these into the brains of patients, specifically in a region called the ‘striatum’.

Some patients improved, but others reported significant side effects, particularly uncontrollable jerky movements known as dyskinesia. Questions were asked about whether the correct types of cells were being transferred to the correct part of the brain and further experiments were put on hold. A key question was whether pluripotent stem cells could offer a more precise and reliable source of dopamine-producing cells.

Jump forward to 2018 and several groups are on the cusp of testing new types of replacement cells for PD in a series of clinical trials. Years of research has shown that ES cells and iPS cells can be directed to develop into the correct type of neurons and that sufficiently large numbers can be generated.

When tested in animals, the dopamine-producing cells corrected movement disorders and did not form tumours.

This time around, rather than working in silos, different groups of researchers in Japan, Sweden, UK and US have banded together in a coalition called G-Force PD. Although each group is using a slightly different approach for their clinical trial, by sharing their results and expertise they hope to bring a cell-based therapy for PD closer to reality.

Skin, stem cells and butterfly children

Skin stem cells have long been solid performers for growing skin grafts to treat severe burns. But in November 2017, headlines ran hot with a report that a seven-year-old refugee Syrian boy, on the verge of death from a genetic skin condition, had been saved by a graft of skin stem cells corrected by gene therapy.

Hassan, now living with his family in Germany, suffered from a severe form of Epidermolysis Bullosa (EB). It’s been referred to as the “worst disease you’ve never heard of”. It affects about 500,000 people worldwide, and can be caused by mutations to 18 different genes. In each case, the mutation disrupts the anchoring of the skin’s upper layer, the epidermis, to the underlying dermis. The result is skin that tears as easily as a butterfly’s wing. The only treatment is painful bandaging and re-bandaging.

Hassan’s skin had started blistering from birth but by the time he was seven, a bacterial infection had robbed him of 80% of his skin cover. In a last ditch effort to save his life, his German doctors contacted veteran stem cell researcher Michele De Luca at the University of Modena and Reggio Emilia in Italy. In 2006, De Luca had used skin grafts corrected by gene therapy to treat a leg wound of a woman who suffered from the same form of EB that Hassan suffered from. It was caused by a mutation to a gene called LAMB3.

De Luca’s team took a tiny patch of skin containing stem cells from Hassan’s groin. They also spliced a copy of the LAMB3 gene into a benign virus. Then they infected the skin cells with the virus which ferried the LAMB3 gene into their DNA. The genetically corrected skin grew into a sheet which was grafted onto Hassan’s body. Five months after the first graft, Hassan was discharged. A month later he was back at school and playing soccer. Thanks to the genetically corrected stem cells, his grafted skin no longer blisters or shreds. The executive director of the Dystrophic Epidermolysis Bullosa Research Association of America dubbed Hassan’s treatment “a sea change to the world of EB”. Besides de Luca’s group, Peter Marinkovich and Jean Tang at Stanford University School of Medicine, United States, are also trialling genetically-corrected skin grafts for a different type of EB.

Spinal cord injury

One of the front runners at the start of the stem cell race was spinal cord injury. Perhaps you remember the actor Christopher Reeve, aka Superman? Following a horse riding accident that left him a quadriplegic, he campaigned tirelessly for researchers to be allowed to use human embryonic stem cells to treat spinal cord injury which claims about 180,000 new cases each year. Perhaps thanks to his efforts in 2010, the world saw the first clinical trial using cells made from human ES cells.

Conducted by the California based biotech company Geron, the researchers had directed ES cells to develop into precursors of ‘oligodendrocytes’. These octopus-like cells wind their arms around neurons in the spinal cord to provide electrical insulation as well as nurturing factors. With a spinal cord injury, these important support cells can be lost. Four patients were injected with stem cell-derived oligodendrocyte precursors soon after their injury.

Controversially, Geron discontinued the study in 2011 to refocus their business. Asterias Biotherapeutics picked up the baton and last July, in a company press release, reported the results of an early clinical trial on 25 additional patients who were all injected with oligodendrocyte precursors three to six weeks post-injury. They reported no serious adverse events and that four patients recovered a degree of motor function that may increase their ability to lead an independent life. However, we have to wait to see the peer reviewed published results before we can assess the state of progress.

Beyond replacing oligodendrocytes made from ES cells, other clinical trials are testing different types of cells ranging from neurons obtained from donated foetal tissue to using the patient’s own cells obtained from the back of the nose where they play an important role in supporting the regeneration of the olfactory neurons. Some types of transplanted cells may act as paramedics, helping damaged motor neurons to recover. Others are designed to directly replace spinal cord neurons.

It remains too early to tell which approach will result in long-term improvements. While many with spinal cord injury are eager for even small improvements such as bladder or bowel control, patients should be careful about trying marketed experimental procedures outside well-conducted clinical trials as they may cause further harm. In a chilling example, one young woman who sought treatment using olfactory cells developed a large, painful mucus-secreting tumour in her spine and no improvement of her paraplegia. Unfortunately, many stem cell ‘cures’ promoted online, especially for spinal cord injury, lack credibility.

Seeking advice from your medical specialist is the best way to find out more. If they don’t know about a trial or claimed treatment, it is probably a mirage.

Kidney disease

Marked as a long shot for many years, stem cell research is starting to pay dividends for kidney disease. Though it’s not ready to provide transplants, it is already helping to discover new treatments.

Kidneys are the body’s vital cleansing and balancing system. They filter waste products and toxins from our blood into urine, maintain the body’s water balance and also make hormones important for regulating blood pressure and the production of red blood cells.

Kidney disease, which affects one in 10 Australians, damages the filtration units called nephrons. The major causes are diabetes and high blood pressure. Once gone, the nephrons cannot regenerate. But waiting for a donated kidney can take years; close to 1,000 Australians are currently on the waiting list for a transplant. This health crisis has catapulted researchers into trying to recreate kidney tissue from pluripotent stem cells – an immense challenge as these are complex biological machines composed of many interacting parts.

Melissa Little’s group, based at the Murdoch Children’s Research Institute in Melbourne, have pioneered this research. In 2015, they successfully grew tiny kidney-like structures that were showcased on the cover of Nature with the headline: “Kidney in a dish”. While their mini-kidneys possess many of the working parts of a mature kidney, there’s a long way to go before they can be used as transplants. The plumbing for example – bringing blood in and taking waste out – is not yet functional. Also they are tiny, smaller than the tip of your finger.

Nevertheless, these mini-kidneys are already making a difference to our understanding of how kidneys develop and what goes awry in kidney disease, especially the hereditary form. For example, researchers were recently able to make mini-kidneys from a child suffering from a rare genetic condition that can cause end-stage kidney disease. They did it by first generating iPS cells from the child’s skin. In the lab they were able to observe structural abnormalities in the child’s cells and also showed that when the genetic mutation was corrected, the structural defect was corrected. This provides a new insight into inherited kidney disease where previously we knew very little about how these conditions develop. 

Courtesy: Cosmos, The Science of Everything.

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