2023-10-18 20:15:45
The development of regenerative therapies is one of the great bets of the international biomedical community to address neurodegenerative pathologies such as Parkinson’s disease. In this way, the transplant into the brain of a certain type of neurons derived from stem cells (called dopaminergic neuronal precursors or DA-CM) is considered an alternative to functionally replace the loss of neurons produced by the degenerative condition; In fact, there are three clinical trials underway in different countries to study this therapeutic strategy. However, it is estimated that only 10% of the transferred cells survive post-transplant. Now, work carried out by researchers at the Fundación Instituto Leloir (FIL) in Argentina, published in the academic journal PLoS One, could change this panorama: according to the results of the study, inhibiting a pro-inflammatory molecule called tumor necrosis factor or TNF-alpha It would increase the chances of the transplanted neurons remaining alive.
“Every brain transplant triggers inflammation and for more than 25 years we have been verifying that this modifies the survival (survival time) and the function of dopaminergic neurons,” Fernando Pitossi, head of the Regenerative Therapies Laboratory, told the CyTA-Leloir Agency. and Protectors of the Central Nervous System of the FIL and one of the authors of the study. In the new work, Pitossi and his colleagues have determined, through in vitro tests, that the inhibition of TNF-alpha increases the survival of DA-CMs. “Identifying this molecule is a great step for the design of an anti-inflammatory therapy complementary to cell transplantation against Parkinson’s disease,” added the scientist.
Parkinson’s disease is a progressive neurological disorder whose motor symptoms are mainly caused by the death of dopaminergic neurons in an area of the brain. Current treatments do not stop its progression nor do they allow to restore the functioning of what has been lost. For this reason, regenerative medicine causes a lot of expectation: it focuses on the replacement, repair or regeneration of cells, tissues or organs as a way to restore altered biological functions. It does this based on the use of stem cells that have the ability to become specialized cells.
“One of the types of stem cells that are currently most used in these experimental studies are pluripotent ones, capable of differentiating into more than 200 different cell types such as, for example, specific neurons,” said Pitossi, whose group generated DA- human CM and detected that when transplanted into laboratory animals, even immunosuppressed, the brain generates not only inflammation but also TNF, which can reduce their survival. Therefore, the importance of checking what happened when inhibiting it.
According to Pitossi, there is still one more step of research to refine a possible anti-TNF therapy associated with cell transplantation, given that this type of molecules (cytokines) can have dual effects on neurons. “Depending on their concentration, context, and duration of expression, they can be toxic or protective of neurons,” she described. In the case of TNF, he explained, the molecule exerts its action through two receptors: type 1 and type 2. “We believe that the toxic effect of TNF is through the type 1 receptor. Therefore, our future research will be focused “to study this hypothesis and see if by inhibiting it we can prevent the death of neurons without altering any beneficial effect that TNF could be exerting through the type 2 receptor,” he highlighted.
The first clinical study of cell therapy for Parkinson’s Disease was carried out 35 years ago and since then progress has been made at a slow pace. There are currently three trials to develop regenerative therapies that use DA-CM like those analyzed by Pitossi’s group: one began in 2018 in Japan; another in 2021 in the United States; and another this year, in Sweden and Great Britain.
In red, human dopaminergic neurons (indicated with arrows) incubated in an inflammatory environment (left). The same experiment after inhibiting TNF shows how the number of neurons increases (right). (Images: CyTA-leloir Agency)
Global impact
Parkinson’s disease is a degenerative brain condition associated with motor symptoms (slowness of movement, tremors, rigidity, gait disorders and imbalance) and a wide variety of non-motor complications such as cognitive impairment, mental disorders and sleep disorders, among others. others. As it progresses, it produces limitations in different aspects of daily life and over time leads to high rates of disability and care needs.
According to the World Health Organization (WHO), 8.5 million people in the world suffer from the disease, which mainly affects those over 65 years of age. It is the second most common neurodegenerative disease after Alzheimer’s disease. In Argentina alone, the number of affected patients is estimated to be between 70,000 and 100,000.
Shirley Wenker, María Isabel Farías, Victoria Gradaschi, Corina García, María Celeste Leal and Carina Ferrari also participated in the study published in PLoS One (by the Fundación Instituto Leloir-IIBBA CONICET), in collaboration with Xianmin Zeng, from RxCell (EE .USA) and Juan Beauquis, from IBYME. (Source: CyTA-leloir Agency)
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