Beyond Achondroplasia

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Statins for achondroplasia, at the 12th ISDS meeting -part 1

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The ISDS is registered as a non-profit organization, and the principal aim of the Society is to promote scientific progress in the field of skeletal dysplasias and dysostoses.

At the Nosology and classification of genetic skeletal disorders, Superti-Furga et al. 2011: “Dysostoses are disorders affecting individual bones or group of bones. In contrast to the ‘‘dysplasias,’’ that arise frequently from defects in structural proteins, metabolic processes or in growth plate regulation, the dysostoses often arise from embryonic morphogenic defects and are thus more closely related to multiple malformation syndromes“.

The 12th ISDS meeting was held in Istanbul, with an excellent 3 days scientific program, a list of brilliant attendees and speakers. Two of the invited speakers and their lectures:

Noriyuki Tsumaki (Kyoto University) – iPSC disease modeling of FGFR3 chondrodysplasia
Ravi Savarirayan (Victorian Clinical Genetics Services) – Advances in Treatment of Achondroplasia

In this post- part 1 – I will write about Prof. Tsumaki lecture.

Prof. Tsumaki gave a lecture about the development of iPSC, induced pluripotent cells (This technology was pioneered by Prof. Yamanaka’s lab in Kyoto, who showed in 2006 that the introduction of four specific genes encoding transcription factors could convert adult cells into pluripotent stem cells), and on its joint study with prof. Yamashita, on the use of statins in the treatment of achondroplasia.

Prof. Tsumaki team converted fibroblasts from ACH patients into iPSCs.

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Slide from Prof. Tsumaki lecture – ISDS 2015

Fibroblasts are a type of cell that synthesizes (produce) the extracellular matrix (a group of molecules produced by cells that provides structural and biochemical support to the surrounding cells) and collagen, the structural framework  for animal tissues, and plays a critical role in wound healing. Fibroblasts are the most common cells of connective tissue in animals.

The chondrogenic differentiation (the process by which a less differentiated chondrocyte changes and progresses into a differentiated chondrocyte) of  ACH iPSCs resulted in the formation of degraded cartilage. His team found that statins could correct the degraded cartilage in chondrogenically differentiated ACH iPSCs. Article here

Treatment of ACH model mice with statin led to a significant recovery of bone growth. These results suggested that statins could represent a medical treatment for infants and children with ACH.

This was a laboratory experiment where his team selected a high number of compounds to apply in these iPSC choncrocytes and they obtained a very good outcome with statins (this molecule was previously described in the literature to improve growth – Statins and bone formation. Garrett et al. 2001.) The laboratory results (tests made with chondrocytes in lab dishes) were of high growth and improved development of chondrocytes.

But observing these results from the laboratory and applying statins to a whole body, a child’s body that it’s developing other functions and structures, is a totally different thing.

As is known, statins inhibit cholesterol production. And cholesterol (although many people know only about it’s negative side) is absolutely essential for the natural and healthy development of children, mainly for the neurological (brain development), body tissues and reproductive development. To prevent the blockage of cholesterol production under a statins treatment, Prof. Tsumaki himself confirmed that it is necessary to develop statins that only act at the point of prenylated proteins that do not disrupt cholesterol production.

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Slide from Prof. Tsumaki lecture – ISDS 2015

So, at this point, in order to use statins in children with achondroplasia, we are talking about developing a new study for a whole new molecule that only would interfere with the prenylated proteins and not with the cholesterol cascade. And therefore, the obvious conclusion seems that the use of statins in achondroplasia as they are, is not an eligible approach and can´t be considered as a potential treatment for achondroplasia.

From least- to terminally-differentiated, the chondrocytic lineage is:

  1. Colony-forming unit- fibroblast (CFU-F)
  2. Mesenchymal stem cell / marrow stromal cell (MSC)
  3. Chondrocyte
  4. Hypertrophic chondrocyte

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