Neutralizing antibodies: Addressing barriers to gene therapy treatment

Imagine being diagnosed with a rare disease that will significantly impact the quality and longevity of your life or that of a loved one. For people living with rare, monogenic diseases, gene therapies may offer a cure to a life-long condition by introducing genetic material that compensates for a defective gene. However, if the therapy is based on the use of Adeno Associated Viruses (AAV) vectors, the immune system may carry neutralizing antibodies (NAbs) that counteract the gene therapy treatment preventing its success. Currently, it is estimated that NAbs prevent up to 1 in 3 people from benefiting from gene therapy treatments.

At Hansa, we are advancing science to find ways to prevent the impact of NAbs on gene therapy thus enabling people living with rare genetic diseases to benefit from gene therapy treatments. With our work we aim to advance scientific understanding of these rare, complex conditions and accelerate the development of innovative treatment options in areas where high unmet need remains.

The impact of monogenic diseases

There are approximately 7,000 known rare monogenic diseases worldwide.¹ Monogenic diseases are genetic and caused by a mutation in a single gene. They can affect any part of the body and can range in severity from mild to life-threatening.²

Genetic diseases are caused by defects in the genetic material that manifest in a wide variety of known severe disorders, including neuromuscular, bleeding, metabolic, neurodegenerative, and inflammatory diseases.³ It is estimated that close to 70% of these disorders may affect the nervous system. These diseases have a detrimental impact on quality of life, and can lead to chronic illness, disability, and premature death.⁴

The opportunities of gene therapies

There are several gene therapy treatments currently in development for a variety of human genetic diseases, with the potential to improve patient outcomes.

Gene therapy treatments are designed to introduce small portions of genetic material into cells to compensate for the non-functional gene.⁵ Most gene therapies utilize modified viral vectors such as Adeno Associated Viruses (AAV) vectors to transfer the genetic material into the cells.^5-8 Adeno associated viruses are common in nature and the cause of many common infections such as colds and stomach disease. AAVs used in gene therapy are modified so that the disease-causing parts of the virus are removed from the viral shells and the remaining structure is used to deliver genetic material into a patient to compensate for a defective gene.  

The unmet need in gene therapy, and the impact of NAbs

As AAVs are derived from common viruses, a large portion of the population has been exposed to some of these viruses⁸ and has subsequently developed antibodies called neutralizing antibodies (NAbs) to protect the body against them. The presence of these NAbs is a challenge for gene therapies based on AAVs, preventing up to 1 in 3 people from benefiting from these treatments.^6-14

Lena Winstedt, Global Franchise Lead, Gene Therapy, Hansa Biopharma, explains: “It Is an exciting time for the research on gene therapies, in which we see many innovative promising treatments being developed and more becoming available to patients. However, the presence of NAbs means that as of now, a significant portion of patients in need of gene therapy are prevented from benefitting from gene therapy treatments”.

The prevalence of NAbs in patients varies widely from 5-70% depending on the AAV vector used.^6-14 The attack of NAbs prevents the delivery of the genetic material into cells, therefore rendering the therapy ineffective.

Scientists are addressing this challenge in multiple ways including engineering vectors that are less likely to be recognized by the NAbs, or by inactivating or removing the NAbs.

Collaborating to advance scientific understanding and deliver innovative new treatments

At Hansa we believe that multi-stakeholder collaboration is key in our aim to tackle the high unmet medical needs in rare disease and deliver treatments that will help patients live long and healthy lives. Our strategic approach in gene therapy is to partner closely with cutting-edge gene therapy companies to advance the scientific understanding of these genetic conditions.

“Our primary focus is patients, and our priority is ensuring we can enable all patients, including those with both preformed and acquired NAbs, to receive innovative treatments” continues Lena. “To do that, we must keep advancing and strengthening understanding of the disease for all key stakeholder communities – from researcher to clinician, from industry to patient. With more knowledge we can more quickly advance clinical trials, develop more targeted treatments and evolve clinical practice to benefit patients.”

“We see collaboration not simply as lending our technology, but as an opportunity to share knowledge and combine different expertise.  We work with our partners and collaborators in cross-functional teams to drive advancement and innovation towards the common goal of helping those in need. This collaborative approach is a fundamental trait we look for when evaluating partnering opportunities, and that we embed in the way we manage our existing collaborations”.

In Spring 2023, we announced a partnership with Genethon, a leading gene therapy research not for profit organization. Together, Hansa and Genethon scientists are working to enable gene therapy treatment in patients with Crigler-Najjar syndrome, a genetic disease-causing bilirubin accumulation. About 30% of patients with Crigler-Najjar have pre-formed NAbs, and our technology could offer a new opportunity to give those patients access to a life-saving gene therapy treatment. Similarly, we have partnered with Sarepta to advance the use our enzyme as a per-treatment to their recently approved medication for Duchenne Muscular Dystrophy (DMD).  Through this partnership we hope to better understand how our technology can be used to enable treatment in patients with DMD and NAbs against this new and innovative treatment.

References

1. Boycott K.M, et al. Nature Reviews Genetics. 2013;14(10):681–691
2. Cepika A.M, et al. Journal of Allergy and Clin Immunol. 2018;142(6):1679-1695
3. Genetic disorders. NIH. Available at: https://www.genome.gov/For-Patients-and-Families/Genetic-Disorders. Last accessed May 2023.
4. What are Rare Diseases? Rare Diseases. Available at: https://www.rarediseasesnetwork.org/about/what-are-rare-diseases. Last accessed May 2023.
5. Au H.K, et al. Frontiers in Medicine. 2022;8:2746.
6. Boutin S, et al. Hum Gene Ther. 2010 Jun;21(6):704-12
7. Griffin JM, et al. Gene Ther. 2019 May;26(5):198-210
8. Calcedo & Wilson. Front Immunol. 2013 Oct 18;4:341
9. Falese L, et al. Gene Ther. 2017 Dec;24(12):768-778
10. Wang Y, et al. Exp Neurol. 2017 May;291:134-140.
11. Ellsworth JL, et al. Hum Gene Ther Clin Dev. 2018 Mar;29(1):60-67
12. Greig JA, et al. Hum Gene Ther. 2017 May;28(5):392-402
13. Krisik A, et al. Mol Ther Methods Clin Dev. 2019;7(14):126-133
14. Leborgne C, et al. Nat Med. 2020; 26, 1096–1101