Creation of CAR-Tregs that are resistant to the senescent environment

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To date, there is no effective drug to treat the neurodegenerative disease amyotrophic lateral sclerosis (ALS). ALS is a fast-progressing and ultimately fatal condition which leads to selective motor neuron loss and death within two to five years after symptom onset. The current gold standard treatment for ALS is riluzole, a drug without a proven mechanism of action that was developed in the early 1990s. As an unmet need, ALS is a target for drug development. ALS involves abnormalities of the immune system, most strikingly changes to T cells, a specific type of white blood cell. In particular ALS causes the loss of a specialised T cell called a T regulatory cell or Treg. These cells act to dampen down the immune response and maintain self-tolerance, the ability of the immune system to recognise the body as a non-threat and only mount a response to foreign substances. In ALS not only do the numbers of Tregs decline but so also do their potent suppressive ability. Cell therapies are in clinical development and involve expanding patient-derived Tregs but the treatment requires large doses of Tregs and patients decline soon after stopping the infusion. We believe this to be due to the highly pro-inflammatory and pro-senescence (ageing) ALS environment. Reflection Therapeutics have developed a new targeted methodology called a CAR-Treg (CAR, Chimeric Antigen Receptor) that shows improved performance over conventional cell therapies, however, the hostile environment these engineered cells find themselves in needs addressing. Therefore the main aim of this grant is to create a CAR-Treg that specifically targets inflamed areas while also being resistant to the damaging environment. The creation of this next generation CAR-Treg therapy is of vital importance as there is no effective treatment for ALS.