Gene Therapy for Alpha-1 Antitrypsin Deficiency (AATD)

What Is Alpha-1 Antitrypsin Deficiency?

Many of us have heard the stories of healthy young persons suffering from serious breathing and digestion issues. We might wonder what may cause such a serious problem. Well, you would be surprised to know that such a problem might be caused by a serious genetic disease. Among the millions of chemicals present in our body, a compound named alpha-1 antitrypsin (AAT) plays an important role in the health of the lungs. Our liver produces this protein, which protects the lungs from injury. Such injuries happen due to the action of white blood cells in infection or the presence of pollutants. However, alpha-1 antitrypsin (AAT) prevents the gathering of white blood cells, especially neutrophils, inside the lungs and protects the air sac. As a result, an absence of faulty functioning of alpha-1 antitrypsin (AAT) can damage your lungs and air sacs. Though this seems relatively uncommon, such complications are quite common. This disorder affects European and American people. This complication is known as alpha-1 antitrypsin deficiency (AATD). As this condition is passed on to the generations, genetic involvement is the root cause of the disease.

What Are the Commonly Used Treatment Options?

Anyone who suffers from alpha-1 antitrypsin deficiency (AATD) experiences severe breathing issues, cough, and gut problems at an early age. This happens due to the damage of the lungs and liver. If your condition is serious, you might suffer from problems like chronic obstructive pulmonary disorder (COPD, a disease in which the airway is damaged and blocked), and emphysema (a prolonged lung disease that causes damage to the air sac) at an early age or before the age of 45 years.

Still, now no complete cure for this disease has been found. As a result, doctors try to protect your lungs from further damage. Nowadays, doctors are trying to increase the level of AAT through augmentation therapy. In this procedure, a purified version of human AAT is injected into the body. This helps to maintain the balance of AAT in the body. However, you need to take these injections multiple times to maintain the balance of the enzyme. Though this treatment option can protect your lungs and improve symptoms like breathing problems, it has many limitations. These are;

1. Recent research has shown that augmented therapy does not reduce the death rate due to long-term illness.

2. You need to take an injection of AAT every month or a gap of a few weeks. Taking repeated injections is painful.

3. If your lungs and livers are severely damaged and you are suffering from extreme discomfort, these injections might not be effective for you.

4. Regular injections might further damage your liver. In extreme cases, a liver transplant might be necessary to save your life.

5. These injections are costly and might pinch hard in your pockets.

6. Regular injections often increase the chances of viral infections or allergies.

Overview of Alpha-1 Antitrypsin Deficiency Gene Therapy

Alpha-1 antitrypsin gene mutation is a problem in the SERPINA1 gene that is responsible for alpha-1 antitrypsin deficiency. These problems in the gene are responsible for a lack of AAT level in the blood along with structural and functional problems. As genetic factors are involved this disease is passed on to the generations. Gene therapy for genetic disorders makes changes in these genes and helps in the complete cure of this disease.

How Gene Therapy Works: Genes are the most tiny portion of our body. These tiny segments pass on to generations and regulate different functions of our body. The aim of gene therapy is to change any problems related to the gene. You must be wondering how such a tiny portion of our body is treated. Well, with the progress of modern science, several types of gene therapy do genetic corrections in different ways. In genetic addition therapy, a healthy copy of the faulty or missing gene is added to the patient's body. Scientists use a delivery vehicle to insert this gene into a patient’s body. These vehicles are known as vectors, which are nothing but different viruses or chemicals.

Another type of gene therapy is gene editing, in this process, they remove faulty or unwanted portions of the gene. Also, by the use of gene therapy doctors can suppress the functioning of faulty genes. Such treatment is known as post-transcriptional gene silencing.

Types of Gene Therapy:

Currently, gene therapy for AATD is in the development stage. Researchers are using different processes to treat our defective gene in AATD. However, most scientists prefer genetic addiction therapy to replace faulty genes. Different scientists use different techniques for this purpose. These techniques are broadly divided into two different categories based on different vectors and different sites of injections.

The non-harmful viruses are very popular vehicles for gene therapy. These viruses can be retrovirus or adenovirus. Nowadays, engineered viruses like adeno-associated virus (AAV) are gaining popularity as vectors for their low side effects and high stability.

In our body liver cells produce AAT. As a result, gene therapy usually targets liver cells to produce fine AAT. For this purpose, injection for gene therapy is given in the blood circulating channels around the liver. Recently, scientists have found out that muscles too can produce AAT. As a result, injecting drugs for genetic therapy within the muscles is an easier option.

Benefits and Risks:

One of the biggest advantages of gene therapy is a single-shot technique. As a result, you rarely get an infection or allergy. Plus, genetic therapy can cure alpha-1 antitrypsin gene mutation completely.

The risks associated with genetic therapy are;

1. Genetic therapy is still developing. The number of human experiments related to gene therapy is still small.

2. There is evidence that genetic therapy can also cause allergic reactions.

Current Research and Developments in Gene Therapy:

Recently, scientists are trying to apply gene editing for AATD. This method can increase the efficiency of gene therapy.

1. Recent Studies on Gene Therapy for Alpha-1 Antitrypsin Deficiency: Currently, scientists are working on CRISPR-Cas9 (clustered regularly interspersed short palindromic repeats (CRISPR) gene editing method in AATD. These methods not only minimize your side effects but also increase the effectiveness of the treatment.

2. Ongoing Clinical Trials: Though gene therapy looks promising but number of scientific studies going on in gene therapy is relatively less. For more than thirty years scientists have been working on gene therapy in AATD. However, most of the experiments are done on animals. In the past, a few trials were not satisfactory. There was no significant improvement in the body's AAT level after gene therapy.

Despite this, ongoing human trials show promising results. Though the number of patients in these studies is less, they show significant improvement in patients' symptoms. Also, after receiving gene therapy liver health of those patients has improved.

Regulatory Approvals and Challenges:

Gene therapy is a new field in medicine. As drugs act on the genetic level the chances of potential harm or adverse reactions are more than conventional medicines. That is why getting regulatory approval for these drugs is difficult. The process is long, tedious, and difficult.

Future Directions in Gene Therapy in Alpha-1 Antitrypsin Deficiency:

The scientists are trying to solve difficulties related to genetic therapy. This will not only provide better results but also will help to cure the disease completely.

1. Emerging Technologies: For gene therapy, scientists are trying to use human liver cells. These liver cells will be modified and placed in your body. After injection, these cells will repair your damaged liver cells and form new fully functional liver cells. These cells will maintain a normal level of AAT in the body. Also, if your liver is damaged it can regenerate the whole liver. Also, scientists are trying to develop new methods of genetic editing. Such methods can alter genetic structure with pin point precision. This new concept is known as prime editing.

2. Potential Impact on Treatment: With the application of newer technologies, scientists are solving issues like;

• • Allergy and the body’s adverse response towards gene therapy.
  • A useful and easy technique for injecting medicines related to gene therapy.
  • AATD often causes severe damage to the organs. Such patients need organ transplants to survive. The techniques in gene therapy might be able to repair the damaged organs completely.

Conclusion:

AATD inherited disease is difficult to treat. In the long run, this disease can completely damage your lungs and liver. You would not have long-term relief through common treatments. Also, the traditional treatment approach is not only tedious but also increases the chances of infections. Gene therapy for AATD is a ray of hope. This therapy not only can cure the disease completely but also can regrow your damaged organ.

Key Takeaway:

Alpha-1 antitrypsin deficiency can destroy your lungs and liver forever. It is difficult to cure this forever. Gene therapy, which is still an emerging method of treatment, can cure this completely.