̽��ֱ�� of Cambridge - Stefano Pluchino

Early-stage stem cell therapy trial shows promise for treating progressive MS

cjb250 — Mon, 27 Nov 2023 16:00:22 +0000

̽��ֱ��study, led by scientists at the ̽��ֱ�� of Cambridge, ̽��ֱ�� of Milan Bicocca and Hospital Casa Sollievo della Sofferenza (Italy), is a step towards developing an advanced cell therapy treatment for progressive MS.

Over 2 million people live with MS worldwide, and while treatments exist that can reduce the severity and frequency of relapses, two-thirds of MS patients still transition into a debilitating secondary progressive phase of disease within 25-30 years of diagnosis, where disability grows steadily worse.

In MS, the body’s own immune system attacks and damages myelin, the protective sheath around nerve fibres, causing disruption to messages sent around the brain and spinal cord.

Key immune cells involved in this process are macrophages (literally ‘big eaters’), which ordinarily attack and rid the body of unwanted intruders. A particular type of macrophage known as a microglial cell is found throughout the brain and spinal cord. In progressive forms of MS, they attack the central nervous system (CNS), causing chronic inflammation and damage to nerve cells.

Recent advances have raised expectations that stem cell therapies might help ameliorate this damage. These involve the transplantation of stem cells, the body’s ‘master cells’, which can be programmed to develop into almost any type of cell within the body.

Previous work from the Cambridge team has shown in mice that skin cells re-programmed into brain stem cells, transplanted into the central nervous system, can help reduce inflammation and may be able to help repair damage caused by MS.

Now, in research published in the Cell Stem Cell, scientists have completed a first-in-human, early-stage clinical trial that involved injecting neural stem cells directly into the brains of 15 patients with secondary MS recruited from two hospitals in Italy. ̽��ֱ��trial was conducted by teams at the ̽��ֱ�� of Cambridge, Milan Bicocca and the Hospitals Casa Sollievo della Sofferenza and S. Maria Terni (IT) and Ente Ospedaliero Cantonale (Lugano, Switzerland) and the ̽��ֱ�� of Colorado (USA).

̽��ֱ��stem cells were derived from cells taken from brain tissue from a single, miscarried foetal donor. ̽��ֱ��Italian team had previously shown that it would be possible to produce a virtually limitless supply of these stem cells from a single donor – and in future it may be possible to derive these cells directly from the patient – helping to overcome practical problems associated with the use of allogeneic foetal tissue.

̽��ֱ��team followed the patients over 12 months, during which time they observed no treatment-related deaths or serious adverse events. While some side-effects were observed, all were either temporary or reversible.

All the patients showed high levels of disability at the start of the trial – most required a wheelchair, for example – but during the 12 month follow up period none showed any increase in disability or a worsening of symptoms. None of the patients reported symptoms that suggested a relapse and nor did their cognitive function worsen significantly during the study. Overall, say the researchers, this points to a substantial stability of the disease, without signs of progression, though the high levels of disability at the start of the trial make this difficult to confirm.

̽��ֱ��researchers assessed a subgroup of patients for changes in the volume of brain tissue associated with disease progression. They found that the larger the dose of injected stem cells, the smaller the reduction in this brain volume over time. They speculate that this may be because the stem cell transplant dampened inflammation.

̽��ֱ��team also looked for signs that the stem cells were having a neuroprotective effect – that is, protecting nerve cells from further damage. Their previous work showed how tweaking metabolism – how the body produces energy – can in turn reprogram microglia from ‘bad’ to ‘good’. In this new study, they looked at how the brain's metabolism changes after the treatment. They measured changes in the fluid around the brain and in the blood over time and found certain signs that are linked to how the brain processes fatty acids. These signs were connected to how well the treatment works and how the disease develops. ̽��ֱ��higher the dose of stem cells, the greater the levels of fatty acids, which also persisted over the 12-month period.

Professor Stefano Pluchino from the ̽��ֱ�� of Cambridge, who co-led the study, said: “We desperately need to develop new treatments for secondary progressive MS, and I am cautiously very excited about our findings, which are a step towards developing a cell therapy for treating MS.

“We recognise that our study has limitations – it was only a small study and there may have been confounding effects from the immunosuppressant drugs, for example – but the fact that our treatment was safe and that its effects lasted over the 12 months of the trial means that we can proceed to the next stage of clinical trials.”

Co-leader Professor Angelo Vescovi from the ̽��ֱ�� of Milano-Bicocca said: “It has taken nearly three decades to translate the discovery of brain stem cells into this experimental therapeutic treatment This study will add to the increasing excitement in this field and pave the way to broader efficacy studies, soon to come.”

Caitlin Astbury, Research Communications Manager at the MS Society, says: “This is a really exciting study which builds on previous research funded by us. These results show that special stem cells injected into the brain were safe and well-tolerated by people with secondary progressive MS. They also suggest this treatment approach might even stabilise disability progression. We’ve known for some time that this method has the potential to help protect the brain from progression in MS.

“This was a very small, early-stage study and we need further clinical trials to find out if this treatment has a beneficial effect on the condition. But this is an encouraging step towards a new way of treating some people with MS.”

Reference
Leone, MA, Gelati, M & Profico, DC et al. Intracerebroventricular Transplantation of Foetal Allogeneic Neural Stem Cells in Patients with Secondary Progressive Multiple Sclerosis (hNSC-SPMS): a phase I dose escalation clinical trial. Cell Stem Cell; 27 Nov 2023; DOI: 10.1016/j.stem.2023.11.001

An international team has shown that the injection of a type of stem cell into the brains of patients living with progressive multiple sclerosis (MS) is safe, well tolerated and has a long-lasting effect that appears to protect the brain from further damage.

I am cautiously very excited about our findings, which are a step towards developing a cell therapy for treating MS

Stefano Pluchino

Early-stage stem cell therapy trial shows promise for treating progressive MS

eyecrave productions (Getty Images)

Mature Adult Female with Disability

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Study in mice suggests personalised stem cell treatment may offer relief for progressive MS

cjb250 — Thu, 22 Feb 2018 17:00:03 +0000

̽��ֱ��study, led by researchers at the ̽��ֱ�� of Cambridge, is a step towards developing personalised treatments based on a patient’s own skin cells for diseases of the central nervous system (CNS).

In MS, the body’s own immune system attacks and damages myelin, the protective sheath around nerve fibres, causing disruption to messages sent around the brain and spinal cord. Symptoms are unpredictable and include problems with mobility and balance, pain, and severe fatigue.

Key immune cells involved in causing this damage are macrophages (literally ‘big eaters’), which ordinarily serve to attack and rid the body of unwanted intruders. A particular type of macrophage known as microglia are found throughout the brain and spinal cord – in progressive forms of MS, they attack the CNS, causing chronic inflammation and damage to nerve cells.

Recent advances have raised expectations that diseases of the CNS may be improved by the use of stem cell therapies. Stem cells are the body’s ‘master cells’, which can develop into almost any type of cell within the body. Previous work from the Cambridge team has shown that transplanting neural stem cells (NSCs) – stem cells that are part-way to developing into nerve cells – reduces inflammation and can help the injured CNS heal.

However, even if such a therapy could be developed, it would be hindered by the fact that such NSCs are sourced from embryos and therefore cannot be obtained in large enough quantities. Also, there is a risk that the body will see them as an alien invader, triggering an immune response to destroy them.

A possible solution to this problem would be the use of so-called ‘induced neural stem cells (iNSCs)’ – these cells can be generated by taking an adult’s skin cells and ‘re-programming’ them back to become neural stem cells. As these iNSCs would be the patient’s own, they are less likely to trigger an immune response.

Now, in research published in the journal Cell Stem Cell, researchers at the ̽��ֱ�� of Cambridge have shown that iNSCs may be a viable option to repairing some of the damage caused by MS.

Using mice that had been manipulated to develop MS, the researchers discovered that chronic MS leads to significantly increased levels of succinate, a small metabolite that sends signals to macrophages and microglia, tricking them into causing inflammation, but only in cerebrospinal fluid, not in the peripheral blood.

Transplanting NSCs and iNSCs directly into the cerebrospinal fluid reduces the amount of succinate, reprogramming the macrophages and microglia – in essence, turning ‘bad’ immune cells ‘good’. This leads to a decrease in inflammation and subsequent secondary damage to the brain and spinal cord.

“Our mouse study suggests that using a patient’s reprogrammed cells could provide a route to personalised treatment of chronic inflammatory diseases, including progressive forms of MS,” says Dr Stefano Pluchino, lead author of the study from the Department of Clinical Neurosciences at the ̽��ֱ�� of Cambridge.

“This is particularly promising as these cells should be more readily obtainable than conventional neural stem cells and would not carry the risk of an adverse immune response.”

̽��ֱ��research team was led by Dr Pluchino, together with Dr Christian Frezza from the MRC Cancer Unit at the ̽��ֱ�� of Cambridge, and brought together researchers from several university departments.

Dr Luca Peruzzotti-Jametti, the first author of the study and a Wellcome Trust Research Training Fellow, says: “We made this discovery by bringing together researchers from diverse fields including regenerative medicine, cancer, mitochondrial biology, inflammation and stroke and cellular reprogramming. Without this multidisciplinary collaboration, many of these insights would not have been possible."

̽��ֱ��research was funded by Wellcome, European Research Council, Medical Research Council, Italian Multiple Sclerosis Association, Congressionally-Directed Medical Research Programs, the Evelyn Trust and the Bascule Charitable Trust.

Reference
Peruzzotti-Jametti, L et al. Macrophage-derived extracellular succinate licenses neural stem cells to suppress chronic neuroinflammation. Cell Stem Cell; 2018; 22: 1-14; DOI: 10.1016/j.stem.2018.01.20

Scientists have shown in mice that skin cells re-programmed into brain stem cells, transplanted into the central nervous system, help reduce inflammation and may be able to help repair damage caused by multiple sclerosis (MS).

Our mouse study suggests that using a patient’s reprogrammed cells could provide a route to personalised treatment of chronic inflammatory diseases, including progressive forms of MS

Luca Peruzzotti-Jametti

Andrew c

Neuron with oligodendrocyte and myelin sheath (edited)

Researcher profile: Dr Luca Peruzzotti-Jametti

It isn’t every day that you find yourself invited to play croquet with a Nobel laureate, but then Cambridge isn’t every university, as Dr Luca Peruzzotti-Jametti discovered when he was fortunate enough to be invited to the house of Professor Sir John Gurdon.

“It was an honour meet a Nobel laureate who has influenced so much my studies and meet the man behind the science,” he says. “I was moved by how kind he is and extremely impressed by his endless passion for science.”

Dr Peruzzotti-Jametti began his career studying medicine at the ̽��ֱ�� Vita-Salute San Raffaele, Milan. His career took him across Europe, to Switzerland, Denmark, Sweden and now to Cambridge. After completing a PhD in Clinical Neurosciences here he is now a Wellcome Trust Research Training fellow.

His work focuses on multiple sclerosis (MS), an autoimmune disease that affects around 100,000 people in the UK alone. Despite having several therapies to help during the initial (or ‘relapsing remitting’) phase of MS, the majority of people with MS will develop a chronic worsening of disability within 15 years after diagnosis. This late form of MS is called secondary progressive, and differently from relapsing remitting MS, it does not have any effective treatment.

“My research sets out to understand how progression works in MS by studying how inflammation is maintained in the brains of patients, and to develop new treatments aimed at preventing disease progression,” he explains. Among his approaches is the use of neural stem cells and induced neural stem cells, as in the above study. “My hope is that using a patient’s reprogrammed cells could provide a route to personalised treatment of chronic inflammatory diseases, including progressive forms of MS.”

Dr Peruzzotti-Jametti is based on the Cambridge Biomedical Campus where he works closely with clinicians at Addenbrooke’s Hospital and with basic scientists, a community he describes as “vibrant”.

“Cambridge has been the best place to do my research due to the incredible concentration of scientists who pursue novel therapeutic approaches using cutting-edge technologies,” he says. “I am very thankful for the support I received in the past years from top notch scientists. Being in Cambridge has also helped me competing for major funding sources and my work could have not been possible without the support of the Wellcome Trust.

“I wish to continue working in this exceptional environment where so many minds and efforts are put together in a joint cause for the benefit of those who suffer.”

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