The First Gene Therapy

Gene therapy is a new type of treatment strategy. It involves the replacement of a defective gene with a normal gene. It helps to restore the lost gene function in the body. The first gene therapy in humans was carried out in the year 1990 by French Anderson. The therapy helped in treating a child suffering from ADA deficiency. The deficiency of ADA involves an enzyme deficiency known as adenosine deaminase. The WBCs become functionally inactive in ADA deficiency. The disease leading to the ADA deficiency is known as SCID or severe combined immunodeficiency. The gene therapy proved to be successful in the child suffering from SCID. However, only the somatic gene therapy was successful. It was because the somatic gene therapy helped in treating the disease. With time, the advancements in the gene therapy kept on progressing. However, the first gene therapy set an example of new treatment mode. The idea of gene therapy helped the healthcare sector in advancing and treating rare diseases and disorders with no drug treatment.

The gene therapy encompasses many types of genetic engineering applications for inserting the relevant genes in humans. Among all, the somatic cell gene therapy technically sounds simple and convenient. The children with the ADA deficiency die early due to the lack of an essentially functional immune system. They fail to fight the recurrent microbial infections. Most of the patients suffering from ADA deficiency die due to imbalanced platelets or WBCs due to viral or bacterial infections.

Image 1: Gene therapy

Severe Combined Immunodeficiency (SCID):

Before understanding the gene therapy in SCID patients, we must know more about this immunodeficiency syndrome. SCID stems from a defective lymphoid development. It mainly affects the T-cells, B cells and the natural killer cells (NK cells). Although SCID is an immunodeficiency disorder, it mainly arises due to the gene defects. The circulating lymphocytes in SCID individuals are very less in number. Thus, the entire immune system gets hampered. The failure of the T-cell response and development directly affects the thymus. The thymus is a specialized primary lymphoid organ, important for the immune system. The T-cell maturation mainly occurs in the thymus. They mainly help in building the adaptive immunity and fight with the foreign invaders. The thymus poorly develops in the individuals with the condition such as SCID. The development of the thymus gets affected in this condition. The individuals with SCID experience a low adaptive immunity and hence face the difficulty in fighting the invading microbes. The T-cell count is lower than the expected range. Although the individuals with SCID exhibit normal levels of the myeloid and erythroid cells, the impact of the depleted lymphoid cells is extremely high. Hence, it leads to severe complications.

While designing the gene therapy for the individuals with SCID, the WBCs were thoroughly studied. Since the root of the disease lies in the nucleus of the WBC, it was thus important to study the genes and deduce a therapy. The platelets and erythrocytes lack a nucleus. The white blood cells show a well-defined nucleus. The SCID infants and children always suffered due to recurrent infections, opportunistic infections, chronic diarrhea, pneumonia and skin infections, mouth and throat lesions. The patients with SCID show a highly compromised immune system. Even the vaccines revert and lead to severe infections. Another feature of SCID involves a defective antibody response arising due to affected B-lymphocytes. SCID affects one in a lakh newborn babies.

Although the somatic gene therapy in ADA deficiency was easy to define theoretically, it was an extremely difficult and careful activity conducted by a group of experts in medicine, immunology, and genetics. 

Following are the types of severe combined immunodeficiency:

Type of SCID	Genetic Condition
X-linked IL-2RγChain deficiency	Mutations arise in a gene encoding a common gamma chain for an interleukin receptor protein.
JAK-3 deficiency	JAK 3 gene mutation leads to JAK 3 enzyme deficiency.
CD45 deficiency	Mutant CD45 alleles, uniparental disomy
IL-7R αchain deficiency	IL-7R gene mutations encoding an IL-R alpha chain.
CD3 δchain deficiency	Mutations in gene encoding CD3 delta chain
Adenosine deaminase deficiency (ADA)	Defective adenosine deaminase enzyme production.
Artemis deficiency	Lack of Artemis gene.
RAG1 and RAG 2 deficiency	Mutations in RAG-1 and RAG-2 genes result in prevention of VDJ recombination.

Table: Types of SCID

The first gene therapy was carried out in a girl suffering from SCID due to ADA deficiency. The enzyme known as adenosine deaminase catalyzes the conversion of adenosine to inosine. Hence, the deficiency of adenosine deaminase results in accumulation of adenosine. It interferes with the purine metabolism and DNA synthesis. It also results in the accumulation of toxic metabolites in the T cells and B cells. It is an autosomal recessive disease since it follows a pattern of autosomal recessive inheritance. The chromosome 20q13 possesses the defect. It means that the mutant allele is present in a double dose.

The gene therapy in ADA deficiency consisted of following steps:

Step 1: Collection of the patient's blood sample

Dr. French Anderson and his colleagues decided to conduct a clinical trial in ADA deficient girls. The blood sample collected from the affected girl involved careful analysis. The patient and her parents signed the consent form for the therapy. Analysis followed the culturing of the cells.

Step 2: Filtration of WBCs

The process of filtration helped to retain the white blood cells. Hence the white blood cells were filtered out of the red blood cells and platelets. The WBCs stored carefully helped in analyzing them.

Step 3: Alteration of the viral vector

The viral vector used in the therapy was known as an Adenovirus. It belongs to the class of retroviruses. The therapy involved a careful manipulation of viral genes for preventing its replication in the cells. It must only do the job of delivering the life-saving ADA gene.

Step 4: Culturing WBCs mixed with a viral vector having ADA gene

The cells grew in large numbers in tissue culture plates. The process involved mixing the cells with the genetically engineered virus. The virus inserted the ADA gene into the target cell’s DNA.

Step 5: Injection of WBCs containing the life-saving ADA gene

After screening the cells containing the therapeutic gene, the further procedure involved returning the cells with the ADA gene to the patient’s body. Hence, the correct gene gets inserted into the patient’s genome. 
References:
[1] Human Genetics, 3/e, Gangane
[2] Medical genetics, G.P. Pal

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