While gene therapies promise hope, why are pre-existing antibodies raising a stop sign for so many?
There are approximately 7,000 known rare, monogenic diseases worldwide – diseases that are caused by a single defective gene that, as a result, do not produce a functional protein. They can affect any part of the body and range in severity from mild to life-threatening.
While some genetic diseases have approved treatments that improve the quality of life for patients, medicines have not historically modified the root cause of the disease, only addressing the symptoms.
In far too many cases, no approved treatments exist at all. Gene therapies, which target the underlying cause of disease at the genetic level, offer the potential of a cure.
Game changer
With an influx of innovation over the last decades, gene therapies are now being developed for a variety of human genetic diseases, with the aim of introducing healthy genetic material into cells.
In theory, the new genetic material compensates for the non-functional gene, enabling the production of the functioning protein needed for normal bodily processes.
There are several gene therapy treatments currently in development for a variety of human genetic diseases, with the potential to vastly improve patient outcomes. Yet, despite the continued clinical and regulatory success of gene therapies in multiple diseases, sadly not all patients can currently benefit from this pioneering technology.
Talking therapies
When the body encounters a foreign invader, such as the flu virus, it initiates an immune response and creates antibodies against the virus. If the same virus enters the body again, the antibodies are very quickly able to identify and signal the destruction of the virus before it can cause harm.
This is an example of an adaptive or acquired immune response, which is vital for fighting off a specific pathogen. However, when it comes to repurposing viruses as vectors to deliver gene therapies into cells, this immune response – that exists in all of us – can present a huge problem.
Most gene therapies utilise viral vectors such as adeno-associated virus (AAV) vectors to transfer the genetic material into the cells.
According to the Alliance for Regenerative Medicine, there were 23 AAV gene therapy phase 3 clinical trials as of December 2022, with these gene therapies being developed across a range of therapeutic areas including cancer, neurodegenerative and infectious diseases.
Unfortunately, around 30-60% of patients are unable to use and benefit from gene therapies because they have pre-existing antibodies to the AAV vector that is often used to deliver gene therapies.
In these people, the immune system contains pre-existing neutralising antibodies from a prior viral infection that can block the gene therapy vector and prevent successful gene therapy treatment.
Despite the AAV vectors being repurposed for ‘good’, the body’s pre-existing antibodies recognise the viral vector from a previous encounter as being foreign and mistakenly attack them when they are introduced into the body.
This prevents the transfer of genetic material into cells and prevents 30-60% of people from being able to benefit from gene therapy treatments.
The presence of these neutralising antibodies in patients comes from previous exposure to viral infections, with some gene therapy patients having them as part of the body’s normal humoral response of the immune system against viruses.
With a number of potentially curative gene therapy treatments currently in development for a variety of human genetic diseases, alongside those already approved, there is a need to address this treatment gap for patients with pre-existing AAV vector antibodies so that they too can benefit from cutting-edge treatment.
Overcoming barriers
Researchers are investigating whether existing antibody-cleaving treatments, already available in use to counteract immune reactions in areas like kidney transplantation, can similarly silence the AAV antibodies and enable gene therapies to be a viable option for more patients.
This approach – exploring how a medicine that works in one area might also work in another – has benefits because of its potential to accelerate drug discovery when compared to testing novel compounds.
For example, having completed the rigorous clinical trial process to receive regulatory approval, companies already have a good understanding of an existing drug’s safety profile and dosing levels. If successful, this could help quickly deliver a pre-treatment option to enable greater access to AAV-mediated gene therapies.
It is something we are exploring at Hansa, in partnership with companies in the gene therapy space. This potential, however, has been recognised even beyond pharma. This year, a collaboration of patient groups (CureDuchenne, Muscular Dystrophy Association (MDA), and Parent Project Muscular Dystrophy (PPMD)) decided to fund their own independent clinical trial in this space.
Exploring whether existing immune-impacting therapies can help overcome the barriers presented by AAV vectors in gene therapies is an exciting prospect. Only time will tell the outcome of these trials, but, if successful, it could significantly expand access to gene therapies for those who have AAV antibodies now, and in the future.
Closing the gap
Gene therapies, which once seemed the plot line of science fiction, are today delivering results and transforming the lives of individuals who previously had few, if any, options.
While research into these technologies needs to continue there also needs to be investment to ensure those with genetic disease can benefit from it.
If the presence of AAV antibodies means a significant number of patients are ineligible for approved gene therapies and the wide-reaching implications this will have on them, the clinical trials researching the viability of using immunomodulating therapies are an important first step in identifying a suitable pre-treatment.
With no slowdown in gene therapy research and approvals, it is critical for the research community to spread the net wider and investigate the potential of other immunomodulating therapies in minimising the impact of AAV antibodies that otherwise limit eligibility to gene therapies.
Ultimately, no one with a genetic disease should be left behind, especially when life-changing treatments are available.
Lena Winstedt is Global Franchise Lead Gene Therapy at Hansa Biopharma. Go to hansabiopharma.com
