Pursuing a wide variety of treatment options, both in Gene and Drug therapies.
Creating brain cells from each child (or adult) with a GRIN2B disorder. We create a cell bank from each person’s skin or blood cells through a minimally invasive procedure.
The cells grow in the lab and produce an endless reservoir for any future requests. Since GRIN genes are expressed in the brain, we will create neurons and use them to test drugs or specific personalized gene therapies uniquely designed for any individual variant/patient.
Animal Models For Testing The Various Treatments
Creating animals with human mutations to test both drug and gene therapies before performing clinical trials on humans. Safety is a major issue, therefore we need to test treatments, even if they are considered to be safe.
Using high throughput automatic screening (executed by a robot) of several thousands of FDA-approved drugs, natural compounds and more. If successful, they can be given without further testing to the children.
Using computational tools to design and screen millions of compounds, with the drawback of having to test for toxicities and side effects prior to use.
Gene therapy can be divided into two: gene adding and gene editing.
GRIN disorders are usually caused by a mutation which disrupts one of the two copies of the gene. This means that there is only one good copy instead of two. With gene adding, a normal copy is introduced into the cell thus compensating for the mutated one. In case of a deletion or a nonsense mutation as a cause for GRIN disorder this might lead to a complete cure. In other cases (missense mutations) this method can be used as well, depending on the exact mutation. Gene adding is no longer a dream, this therapy is already on the market and is approved for human diseases curing blindness, neurologic diseases with many awaiting to enter the market.
Much of the excitement around gene editing is fueled by its potential to treat human diseases. In gene editing, we can target the root of the problem. Gene editing rewrites DNA, the code that makes up the instruction manuals of biology. It is equivalent to finding and replacing features used to correct misspellings in documents written on a computer. With gene editing, it is possible to disable target genes, correct harmful mutations, and change the activity of specific genes.
This can be achieved by several technics of gene editing, to be described later here. The approach is personalized: As a whole, most of the procedure is the same for all mutations, with the exception of designing a unique correction for the specific mutation. Every mutation’s design will be different.
Once Gene Editing works on human cells (in the laboratory), we will test it on animals, and then continue with clinical testing in humans.
How Does Gene Editing Work?
The molecular tool is called CRISPR-Cas9. It uses a guide molecule (the CRISPR part) to find a specific region in an organism’s genetic code – a mutated gene, for example – which is then cut by an enzyme (Cas9) and effectively disables the gene. This is useful for turning off harmful genes, but other kinds of repairs are possible. For example, to mend a faulty gene, scientists can cut the mutated DNA and replace it with a corrected version that is added alongside the CRISPR-Cas9 molecules. Different enzymes can be used instead of Cas9, such as Cpf1, which may help edit DNA more effectively.
How Do You Get To The Right Cells?
Most drugs are small molecules that can enter the bloodstream and delivered to organs and tissues on the way. The gene editing molecules are big and have trouble getting into cells, but it can be done. One way is to pack the gene editing molecules into harmless viruses that infect particular types of cells. Millions of these are then injected into the bloodstream or directly into affected tissues. Once in the body, the viruses invade the target cells and release the gene editing molecules to do their work and correct the faulty genes. Viruses are not the only way to do this. Researchers have used fatty particles (nanolipids) and exosomes to carry CRISPR-Cas9 molecules inside the body.
Once the editing machinery is inside the cells, our specially designed guide RNA will lead CRISPR to the mutation, cut the faulty DNA and abolish it.
A gentler form of gene editing that doesn’t cut DNA into pieces, but instead uses chemical reactions to change the letters of the genetic code. It is more precise and with fewer side effects.
base editing is available to some but not all mutations. For instance, it can change A to G and vice versa. Therefore, if the disease is caused by a G to A switch, we can change it back. But for G to T, there is currently no enzyme. The good news is that a newer technology was very recently developed, showing its ability to mend every point mutation. This is a very promising solution for all missense mutations, but more research is needs before it can be used as a cure.
Another approach when you don’t want to completely remove or replace a gene, but simply reduce or increase its amount and activity. This is suitable to deletions when you don’t have enough of your normal GRIN gene and you want to increase its amount.
Why gene therapy?
It is a one-time procedure, changing the root of the problem and curing the disease.
We believe this is the preferred method because it allows us to change a single base. Gene adding and Base editing don’t cut the DNA, therefore it is potentially much safer than other gene manipulations.
How Long Before It Is Ready For Patients?
Gene therapies are one of the major excitements in recent years. Gene adding technologies are saving lives and are approved for human diseases (for inherited vision loss and SMA disease). Many more are in clinical trials and waiting for FDA/EMA approvals.
Gene editing is next. The race is on to get gene editing therapies into the clinic. A dozen or so CRISPR-Cas9 trials are underway or planned. Gene editing has already been used to modify people’s immune cells to fight cancer or be resistant to HIV infection. More US and European trials are expected in the next few years.