Spanish study may lead to better therapies for cancer and progeria

Premature aging diseases provide ‘models’ through which many hope to gain insight into the human aging mechanism. They provide an effective model for analyzing the body’s maturation process. The observation in mice of the effects of Prelamin A, the protein that causes progeria, has shed some light in the complex connection taking place between the ageing processes and cancer, since these are closely related. Several years of collaboration between the Institute of Molecular and Oncological Medicine of Asturias (Imoma) and the University of Oviedo has lead to new findings. The spanish scientists discovered that the protein Prelamin A, that speeds up ageing, may slow cancer.

In order to carry out their research, the Spanish scientists have used mosaic mice, genetically modified, to keep 50% of cells with Prelamin A in their tissues during their whole life. The study showed that the Prelamin A causes progeria through cell-extrinsic mechanisms, but also prevents cancer. Suprisingly, these mosaic mice are completely healthy and do not show progeria in spite of having the ageing protein in half of their cells. They live as long as normal mice. This suggests that in order to treat fast ageing it would not only be necessary to fix defects from the affected patient’s cells.

The study made two important discoveries. Firstly that the mosaics are totally healthy, showing none of the alterations that the mice with progeria caused by prelamin A have. Secondly, although the mosaics develop the same number of tumours as normal mice, they have far fewer malignant tumours (those capable of breaking down the barriers that confine them and invading the surrounding tissue).

Carlos López-Otín, one of the researchers, remarked that the achieved results are very encouraging from the scientific point of view, although the development and application of therapies need to be carefully stated. 

José María Pérez Freije, of the University of Oviedo, noted that 'these results invite hope for treating patients with rapid ageing, as they suggest that it is not necessary to correct defects in all cells, but probably only in some of them'. Rubén Cabanillas, of IMOMA said: 'by inducing prelamina A production in cells obtained from human malignant tumours, we observed that their invasive capacity is drastically reduced'.

The finding that the protein that causes fast ageing, Prelamin A, is capable of halting the advancement of malignant tumors, may allow the development and application of new therapies to fight cancer as well as progeria.


special... with good reason

In this documentary three members of the progeria family circle 'dreamteam' explain why they help to bring the progeria children and their families together.


new approach for progeria treatment with inhibitor for ICMT

Researchers at Sahlgrenska Academy, the University of Gothenburg, Sweden, have published new results of their work in Science. The group investigated the progeria mutation, that occurs in the protein prelamin A and causes it to accumulate in an inappropriate form in the membrane surrounding the nucleus.

The target enzyme of this study is called ICMT, it attaches a small chemical group to one end of prelamin A. In progeria, blocking this attachment could possibly reduce the development of premature ageing symptoms more effectively. The publication in Science is based on in vitro studies on cells, and has been tested in vivo on mice, treated with a common inhibitor of ICMT. The impact of inhibiting ICMT will need further testing on progeria mouse models with more specified candidate ICMT inhibitor drugs -developped by a collaborating group in Singapore- before it can be offered in a trial to patients.

ICMT has also become the focus of research in the quest for discovering new and more effective cancer therapies. The article Targeting Isoprenylcysteine Methylation Improves Disease Phenotypes in a Mouse Model of Accelerated Aging has been published on May 16. Further reading at Science and the University of Gothenburg.


Unique molecular mechanism protects neurons in progeria patients

Progeria is an extremely rare genetic disease, which induces premature and accelerated ageing in patients. The mutation causing the syndrome affects the LMNA gene that encodes proteins called “lamins” A and C.

Lamins are involved in maintaining the structure of the nuclear membrane. They determine nuclear shape and stiffness and allow communications within the cells. In the case of progeria, lamin A is defective. In its mutated form, it becomes toxic and damages the membranes of the nucleus, disrupts the message and causes accelerated ageing of cells. In 2003 the research team of Dr. Nicolas Levy in Marseille identified the origin of this disease.

The development of this syndrome is rapid: it is estimated that each year, affected children age by more than ten years, leading to their premature death between 13 and 16 years. This accelerated ageing affects most tissues: skin, blood vessels, heart, bones or muscles. Very quickly, patients suffer from muscular and skeletal disorders, stunted growth (their size does not exceed 110 cm for a weight of 15 kg). In contrast, their cognitive abilities are usually not affected. This has always been considered a surprising phenomenon, given the overall disease involvement to which these patients are subjected.

One of the studies of Xavier Nissan et al. in their progeria project showed a unique molecular mechanism that specifically protects neurons in patients with Hutchinson-Gilford progeria syndrome from the defective prelamin A processing.

Skin cells sampled from patients with progeria were induced into pluripotency then differentiated into mature nerve cells. Tuj1 markers highlight nerve cells in green; other markers highlight DNA in blue. Lamin A, if present, would appear in red; the protein is however completely absent in this cell view. 
Copyright: Xavier Nissan, I-Stem 

You can download the extended PDF file of this publication HERE.

The strategy at I-Stem

Recently two phase II clinical trials were initiated by treating HGPS patients with Farnesyltransferase inhibitors (FTIs) and/or the combination of Zoledronate and Pravastatin to prevent or delay the gravest infringements of the disease. Although these two studies have produced promising results, as well as in vitro and in vivo, there is currently no cure for HGPS patients.

In collaboration with Professor Nicolas Lévy, the I-Stem team has generated induced pluripotent stem cells from progeria patients’ cells. Thanks to this unlimited and standardized biological resource they are preparing a high throughput screening campaign of pharmacological compounds in order to identify new treatments of this disease.