Serious brain diseases such as ALS, Alzheimer’s and Parkinson’s are currently incurable, but that will probably change in the next ten years. The young biotechnology company VectorY expects to start clinical testing of a new therapy to treat ALS, the disease that leads to general paralysis, in about two years. This new therapy, it now appears, is tackling the disease at its root. In line with this, VectorY also expects to be able to offer therapies for other brain diseases in a few years’ time.

“With the development of new therapies for brain diseases, we have reached a crossroad. Diseases such as ALS, Alzheimer’s, Parkinson’s and Huntington’s are still known to be incurable. Only the symptoms can be treated. For example, if you have Parkinson’s and tremble a lot, you can get a remedy that reduces that trembling, but the disease will continue. We are working on therapies that target the very cause of those diseases”, says Sander van Deventer, CEO of VectorY, at the Amsterdam Science Park.

In 2020, he founded the biotechnology company together with Chief Scientific Officer Pavlina Konstantinova. There are now 70 people working there.
Van Deventer has a long track record. In 1998, he and others founded the gene therapy company Amsterdam Molecular Therapeutics (AMT), now called UniQure. Here he held the position of both Scientific Director and CEO.
Konstantinova was previously Vice President of Research at UniQure and has been developing gene therapy, such as for Huntington’s disease, for more than 20 years.

Tackling clotted proteins

Earlier, in 2012, UniQure was the first in the world with the gene therapy Glybera to treat the metabolic disease lipoprotein lipase deficiency. In November 2022, UniQure’s haemophilia gene therapy Hemgenix received approval for the US market. Furthermore, the first results of the clinical trial with a therapy for Huntington’s disease look promising. Why didn’t Van Deventer and Konstantinova stay with UniQure?
Van Deventer: “We had ideas about improving gene therapies for diseases in the brain. In classical gene therapy you only replace a gene, such as in a patient with haemophilia, who is then able to produce a coagulation factor for the blood itself. Here we are working with a completely different approach. This is aimed at preventing the clotting of proteins in nerve cells in the brain and cleaning up clotted proteins. Due to the presence of clotted proteins, the nerve cells slowly die”.

Konstantinova: “This clotting of proteins is the underlying cause of brain diseases, including various types of dementia, Parkinson’s disease, ALS and Huntington’s disease (hereditary disease, which makes talking and swallowing more difficult and increases gloom, fear and anger – ed.). By developing a technology that prevents the clotting of proteins and helps to clear clotted proteins, we will soon have a platform for combating various brain diseases”.

In ALS, clotted proteins break the connection between the nerves that control the muscles and the muscles themselves, leading to paralysis. In Parkinson’s disease, the cells can no longer produce dopamine due to the clotted proteins, which means that the coordination of the muscles is lost.

Gene therapy with antibodies

The trick is to insert a piece of DNA into the brain’s nerve cells, which prompts them to produce a fragment of an antibody that targets the clotted proteins.
“It looks like a mission to the moon. You send a rocket with a lunar lander on its way. Once at the moon, the lunar lander leaves the rocket and once it has landed on the lunar floor, you can perform all kinds of activities there with a lunar rover. In our case, you ot only have to penetrate to the brain, which is an obstacle in itself, but also to the nerve cells themselves”, explains Van Deventer.

Konstantinova: “We apply gene therapy in the brain cells. Based on progress in developing a therapy for Huntington’s disease, we know that this works within the brain. When we present DNA in the nerve cells, this can lead to years of expression. The nerve cells then produce antibodies that counteract the clotting of proteins. With a single treatment, a patient can probably last ten years.”

VectorY thus combines knowledge of gene therapy and knowledge of antibody treatments. It is of great importance that the antibody fragments only bind to the clotted proteins and leave the non-clotted proteins alone.

“If you also tackle the non-clotted proteins, all cells will die with fatal consequences”, says Konstantinova.
“ We have shown that you can tackle the clotted proteins very selectively with antibodies. This makes us unique in the world”, adds Van Deventer.”

Postal Code

If all goes well, ALS patients will be injected with capsids in a few years’ time, a kind of protein container that carries a piece of DNA. The capsids are provided with a kind of postal code, so that they reach the nerve cells in the brain. They then invade the nerve cells and disintegrate there. The piece of DNA that is released in this process enters the cell nucleus and forms a kind of chromosome there, separate from the host DNA. The DNA fragment contains an instruction, for example ‘make a small antibody fragment that only binds to malformed and clotted protein and clean it up’.

“Cleaning is done through autophagy, a process by which cells normally break down and digest malformed and clotted proteins”, explains Konstantinova.
“There are more break-down pathways for proteins. We know them all and can send clotted proteins down those pathways. We have filed a cloud of patent applications for this. To date it concerns three patent families. Two more patent families will follow in 2023”, adds Van Deventer.

VectorY mainly uses so-called induced pluripotent stem cells (iPSC) for the preclinical testing of the new technology. It is created from body cells. Researchers at the company grow neurons and other nerve cells, as well as muscle cells, using iPSC cells. This also allows them to mimic the breakdown of the connection between nerves and muscles, such as in ALS. “For preclinical purposes, research with iPSC cells is much more valuable than with mice”, says Van Deventer.

Clinical trials of the new therapy for ALS are expected to start in a few years. “After six months of study, we think we can already say something about the effectiveness of the treatment. This has to do with the fact that patients with ALS deteriorate much faster than with other brain diseases, so that you can quickly determine whether a treatment is effective or not”, explains Van Deventer.

Scale up production quickly

In order to conduct clinical research, VectorY must be able to produce enough of the new product. “We know from experience that you have to start setting up production on time. In 2020, we therefore decided to start production immediately parallel to the development of the therapy. That is why 70 people are already employed here”, explains Van Deventer. “With the financial lease construction of Mibiton, a 50 litre bioreactor has been purchased, where the product is already being produced. The nice thing about this financing is that more of the starting capital remains to pay employees”, he explains.

VectorY uses an insect cell line to produce both the protein coat, the DNA that codes for the antibodies, and a protein that squeezes the DNA into the protein coat. This all comes together in the bioreactor where the cells ultimately excrete particles, namely the DNA wrapped in the protein coats. The particles are harvested and then purified in other devices. The protein coat is a so-called adeno-associated virus (AAV), which is much smaller than an adenovirus and also has very different properties. It serves as a packaging and transporter to get the DNA to its destination.

According to Konstantinova, VectorY differs from other companies that can produce such particles in that it is better able to scale up production, which lowers the cost per unit of product.

“We only use the current 50 litre bioreactor for process development. We are now working on bringing the process to a scale of 200 litres. Ultimately, we want to carry out the process in a 2000 litre bioreactor, which will allow us to produce much more cheaply”, adds Van Deventer.

It is hard to say when VectorY will make a profit for the first time. “Before the first results of clinical research become available, you can easily incur costs of 200 to 300 million Euro in a medical biotechnology company. But you earn that back many times over if the therapy is successful. If our ALS therapy is successful, it will open a market of an estimated 5 billion Euro per year”, says Konstantinova.

Addressing the cause of the disease

“There are already drugs to treat ALS on the market, but they only prolong life by a few months. We expect that the clinical picture will change drastically through our product, which means that patients will be cured for years. We really want to tackle the cause of the disease”, emphasises Van Deventer.

Van Deventer mentioned UniQure’s Hemgenix as an example. Haemophilia patients now have to inject themselves twice a week with the clotting protein they are missing. Yet they still suffer from bleeding and joint complaints or have had a cerebral haemorrhage, as a result of which they are paralysed on one side. As a result, the medical costs for a haemophiliac patient over their lifetime can amount to 9 to 12 million Euro.
“With Hemgenix you get an infusion in the clinic for half an hour and you stay there for observation overnight. Then you go home and it’s goodbye, because from now on you make your own clotting factor and don’t have to come back for years”, says Van Deventer.

Exactly when VectorY’s therapy for ALS will become available is difficult to predict. “That could still be a few years away. You can add another two years to this for the Netherlands, because the registration of medicines here lags an average of two years behind other countries in Europe.

That does not alter the fact that he is optimistic about the treatment of brain diseases in the future. “In 1987 I was registered as an internist. At that time, people died of AIDS and people suffered serious consequences from diseases such as rheumatism, multiple sclerosis and so on. These diseases are now treatable, including haemophilia recently. For diseases of our brain, such as ALS, Parkinson’s and dementia, similar successes lie ahead thanks to the new technology.”