By Aditi Goyal, Genetics & Genomics, Statistics, ‘22

Author’s Note: I heard about this therapy during a freshman seminar, and I presented on this during that class. This article is an adaptation of that presentation. 

ADA-SCID is a rare, autosomal recessive disease that cripples one’s immune system. ADA SCID stands for Severe Combined Immunodeficiency due to Adenosine Deaminase Deficiency, which occurs due to a mutation in the ADA gene [1]. This gene normally assists in the production and regulation of lymphocytes, also known as white blood cells [1]. Specifically, ADA (Adenosine Deaminase) breaks down deoxyadenosine, which is toxic to lymphocytes [2]. In the absence of a working ADA gene, this deoxyadenosine collects in the body and continues to degrade lymphocytes. Eventually, the lack of functioning lymphocytes leads to severe combined immunodeficiency (SCID) [2].

ADA-SCID is typically screened for at birth and has a variety of treatment options. The most common treatment is a bone marrow transplant from a sibling. In this process, stem cells are taken from someone with a matching blood type, and transplanted into the patient, with the hope that these cells will proliferate and produce healthy lymphocytes [3]. While this approach is effective approximately 70% of the time, the real challenge is in matching a patient to a donor. Because the patient’s immune system is already so impacted, there is a high possibility of rejection of the transplant. Additionally, for patients who do not have a sibling or someone in the family who is able to donate, finding a match can be incredibly difficult.

For patients unable to have a transplant, enzyme therapy is also a possible form of treatment [3]. Enzyme Replacement Therapy, ERT, is simply providing the patient with a working copy of an enzyme, ADA in this case [4]. The drawback to this form of treatment is that it requires a patient to be dependent on a hospital for their entire lives. They cannot travel too far away from a hospital for too long, because if they miss a delivery of the enzyme, there can be drastic consequences [5]. Additionally, ERT can lose effectiveness over the years [4].

The third, and still experimental, treatment option is a gene therapy known as Strimvelis [6]. Strimvelis is one of the first gene therapy products to be used anywhere in the world. While it has yet to be approved by the FDA in the United States, it marks a milestone in the development of personalized medicine.

Strimvelis treatment has three steps, starting with harvesting hematopoietic stem cells (HCS’s)  from the patient. These cells carry the mutated ADA gene and are ineffective at supporting catalyzing deoxyadenosine. Once extracted, the corrected ADA gene is delivered to the HCSs in an ex vivo environment using a gammaretrovirus [7]. Once the cells have been transformed, they are delivered back to the patient using an IV drip, and take hold in the body, subsequent to a dose of Busulfan or Melphalan [8]. These two chemotherapy drugs are intended to kill any remaining damaged HCS’s in the body, allowing for the corrected cells to grow without interference. Once injected, the corrected cells will continue to proliferate, producing a healthy amount of ADA. The reason this therapy works well is that the patient’s own HCS’s are used, so there is little to no risk of rejection by the body’s immune system. Another key advantage to using Strimvelis is that it is a single treatment. Once the corrected HCS’s are delivered to the body, the patient is considered “cured” and is no longer reliant on any medical procedures to maintain their immunity.

The results of Strimvelis trials have been incredibly promising. A clinical trial conducted by the European Medicines Agency (EMA) found Strimvelis to have a 100% success rate, leading to its approval by the European Commission about one month later [9]. However, there have been rare cases of Strimvelis leading to patients developing T-cell leukemia [10]. These cases have led to the parent company of Strimvelis, Orchard Therapeutics, halting all administration of Strimvelis until an investigation on the possibly cancerous effects of Strimvelis has been completed [11].

Another primary drawback of Strimvelis is its cost. Strimvelis costs 594,000 euros per patient, which is equivalent to approximately 650,000 dollars [12]. While Strimvelis is not the most expensive gene therapy on the market, the cost is still incredibly restrictive, as the average middle-class family would not be able to afford this treatment.

The reason the cost for this treatment is so high is that ADA-SCID is considered an orphan disease. Orphan diseases are conditions that affect under 200,000 people worldwide [13], which means that from the perspective of a pharmaceutical company, it is not cost-effective to develop a treatment. ADA-SCID only affects around 350 people worldwide [2]. Therefore, the cost per patient is high, since there are not that many people affected by this disorder and because the therapy cannot be mass-produced.

Strimvelis is not perfect, by any means. There are still thousands of unknowns surrounding gene editing, and the side effects are dramatic. Even with Strimvelis on the market, it is not the number one treatment option for most ADA-SCID patients. Nevertheless, it is a step forward. In a world where we learn more about our genetics every day, Strimvelis is a milestone in the development of personalized medicine. 

References

1. Adenosine deaminase DEFICIENCY: MedlinePlus Genetics. (2020, August 18). Retrieved March 10, 2021, from https://medlineplus.gov/genetics/condition/adenosine-deaminase-deficiency/
2. Hershfield M. Adenosine Deaminase Deficiency. 2006 Oct 3 [Updated 2017 Mar 16]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2021. Available from: https://www.ncbi.nlm.nih.gov/books/NBK1483/
3. Kohn DB, Hershfield MS, Puck JM, Aiuti A, Blincoe A, Gaspar HB, Notarangelo LD, Grunebaum E. Consensus approach for the management of severe combined immune deficiency caused by adenosine deaminase deficiency. J Allergy Clin Immunol. 2019 Mar;143(3):852-863. doi: 10.1016/j.jaci.2018.08.024. Epub 2018 Sep 5. PMID: 30194989; PMCID: PMC6688493.
4. Adenosine deaminase deficiency: Treatment and prognosis. (n.d.). Retrieved March 10, 2021, from https://www.uptodate.com/contents/adenosine-deaminase-deficiency-treatment-and-prognosis#H2288540670
5. Scott O, Kim VH, Reid B, Pham-Huy A, Atkinson AR, Aiuti A, Grunebaum E. Long-Term Outcome of Adenosine Deaminase-Deficient Patients-a Single-Center Experience. J Clin Immunol. 2017 Aug;37(6):582-591. doi: 10.1007/s10875-017-0421-7. Epub 2017 Jul 26. PMID: 28748310.
6. Aiuti, Alessandro et al. “Gene therapy for ADA-SCID, the first marketing approval of an ex vivo gene therapy in Europe: paving the road for the next generation of advanced therapy medicinal products.” EMBO molecular medicine vol. 9,6 (2017): 737-740. doi:10.15252/emmm.201707573
7. Candotti F (April 2014). “Gene transfer into hematopoietic stem cells as treatment for primary immunodeficiency diseases”. International Journal of Hematology. 99 (4): 383–92. doi:10.1007/s12185-014-1524-z. PMID 24488786. S2CID 8356487.
8. Touzot F, Hacein-Bey-Abina S, Fischer A, Cavazzana M (June 2014). “Gene therapy for inherited immunodeficiency”. Expert Opinion on Biological Therapy. 14(6): 789–98. doi:10.1517/14712598.2014.895811. PMID 24823313. S2CID 207483238.
9. https://www.ema.europa.eu/en/documents/product-information/strimvelis-epar-product-information_en.pdf
10. Stirnadel-Farrant, Heide et al. “Gene therapy in rare diseases: the benefits and challenges of developing a patient-centric registry for Strimvelis in ADA-SCID.” Orphanet journal of rare diseases vol. 13,1 49. 6 Apr. 2018, doi:10.1186/s13023-018-0791-9
11. Orchard statement on Strimvelis®, a Gammaretroviral Vector-Based gene therapy For ADA-SCID. (n.d.). Retrieved March 10, 2021, from https://ir.orchard-tx.com/index.php/news-releases/news-release-details/orchard-statement-strimvelisr-gammaretroviral-vector-based-gene
12.   Mullin, E. (2020, April 02). A year after approval, gene-therapy cure gets its first customer. Retrieved March 10, 2021, from https://www.technologyreview.com/2017/05/03/152027/a-year-after-approval-gene-therapy-cure-gets-its-first-customer/#:~:text=Strimvelis%2C%20used%20to%20treat%20an,Money%2DBack%20Guarantee%E2%80%9D).