Spondylopiphyseal dysplasia congenita, or SEDC, is a rare type of skeletal dysplasia, which refers to the family of bone and cartilage disorders that affect bone growth at birth. SEDC is genetic and hereditary, and it is a disorder that usually results in short stature (or dwarfism) and other skeletal anomalies.
SEDC mainly affects the spine, hips, and knees, but can also even affect areas such as the eyes. The disorder generally leads to children being shorter than expected, and some may also develop hearing and vision problems. People who live with SEDC however can still enjoy a normal life span and have normal intelligence.
Recent studies have shed light on the mysterious origins of SEDC. A study conducted by McGill University (Canada) has laid a conclusion that the basis of this rare bone disorder may be due to a potential variance or mutation in the MGP, or matrix gla protein, gene. This research could be fundamental for healthcare professionals to address and develop future potential treatments for this rare disorder, as well as for the prospects of CRISPR/Cas9 and gene-editing therapy as a treatment option in this field.
The MGP Gene and McGill University’s Research
MGP is a unique protein that is found across blood vessels and cartilage in humans. The gene has the purpose of preventing the atrophying of tissues and promotion of bone formation. If for instance, MGP is completely absent in an individual, it can lead to disorders such as Keutel syndrome. Keutel syndrome is another rare bone disease that causes calcification of cartilage across the body, leading to problems in the functioning of the skeleton and blood vessels. Yet variation of MGP is nevertheless different from Keutel syndrome in terms of both cellular and molecular movement. Its manifestations in humans also vary individually.
McGill University found that it is the heterozygous mutational variants within MGP that cause skeletal dysplasia disorders. Researchers sampled four people from two different families who had slight variations in their MGP genes. These four people all had different changes in their proteins and it was also found that they also all had specific bone disorders.
This heterozygous MGP variant was also used on mice to give a better picture of what is happening on the cellular and molecular levels. Researchers found that this mutated MGP led to the same bone issues as exhibited by humans in the mice. The mutated protein did not go out of the cells, which led to increased pressure on the protein-folding part of the cell, also called the endoplasmic reticulum. In other words, the mutated MGP led to cartilage cells not being able to manage this stress, leading to apoptosis (or cell death), and therefore causing calcification and bone disorders such as SEDC.
The research conducted by McGill University is important as it ensures that there is an understanding of genetic agents that contribute to skeletal dysplasia disorders like SEDC and Keutel syndrome. With understanding also comes prospects for improved management and treatment methods of not just SEDC, but of many other rare bone diseases with technologies like CRISPR/Cas9.
CRISPR Gene-Editing Technologies for Rare Bone Disorders: Potential Treatment Option
Due to CRISPR/Cas9 being an efficient, specified, and non-invasive therapeutic technology, its potential for treating rare bone diseases such as skeletal dysplasia is highly attractive.
SEDC and other skeletal dysplasia disorders are hereditary genetic bone diseases. Currently, much of its conventional treatments consist of either growth hormone therapy, orthopedic surgeries, bone replacement therapy, or limb lengthening. These conventional treatment methods can be expensive, can leave many complications, and usually involve long recovery periods. However, CRISPR/Cas9 and other gene-editing technology may be an effective replacement for these traditional treatments and may also be a far cheaper and far less consequential alternative. Compared to using chemical agents, gene therapy would target the essential cause of rare bone disease via optimized disease prognoses.
Achondroplasia is the most common form of genetic dwarfism and skeletal dysplasia, and gene-editing therapies have been making their way as a viable treatment method.
In 2019 BioMarin enrolled 121 children, aged 5-14, with achondroplasia to engage in a clinical trial of Voxzogo (vosoritide), a gene-editing drug developed in 2015 that aims to treat the disorder. Children who received the treatment were found to have grown 1.6 centimeters or more over the year than those who did not.
In 2021, the Food and Drug Administration (FDA) made a landmark decision in approving the drug, making it the first gene-editing drug to be approved for the treatment of a skeletal dysplasia disorder. While not yet developed, CRISPR/Cas9 has also been shown to be effective in curing achondroplasia in mice. CRISPR/Cas9 effectively made a ‘knockout’ on the heterozygous mutations within the FGFR3, or fibroblast growth factor 3, which is another protein similar to MGP that assists in turning cartilage into bone required for body growth.
CRISPR Gene-Editing Technologies for Rare Bone Disorders: Potential Object of Controversy
The potential use of CRISPR/Cas9 and other gene-editing therapy as a means to treat rare bone diseases and conditions such as dwarfism is not without controversy. For those who have SEDC, achondroplasia, or dwarfism in general, yet live happily with normal and healthy lives, the idea of using CRISPR/Cas9 and general gene-editing potentially reproduces highly unfavorable and even discriminatory circumstances.
For many of those with disabilities who live with inherited rare diseases, the use of CRISPR/Cas9 to ‘correct’ these disorders can draw some uncomfortable parallels to eugenics.
While it is illegal in the U.S. to genetically implant a genetically modified human embryo, these risks and ethical questions should be placed into consideration for the treatment of rare bone disorders such as SEDC or achondroplasia.
Voxzogo has been particularly controversial amongst those affected with achondroplasia and other forms of dwarfism when the FDA approved it. For example, the Little People of America (LPA), an association that provides support for those with short stature, launched a statement denouncing the FDA’s approval of the drug, and that there should be instead greater focus on making the lives of those with short statures more accessible and inclusive.
Recent research by McGill University will be an important addition to understanding the causes of skeletal dysplasia disorders such as SEDC and is something everyone from genetic researchers and nurses to pediatricians and online MSN students should note. It will also be a valuable part of improving and creating new, revolutionary alternative treatment options for individuals who are affected by the disorder. But treatment also means ensuring ethical standards are not forgotten, and the voices of those with these disorders are addressed.