Gene therapy targeting knee osteoarthritis

An injection directly into the knee of a genomic medicine depot could hold a future cure for knee osteoarthritis. This is what Ditte Elisabeth Jæhger, MSc, PhD and her team at DTU Health Tech at the Technical University of Denmark are working towards.

Jæhger has just been awarded a DKK 5 million Frontier Grant by the Lundbeck Foundation for an 18-months plan for maturation of the technology for presentation to potential investors.

Osteoarthritis, a degenerative joint disease, is the result of wear and tear of joint cartilage and tissue. About 270,000 Danes have knee osteoarthritis. Half of all 70-year-olds suffer from the condition, which causes pain and interferes with normal daily activities.

“Patients are  mainly offered symptomatic treatment – painkillers or anti-inflammatory drugs and, in some cases, knee joint replacement. We want to restore the knee – if not fully, then enough to extend use of the natural joint before a replacement is indicated,” says Jæhger.

She is aiming to treat the root cause of knee osteoarthritis by targeting cells deep inside the knee to reduce joint inflammation and degeneration by switching off the genes involved in the disease process.

“It’s all about delivering the treatment to the exact site where we want it to act, and only there, for maximum efficacy and as few side effects as possible,” she says.
 

Vector and depot in one

Other researchers have trialled new therapies in pill form and as injection fluid, but to no effect.

“Our hypothesis is that taking a pill or having a conventional injection does not result in sufficient concentration of the medicine. The technology we’ve developed allows us to target the treatment so precisely that we can deliver a higher concentration of the medicine while patients avoid a lot of side effects,” says Jæhger.

The technology is based on a special material – a clear fluid doubling as both the medicine vector and depot. Named bioMATA, this material has been developed by DTU researchers over the last decade.

The material has many applications, including localised antibiotic therapy and chemotherapy.

Consisting mainly of carbohydrates and fats, the fluid is mixed with medicines and injected at the treatment site.

Once the material is inside the knee it thickens, acting as a depot for slow release of the medicines at a rate determined by the composition of the material. The depot dissolves once it has been emptied of medicine.

As an innovation, Jæhger is using a special type of genomic medicine in combination with bioMATA called antisense oligonucleotides (ASOs).

ASOs are tiny fragments of synthetic nucleotides, which are the building blocks of DNA and RNA. When an ASO is delivered to a cell, it attaches to the mRNA, causing it to block production of a specific protein, since mRNA holds the ‘formula’ for making proteins. If a formula cannot be decoded, the protein will not be produced. This might be a protein involved in inflammation, for example.

At present, ASOs are mainly used in the treatment of rare hereditary diseases to block a specific mutated gene responsible for the disease. The benefit is that there is no risk of blocking healthy cells. But osteoarthritis is different.

“We’re targeting genes in immune cells and cartilage cells, but we don’t want to block genes anywhere other than in the knee. That’s why precision delivery is crucial,” explains Jæhger.

Every ASO is directed at a gene, and multiple genes can be regulated by using multiple ASOs simultaneously. In this study, Jæhger is using two.

“We want to reduce the inflammation but also degeneration of the structures in the joint itself. So one ASO targets a gene that produces a lot of inflammatory molecules that cause knee swelling and pain, and are conventionally treated with a corticosteroid. The other ASO targets a gene involved in breaking down collagen and cartilage. Without treatment the patient may need knee joint replacement surgery.”

The two genes are well-known from other studies. Ultimately, the researchers are aiming to identify other genes that can be regulated.
 

Commercial sparring is part of the project

During the 18 months funded by a Frontier Grant, the team will be optimising composition of the material and validating release of the medicines and their effect on rats and rabbits. A professional laboratory abroad will test some of the results. Finally, all the data will be packaged for presentation to investors.

The grant also comes with the benefit of consulting and sparring.

“It’s unique to receive this sparring too, plus an opportunity to have an idea translated into a physical product for patients. Commercialisation is something we have to learn as researchers. For example, as a scientist you might typically skip the testing by a professional lab. But thanks to input from the Lundbeck Foundation we realised that external validation is important strategically in securing funding.”

For Jæhger the most exciting part of the project is investigating the body’s immune response.

“What role do immune cells play in osteoarthritis, and how can we influence them? When we shut down cell action at one site in the body, what happens at other sites? Do other mechanisms take over, and how many “taps” do we have to turn off? The sense that this therapy is genuinely going to make a difference is thrilling because we’ll be able to orchestrate it all with a targeted intervention.”

About the Frontier Grant:

Frontier Grants

Frontier Grants facilitate transitions from basic research to attractive prospects for biotech investors