Drug Discovery Opinion

T-cell receptors are integral membrane proteins that recognise foreign antigens and initiate a series of intracellular signalling cascades that allow the immune system to fight infection. To avoid autoimmune diseases, T-cells must be able to discriminate between ‘self’ and ‘foreign’ antigens but this discrimination may also prevent the immune system from recognising and destroying tumour cells.

Researchers led by a team from the Max-Delbrück-Center for Molecular Medicine have now developed transgenic mice that produce T-cell receptors that recognise human cancer cell antigens and could potentially be introduced into the T cells of cancer patients. Using embryonic stem cells loaded with human DNA, the team generated transgenic mice that express the entire human T-cell repertoire. Negative selection normally removes maturing T-cells that are capable of binding strongly to ‘self’ antigens but the mouse does not recognise human cancer cell antigens as ‘self’ and T-cells expressing receptors to these antigens are allowed to survive. T-cells with such high affinity receptors for cancer cell antigens are not produced in humans and the researchers hope that introducing the high affinity receptors into the T-cells of cancer sufferers will boost the immune system’s ability to recognise and destroy tumour cells. A first clinical trial to evaluate the efficacy and tolerability of the methodology in cancer patients is planned.

The study is published in the journal Nature Medicine.

Once damaged, heart muscle has very limited capacity for regeneration but scientists at the Gladstone Institute of Cardiovascular Diseases have now discovered how to reprogram structural fibroblasts into functioning cardiac muscle cells (cardiomyocytes). The team explored the effects of transcription factors known to be important for development of the heart and found that a combination of just three (Gata4, Mef2c and Tbx5) was sufficient to rapidly and efficiently convert cardiac or dermal fibroblasts into contractile cardiomyocyte-like cells.

Gladstone scientists have previously converted mouse mesoderm – germ tissue from very early embryos – into cardiomyocytes and have reprogrammed adult cells into induced pluripotent cells which can then be converted into other cell types but, in the present study, adult cells have been directly reprogrammed into a different type of cell without involvement of a progenitor cell state. The team hope that going directly from one adult cell type to another might eliminate some of the perceived risks associated with the use of stem cells and that it will be possible to identify small molecules that are able to trigger the conversion. Although the technique has yet to be tested in human cells, and further refinement and characterisation of the reprogramming process will be needed, the heart has a large pool of fibroblasts which provide a potential source for regenerative treatments if they could be directly reprogrammed to beating cardiomyocytes.

The study is published in the journal Cell.

There has long been debate about the relative merits of a low-carbohydrate diet, as popularised by Atkins, compared to the more traditional low-fat approach to weight loss. A low-carbohydrate diet has also been anecdotally associated with adverse effects on health.

A newly published clinical study, led by researchers at the Center for Obesity Research and Education at Temple University, Philadelphia, has now shown remarkably little difference between the two regimes. The study followed over 300 subjects randomly assigned to either diet over a two year period and, importantly, combined the diets with comprehensive behavioural treatment.

In the low-carb group, carbohydrate intake was limited to 20 g/d for 3 months in the form of low–glycemic index vegetables with unrestricted consumption of fat and protein. After 3 months, participants were allowed to increase their carbohydrate intake (5 g/d per wk) until a stable and desired weight was achieved. The low-fat diet consisted of limited energy intake (1200 to 1800 kcal/d) with less than 30% of the calories derived from fat. For the behavioural treatment, each participant attended group sessions weekly for the first 20 weeks of the study, every other week for the next 20 weeks, and once every other month for the remainder of the study. In each session, participants discussed topics such as goal setting, self-monitoring, and limiting triggers to overeating.

Although attrition was high at 2 years, there were no differences in weight, body composition, or bone mineral density between the groups at any time point. Weight loss was approximately 11 kg (11%) at 1 year and 7 kg (7%) at 2 years. The low-carbohydrate diet group had greater increases in high-density lipoprotein cholesterol (“good” cholesterol) levels at all time points, increasing by approximately 23% at 2 years, suggesting that a low-carb diet may have some cardiovascular benefit.

Gary Foster, Director of Temple’s Center for Obesity Research and Education and lead author of the study said:

When comparing these two popular weight loss plans, none of the existing research had included a comprehensive, long-term, behavioural support component. This research tells us that people wanting to manage their weight need to be less concerned with which diet they choose, and more concerned with incorporating behavioural changes into their plan.

The study is published in Annals of Internal Medicine.

Nitrosylation of proteins is emerging as a key post-translational modification important in both normal physiology and a wide spectrum of diseases, including neurodegenerative diseases. Physiological levels of nitric oxide (NO) can be neuroprotective, in part at least, by inhibiting caspase activity, but excess NO production leads to activation of cell death signalling cascades involved in many neurodegenerative disorders. Neuronal cell injury and death, which are prominent features of disorders such as Alzheimer’s, Huntington’s, and Parkinson’s diseases, are often mediated by the caspase family of cysteine proteases. Caspase activity is inhibited by S-nitrosylation and is also regulated by inhibitors of apoptosis such as X-linked inhibitor of apoptosis (XIAP) which associates with active caspases and represses their catalytic activity. XIAP also functions as an E3 ubiquitin ligase, targeting caspases for degradation by the proteasome.

A team of scientists led by Sanford-Burnham researchers have now discovered a new twist in caspase regulation. They showed that S-nitrosylation of XIAP (forming SNO-XIAP) inhibits the protein’s E3 ligase and antiapoptotic activity and also found that XIAP can be transnitrosylated by SNO-caspase but not vice versa. They found significant amounts of SNO-XIAP, but not SNO-caspase, in the brains of individuals with neurodegenerative diseases, suggesting that SNO-XIAP contributes to neuronal injury or death. The team hope that their study, which is published in the journal Molecular Cell, might lead to better biomarkers and earlier diagnosis for neurodegenerative diseases.

Over 30% of the 50 million people who are affected by epilepsy do not have their seizures adequately controlled, even with the best available medicines. The 29 amino acid neuropeptide, galanin, is a potent endogenous anticonvulsant that activates galanin receptors type 1 (GalR1) and type 2 (GalR2) and a number of groups, including researchers at the Scripps Research Institute, have been trying to develop drugs that mimic the effects of galanin as novel anticonvulsants. Galnon is an example of a systemically active nonpeptide galanin receptor ligand with affinity for the three galanin receptors which has been shown to reduce seizures in animal models. The Scripps team have now identified a compound that acts appears to act as a selective positive allosteric modulator of the galanin receptor type 2 (GalR2) which they hope will have a reduced potential for side effects compared with galnon. The compound, CYM2503, potentiated the effects of galanin in cells stably expressing the GalR2 receptor, but had no detectable affinity for the galanin binding site. In rodent models of epilepsy, intraperitoneal administration of CYM2503 increased the time to seizure, reduced the duration of seizures, and increased survival rate at 24 h.

The study is published in the Proceedings of the National Academy of Sciences.