The hunt for cell and gene therapies for eye diseases

Vision impairment and loss caused by various eye diseases, including those involving degeneration of the retina, affects many millions of people across the globe each year. Yet there are few treatments and even fewer cures. Furthermore, the number of people suffering from degenerative eye conditions will increase as the world’s population ages.

In light of this, Astellas, a global pharmaceutical company based in Tokyo, Japan, has set a long-term goal of advancing cell and gene therapies for treating eye diseases.

Degenerative eye diseases represent a large burden for national healthcare services, not to mention the social cost for patients. With the world’s ageing population, this burden will only increase.

Tackling degeneration

Degenerative eye diseases — such as age-related macular degeneration, glaucoma and retinitis pigmentosa — are caused by the gradual loss of specific cells, usually due to genetic or environmental factors. Therapies using antibodies or small molecules to encourage cellular regrowth don’t work because, unlike most cells, many cell types in the retina don’t regenerate without assistance.

But future therapies involving stem cells or gene delivery might feasibly address these challenging diseases, says Jotaro Suzuki, primary focus lead, Blindness and Regeneration team at Astellas.

The emerging area of gene therapy aims to prevent or treat diseases in various organs by targeting the underlying problem (including genetic mutations); for example, by augmenting a healthy gene or correcting a mutation in a specific gene¹. Scientists do this by delivering genetic material directly into the target cells.

But this isn’t a simple proposition for the eye. “Devising tailored, specific treatments is proving more complex than we had originally thought,” says Alessandro Iannaccone, Astellas’ Global Medical Lead in Cell and Gene Therapy, who is based in Durham, United States. “Years ago, we thought we might find just a dozen genes at the root of most eye diseases — but we’re now at about 350 genes and counting.”

Cell therapies, on the other hand, involve transferring new or modified cells into an organ to prevent or correct disease. This often relies on human embryonic stem cells and induced pluripotent stem cells that can be induced to differentiate into any form of cell. In ocular diseases, for example, differentiated photoreceptor cells might replace lost photoreceptors, restoring visual function.

While both future types of therapy could hold much promise, they also pose many challenges. “Developing gene and cell therapies has been difficult due to significant scientific, technical, regulatory and manufacturing challenges,” notes Suzuki.

That is why adopting a long-term view is important. “Such emerging therapies require longer term investment and more extensive research than established forms of treatment,” says Katsuro Yoshioka, head of Ocular Gene Therapy Research at Astellas in Tsukuba, near Tokyo.

Safety first

Regenerative therapies that use stem cells come with two potential hazards: transplanted cells could ‘escape’ the target treatment zone and proliferate elsewhere in the body, or they could be rejected by the immune system.To address the first problem of cell proliferation, Astellas’ researchers are studying a potential counter measure if things go wrong. “Our cells have been engineered with a ‘kill switch’ — if they do begin to proliferate, we can administer a drug to switch them off,” says Iannaccone.

The risk of the second problem of immune rejection is lower for the eye because of its special nature. “The eye is a unique organ because it is immune privileged — retinal cells are naturally protected from unwanted or excessive immune responses,” says Iannaccone.

Just as transplanting organs poses a threat of immune rejection, so does transferring stem cells into the body. Astellas is now studying ways to make stem cells less visible to the immune system, reducing the risk even further of immune rejection in the eye.

In 2018, Astellas acquired Universal Cells, a biotech company based in Seattle, in the United States. Universal Cells had developed a distinctive method of modifying pluripotent stem cells. These universal donor cells are genetically engineered to lack human leukocyte antigen (HLA) class I and II proteins. HLA is usually expressed on cell surfaces and modulates T-cell responses and immune rejection².

“Without HLA, these cells are essentially invisible to the immune system,” says Suzuki. “That means they can evade detection and complete their therapeutic goal.”

For each treatment, scientists can create a bank of universal donor cells, and a desired group of specific cells are then differentiated from these.

Exploring vision loss

One of Astellas’ projects is a study looking at a stem-cell-based treatment for geographic atrophy — an advanced form of age-related macular degeneration, which is when the part of retina known as the macula deteriorates with age. This involves transplanting newly differentiated retinal pigment epithelial cells, derived from human embryonic stem cells, into the back of the eye. It has helped to restore vision in animals³, and it is now undergoing phase 1b clinical trials in the United States (NCT03178149).

A second treatment for geographic atrophy using universal donor cells is in the preclinical stage.

For gene therapies, Astellas is harnessing a technique involving adeno-associated virus vectors (AAVs), which are used to carry genetic material to specific cells in the body⁴. AAVs are commonly used as a gene-therapy modality with a relatively low immunogenicity. Once in place, AAVs release their genetic load into the cells.

Astellas’ gene-therapy portfolio is still largely in the discovery stages, with AAV modalities being explored for potential treatments for rare monogenic eye disorders as well as more common diseases.

One example that has now reached the preclinical stage is using an AAV-based approach to introduce genes to retinal cells affected by glaucoma. The approach was initially developed by the UK-based gene-therapy company Quethera, which Astellas acquired in 2018.

“Lab tests in animals have shown that this treatment significantly improves the survival of retinal ganglion cells in a glaucoma model,” says Yoshioka.

Reassessing evaluation

For many eye conditions, which develop gradually over years, visual acuity doesn’t fluctuate greatly in the short term. This poses a challenge for elderly and very young patients, because it can take years for a new therapy to show an improvement great enough to satisfy regulatory criteria.

If a treatment enables patients to see better, even by less than ten letters on the optician’s board, the patients themselves would be delighted, but it wouldn’t meet the current efficacy requirements for any regulatory agencies, notes Iannaccone.

“It’s critical that all stakeholders understand what outcomes are clinically meaningful to patients, and what tangibly improves their quality of life,” says Ha Tran, medical head of Cell and Gene Therapy at Astellas and based in South San Francisco, US.

The researchers are hoping for changes in “the efficacy requirements for treatment approval from regulators,” that would benefit those experiencing degenerative eye diseases, adds Iannaccone.

But they say Astellas is in this for the long term. “The market needs time to catch up with innovation,” says Tran. “We will continue to work with regulators to determine acceptable treatment outcomes for this field.”

Collaborative future

A major emphasis at Astellas is collaboration. “We foster a spirit of open innovation, both within the company and with external partners,” says Yongting Wang, head of Research at Astellas Institute for Regenerative Medicine, and based in Boston, United States.

“We see clear benefits in collaborating with others to bring advanced therapies to patients.”

Astellas is keen to foster collaborations and partnerships with industry specialists, biotech companies and academics. Within cell therapy, the teams are looking to expand and refine their cell engineering and cell-fate control technologies.

The company is also boosting its robotic manufacturing capabilities, which are particularly important for cell therapies.

“Cell-therapy manufacturing is highly complex; the process itself defines the product,” says Suzuki. “Achieving a robust, scalable, and regulatory-compliant manufacturing process is challenging because cells aren’t uniform unlike chemical drugs. Robotics can help us achieve this stringent quality control.”

Astellas runs two incubator spaces — one in Massachusetts, United States, and one in Tsukuba, Japan. These high-spec research facilities are open for Astellas’ collaborators and external partners to use. Astellas also allows small biotech companies to use their incubator labs.

“We’re seeking innovative, robust ways to create acceptable biomarkers and industry parameters,” says Tran. “For Astellas, collaboration across the ecosystem is key — it’s about bringing in all different angles and perspectives, and coming up with the best outcomes for patients.”