Genetic Therapy for Cornelia de Lange Syndrome Patient- All you need to know
There have been a lot of advances in the treatment of congenital disorders and diseases during the last century. Genetic Therapy is a new field that has opened a range of new possibilities for future treatment of genetic defects.
Genetic therapy is the treatment of choice for patients with CdLS. This article will outline the goals of treatment, describe the procedures performed, and discuss outcome data for patients undergoing gene therapy.
But first. What is Cornelia de Lange syndrome? Before we get into the specifics of gene treatment, let’s see how it fits into the larger picture of genetics.
Understanding the Problem
Cornelia de Lange Syndrome is a rare genetic disorder that has been around for a long time. As it turns out, the syndrome was so rare that researchers didn’t pay much attention to it until recently.
The limited understanding of Cornelia de Lange syndrome left it difficult to diagnose. And the diagnosis was left to the identification of physical symptoms, among other deformities.
As technology improves, CdLS advances are increasing. For example, it’s currently known that CdLS is a congenital disease caused by a mutation gene.
Even so, this syndrome might not be present despite family history. It is also caused by numerous genes which are supposed to facilitate the growth of body parts and organs.
Some of these genes have been identified through modern-day gene sequencing. These discoveries opened a new way to look at the disease. It also develops a medical intervention in the form of gene therapy.
What is the Cornelia de Lange Syndrome?
CdLS is a rare syndrome characterized by developmental delay, immune dysfunction, and characteristic facial features. It was named after Cornelia de Lange, the doctor who discovered and described the disorder in children in 1933.
Individuals with CdLS can display physical, cognitive, and behavioral differences. But these characteristics vary widely between people with the syndrome. Depending on the person, there may be different degrees of difference in face and limbs.
What Causes Cornelia de Lange Syndrome?
When looking at the causes of CdLS, one cannot avoid talking about chromosomes and genes. Chromosomes, which are present in the nucleus of our cells, carry the genes that make up each person’s unique set of genetic material. These genes convey instructions for the development of a person’s physical features and control many other functions in the body.
Genes are specific in their task. They encode separate instructions that tell the cell how to function. When altered or damaged, genes can lead to proteins without the correct instructions. The result is developmental deformities often seen in patients with CdLS.
Research has shown that CdLS is caused by changes in genetic material. These changes are called mutations.
Mutations in Genes related to CdLS
The changes in living organisms that are not inherited by ancestors are mutations. Genes code for a single protein. In this case, each gene related to CdLS codes for a different part of the cohesin protein complex.
Mutations in these genes can lead to a wide range of physical characteristics and even organ deficiencies. There are three common types of mutations in CdLS related genes:
- Missense Mutations: These single-point mutations—called point mutations—are like typos in a sentence. They change only one letter, and they might sometimes still make sense. But they are harder to understand, and frequently change the intended meaning completely.
- Severe Mutations: This type of mutation results in the loss of a function and is usually followed by a series of detrimental effects such as protein production halting altogether.
- Gene Deletion: Larger deletions of an individual gene can lead to effects similar to a loss of function mutation. Gene deletions may also have more severe consequences than the loss of function mutations.
Cohesinopathies in CdLS Patient
Cohesinopathies are genetic disorders caused by changes in the function of Cohesin. Scientists have identified seven different genes that can be mutated in patients with CdLS.
- NIPBL
- SMC1A,
- SMC3,
- RAD21
- BRD4,
- HDAC8 and
- ANKRD11
These genes are closely related to CdLS. But more importantly, a change in one of these genes affects what is known as the cohesin protein complex.
The cohesin complex is an association of proteins that adheres the DNA in the nucleus of a cell to the nuclear envelope. Cohesin complexes also ensure the correct expression of genes and the maintenance of chromosome stability.
The cohesin complex will not function well with a mutation in one of the CdLS-related seven genes mentioned above. Improper functioning of the cohesin complexes alters human development seen in CdLS patients. However, not all cohesinopathies result in CdLS.
The Hope for a Cure: Genetic Therapy
Gene therapy is a promising innovation in treating genetic diseases. The process consists of re-inserting the normal gene of a person into cells. While several genetic therapies have been developed for other genetic conditions, these results are even more promising for children with CdLS.
Genes Related to CdLS
Researchers have identified seven genes that are responsible for causing Cornelia de Lange syndrome. Mutation of one or all of these genes partially or completely prevents the production of specific proteins in the body.
Ongoing research has uncovered several abnormalities in this group of proteins. But it is still unclear how they cause the physical and internal characteristics seen in Cornelia de Lange syndrome.
|
Genes |
Phenotypic implications |
|
NIPBL |
Congenital abnormalities and loss of function |
|
SMC1A |
Loss of function. Males are more susceptible |
|
SMC3 |
intellectual disability, short stature, and congenital abnormalities. |
|
RAD21 |
impaired growth and development before birth, small head size at birth, and developmental delay. |
|
BRD4 |
including limb and facial deformities |
|
HDAC8 |
widely spaced eyes, happy personality |
CdLS Related gene and their phenotypic effects
CdLS related genes include:
i. NIPBL
Approximately 70% of children with the disorder have mutations in the NIPBL gene, which encodes a protein found with cohesin complex. Most of the time, these mutations do not affect all cells in the person’s body. However, a mutation in the NIPBL gene is responsible for most congenital disorders found in CdLS.
ii. SMC1A
SMC1A is responsible for producing and maintaining the core component of the cohesin complex ring. Changes in SMC1A have been found in nearly 5% of individuals who have CdLS.
The gene SMC1A is located on the X chromosome. Males have only one copy of the X chromosome; females have two. Therefore, males are usually more severely affected by it than females.
iii. SMC3
SMC3 is a protein necessary for the proper functioning of the core cohesin complex. Several changes in SMC3 have been found to lead to intellectual disability, short stature, and congenital abnormalities.
iv. RAD21
The RAD21 gene also forms part of the core cohesin complex. There has been evidence of genetic variation in the RAD21 gene found in around 1 in 10 cases of CdLS.
People with a mutation in the RAD21 gene have a wide variety of symptoms, including impaired growth and development before birth, small head size at birth, and developmental delay.
v. BRD4
The deletion of this gene appears to be a rare cause of CdLS. Individuals with this deletion typically have several problems, including limb and facial deformities.
vi. HDAC8
HDAC8 variants have been found in about 5% of individuals with CdLS. It is also essential to note that changes in HDAC8 have been found in some people who do not have CdLS. So, the role of this gene in CdLS is still being studied.
In addition to the symptoms of CdLS, those with a change in HDAC8 also might have other symptoms that include:
- large soft spot on top of their head
- widely spaced eyes
- happy personality.
vii. ANKRD11
The gene ANKRD11 plays a crucial role in the development of the nervous system. Some changes in this gene have been reported in individuals with a non-classic CdLS phenotype and others have been noted in several clinical observations. Individuals with changes in ANKRD11 show features that overlap with the facial characteristics, and suggestive features of CdLS.
Genetic Therapy and CdLS
Genetic therapy is a medical procedure in which genetic material is introduced into the cells of a living organism to alter the genetic structure. Its target is to prevent, cure, or reduce the symptoms of a particular disease.
Genetic therapy for Cornelia de Lange syndrome patients involves treatment with proteins that affect the way the body recognizes or treats mutated genes.
How it Works
Different gene therapies work by different mechanisms:
- Inactivating: Turning off the machinery that builds the cell components that give rise to disease
- Replacing a faulty copy of a gene with a working version could cure or reverse genetic disease.
- Inserting a new or modified gene into the body to help treat disease.
Scientists have conducted studies to evaluate the use of gene therapy to treat CdLS. New procedures, such as CRISPR/Cas9, are opening up new vistas in correcting genetic disorders.
The prospect of using CRISPR/Cas9 as a targeting mechanism in gene therapy has been demonstrated in laboratory conditions. Several challenges are preventing the technique from being adapted for use in clinical settings. The main hurdle of gene therapy is the difficulty of retargeted gene delivery into stem cells.
. To get a gene into the body’s cells, scientists use a “vector”. The vector must:
- efficiently release the desired sequence of DNA for use in gene therapy
- be very specific
- must be purified to a high degree before it can be produced on a large-scale, and
- not be recognized as a foreign substance by the immune system
Possible Side Effects of Genetic Therapy
The techniques are relatively new and under research. Some of the risks may be unpredictable. However, medical researchers, institutions, and regulatory agencies are working to ensure that gene therapy research is as safe as possible.
Also, Certain gene mutations that cause CdLS are present in multiple cells throughout the body. While recent advances in gene-editing technology offer promise, it is not yet possible to safely edit multiple cell types within a living human.
Technologies like CRISPR-Cas9 carry risks of both over-and under-correcting gene mutations. They might also create new, unwanted genetic changes with unknown consequences.
Other Related Therapy for CdLS
Although gene therapy for CdLS might be in its infancy, various positive research has been done regarding genes related to CdLS. As a result, therapies that help manage some symptoms of the syndrome have been brought into the limelight.
The specific and symptomatic treatment includes:
a. Hormonal therapy
Children with CdLS syndrome often have limb deformities and stunted growth. Research shows that it can be improved with treatment with recombinant Human Growth Hormone.
A case report describes a patient with extremely short stature and very mild clinical features of CdLS. Her height increased substantially following treatment with recombinant human growth hormone.
The observation suggests that short children with CdLS (mildly affected) may be considered candidates for r-hGH treatment.
b. Treatment with L-Leucine
Leucine treatment can improve ribosome production, protein synthesis, cell survival rates and partially rescue developmental defects in CdLS. Lithium treatment has also been implicated as a cure for managing neurodegenerative defects associated with CdLS.
c. Antioxidant
Antioxidant drugs like ascorbic acid and riboceine drugs can reduce both the level of oxidative stress and genome instability. The treatment leads to increased in vitro lifespan of CdLS cell lines.
The Race is On
All stakeholders, including foundations, caregivers, and scientists, are working together to ensure that people living with CDLS get the care they need. The advances in genetic understanding of CdLS have led to the formation of a foundation for future therapies. As well as improvements in routine care and follow-up.
Moreover, as a result of the discovery of CdLS, there has been growth in new concepts and approaches. These have yielded an improved understanding of therapeutic strategies.
