Using Novel Retroviral Gene Therapy to Treat ADA-SCID

Adenosine Deaminase Severe Combined Immunodeficiency Disorder (ADA-SCID), also known as bubble-boy disease, severely impacts the immune system function, which potentiates everyday infections to life-threatening illnesses.¹ The prognosis of ADA-SCID varies depending on factors such as the severity of the condition, although a life expectancy in keeping with the rest of the population is reasonable as long as diagnosis and therefore treatment are initiated early. Otherwise, survival beyond two years of age is unlikely.²

Adenosine Deaminase (ADA) deficiency is an immune disorder caused by mutations in the ADA gene. The ADA gene is used to make an enzyme that is found in specialized white blood cells (lymphocytes), which play a key role in fighting off infections in the body. ADA is characterized by a difficulty in fighting off viral, fungal, and bacterial infections, and its symptoms typically arise before 6 months of age in the form of chronic diarrhea and lung infections.² Although ADA often leads to the development of Severe Combined Immunodeficiency (SCID), not all deaminase deficiencies progress into SCID given that variations of the disorder exist. For example, individuals diagnosed with combined immunodeficiency (CID) experience milder symptoms of SCID, which typically begin in the first decade of life, but may also appear in adulthood. Furthermore, the immune systems of those with partial ADA deficiency remain unaffected, with only some white blood cells having reduced ADA enzyme levels.²

Fortunately, treatment options exist—one of the most recent being Strimvelis, which was approved by European authorities to treat ADA-SCID in 2016.³ However, it has not yet been approved in Canada nor in the US as of 2018.² Nevertheless, it not only offers an alternative treatment to this rare and devastating disease but also opens up the possibility of treating a wide range of previously-neglected diseases.

The mechanism of action of Strimvelis is based on retroviral gene therapy. Since ADA is an autosomal recessive disorder (meaning that an individual has two mutated copies of the ADA gene), gene therapy can be used to target and correct specific gene abnormalities in order to minimize resultant health consequences.² By using a genetically-engineered vehicle called a “vector” to carry the gene, gene therapy is able to insert healthy genes to take over the function of the defective ones, and even “turn off” the function of defective genes.⁴ Strimvelis functions via a “repair and replace” strategy, wherein the correct ADA gene is substituted into a patient’s bone marrow stem cells after removal from the body. These “corrected” cells are then reintroduced into the body via injection.⁵ Gene therapy is mainly used to treat diseases with little to no treatment alternatives—as in the case of many rare and inherited diseases. Although companies are increasingly investing in the development of gene therapy technologies, many of these are still in the research stage while those that are approved come at a high up-front cost, limiting their accessibility to lower-income families in the rare disease community.² Strimvelis is not an exception, with its list price being $920,000 CDN per treatment in Europe, making it one of the most expensive single-use drugs to ever be sold.³ However, what makes Strimvelis so novel is that it seeks to provide a lifelong cure to disease through genetic repair. It has also had no fatalities in its track record: all 18 of the first treated patients are alive to this day.⁶ This is arguably a tremendous feat, considering that a similar gene therapy trial in 2000 led patients with X-linked SCID to develop leukemia, which undermined the public’s trust in this new technology given its risks.¹¹

“As of today, two main challenges exist for scientists employing Strimvelis: the first is how the corrected genes can be put in the right tissues, and the second is how to keep them activated after they have reached their target destination.”

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As of today, two main challenges exist for scientists employing Strimvelis: the first is how the corrected genes can be put in the right tissues, and the second is how to keep them activated after they have reached their target destination.⁷ There are also challenges associated with using viruses as “vectors” that deliver the genes. For example, there is a small chance that a deactivated virus may still trigger an immune response in the patient. viruses may insert the corrected gene into an incorrect region of the genome, which could lead to the activation of cancer genes.⁸ This is what happened in the 2000 trial, which cured patients of SCID, but simultaneously dysregulated cell growth resulting in leukemia.¹¹

Nevertheless, there are also benefits to using retroviral vectors - made up of single-stranded RNA containing a gene of interest - over other vectors, such as plasmids or artificial chromosomes, during permanent gene transfer. For one, they are able to stably and permanently integrate into the target cell’s nuclear genome by being transcribed from single-stranded RNA to double-stranded DNA.⁴ Furthermore, with the recent development of retrovirus vectors that are descended from lentiviruses, scientists are now able to apply gene transfer using viruses that easily integrate into human cells rather than needing to be cultured outside the body.⁹ All in all, although there are certainly risks to using Strimvelis, are minimized with recent technological developments, and more work is still being done to ensure that these pitfalls in gene therapy technologies are addressed. ¹²

Patient groups who might benefit from marketed gene therapy include those who, without treatment, could experience disability or early death.² Given their lack of treatment options, gene therapies may initially be approved to treat their specific condition. Individuals requiring therapies such as protein or enzyme replacement might also benefit from therapy.² Hence, Strimvelis’ potential to provide life-long stabilization or a cure to a variety of rare diseases with little to no alternative treatment options, such as ADA-SCID, hematopoietic cancers (lymphoma and leukemia), or cystic fibrosis, is promising.

For gene therapy to become commonplace, however, one must first overcome several barriers to its implementation. The main issues are: adequacy of evidence, cost of therapy and reimbursement requirements, specialization of procedures and aftercare, and legal and ethical concerns.² To begin with, there must be sufficient evidence that the gene therapy is effective before it is eligible for approval or reimbursement. In the context of a rare disease, this may be hindered by factors such as a small number of patients that participate in research studies which reduces the reliability of study findings or treatments which are only effective only in the short term.² Furthermore, gene therapies do not come cheap, with prices starting from $83,000 and increasing up to $9,200,000.² In addition, these procedures often require specialized manufacturing facilities, as well as trained clinicians with the appropriate technical skills.² Therefore, it may only be feasible to offer the treatment in a limited number of places. Lastly, legal and ethical concerns have been raised about gene therapy, such as its cost, which may put it out of reach of developing nations, or the potential misuse of gene-modifying technologies.² For some potential investors, these downsides might outweigh the benefits of funding gene therapy initiatives—inhibiting their development even further.

The possibility of gene therapy replacing other existing treatments for rare genetic diseases is currently hard to pinpoint; at least, it is unlikely to happen in the near future without changes to policy and administration. As of today, ADA-SCID is primarily treated using bone marrow or stem cell transplantation (BMT/SCT) or enzyme replacement therapy (ERT), intravenous (IV) immunoglobulin to improve the immune system’s ability to fight off diseases, and preventative medications for pneumonia.² As of 2020, there were only 3 approved gene therapies in Canada (Novartis’ Kymriah, Gliead’s Yescarta, and Biogen’s Spinraza), however, a number are in the advanced stages of clinical testing or have already received market authorization abroad.¹⁰ Given that there are gene therapy trials currently listed in Health Canada's Clinical Trials Database, the day that Strimvelis, as well as other such technologies, are brought to the rare disease community in Canada may not be as far as once was thought.

Kseniya Dybatch

Works Cited:

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Gene Therapy. Genome BC. https://www.genomebc.ca/infobulletins/gene-therapy#:~:text=Canadian%20scientists%20were%20involved%20in,deficiency%20(ADA%2DSCID). Published August 7, 2019. Accessed May 3, 2021.

Anson, D.S. The use of retroviral vectors for gene therapy-what are the risks? A review of retroviral pathogenesis and its relevance to retroviral vector-mediated gene delivery. Genet Vaccines Ther 2, 9 (2004). https://doi.org/10.1186/1479-0556-2-9

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Kohn, D. B., Sadelain, M., & Glorioso, J. C. (2003). Occurrence of leukaemia following gene therapy of X-linked SCID. Nature Reviews Cancer, 3(7), 477–488. https://doi.org/10.1038/nrc1122

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Cite This Article:

Dybatch K., Vytlingam K., Charron B., Kord D., Chharawala V., Lombo L. Strimvelis: Using Novel Retroviral Gene Therapy to Treat ADA-SCID. Illustrated by V. Chharawala. Rare Disease Review. November 2021. DOI:10.13140/RG.2.2.19632.89602.