Viral Vector-Based Gene Therapy in Clinical Applications

Gene therapies are currently one of the most investigated therapeutic modalities in both the preclinical and clinical settings and have shown promise in treating a diverse spectrum of diseases. In many cases, a gene therapy requires a vector to deliver gene therapeutics into target cells; viral vectors are among the most widely studied vectors owing to their distinguished advantages such as outstanding transduction efficiency. With decades of development, viral vector-based gene therapies have achieved promising clinical outcomes with many products approved for treating a range of diseases including cancer, infectious diseases and monogenic diseases. In addition, a number of active clinical trials are underway to further expand their therapeutic potential.

Potential of Engineered Viruses for In Vivo Gene Therapy

Current gene therapies fall into two broad categories, that is ex vivo and in vivo gene therapies. A vector is generally required for in vivo gene therapies, with an aim to pack and deliver gene therapeutics into target cells. Engineered viruses are the dominant vectors in current gene therapy clinical studies. To date, a plethora of viral vectors including adenovirus (Ad), adeno-associated virus (AAV), and herpes simplex virus (HSV) have proven their potential in safely and efficiently delivering gene therapies. Excitingly, over a dozen viral gene therapy products have been approved for treating cancer, infectious diseases, and monogenic diseases and their clinical investigation is still expanding.

Fig. 1 Major clinically relevant viral vectors and active clinical trials.

Clinically Relevant Viral Vectors

The primary reason of using a virus as a vector for gene delivery is to employ their natural capability of infecting cells and to efficiently shuttle gene materials of interest into host cells. Major viral vector types used for in vivo gene therapies in the clinic include Ad, AAV, HSV, retrovirus, and lentivirus.

Adenovirus (Ad) is one of the earliest viral vectors investigated in the clinic for in vivo gene therapies. There are more than 50 Ad serotypes, with Ad5 and Ad26 being most widely used for gene therapy.

Adeno-associated virus (AAV) is the most widely used viral vector for in vivo gene therapy applications. AAV has 11 natural serotypes and over 100 variants. AAV is the most suitable viral vector for in vivo gene therapies, especially for conditions that require long-term gene modifications. Their primary clinical applications cover the treatment of a broad array of monogenic diseases including ophthalmological diseases, metabolic diseases, hematological diseases, neurological diseases, and musculoskeletal diseases.

Herpes simplex virus (HSV) is an enveloped virus with a double-stranded NDA genome of over 150 kb. Currently, three major types of HSV vectors have been engineered for gene therapy applications, including amplicon HSV, replication-defective HSV, and replication-competent HSV.

Retrovirus is the first viral vector that was studied in clinical trials for in vivo gene therapy. Retrovirus vectors can reverse transcribe their genetic materials (single-stranded RNA) into double-stranded DNA and integrate it into host cells' genome. However, several major drawbacks limit their applications.

Lentivirus is another important viral vector for gene therapy. Its major application is for ex vivo gene therapies. Lentivirus is a subtype of retrovirus and carries the genetic materials in the form of RNA. However, unlike retrovirus, lentivirus can integrate its genome into and transduce nondividing cells. The primary application of lentivirus vectors for in vivo gene therapies is to treat monogenic diseases and chronic diseases including neurological diseases, ophthalmological diseases, and metabolic diseases.

Current Clinical Trials of Viral Vector-Based In Vivo Gene Therapy

AAV vector-based clinical trials

AAV is the most dominant vector type used in the identified trials for in vivo gene therapies. We identified 137 AAV-based active clinical trials. Majority of them are in early stages (Phases 1 and 2), however, more than 7% of them have reached at least Phase 3, reflective of its outstanding clinical potential. More than 20 serotypes/variants are used in the current clinical trials, with AAV2, AAV9, and AAV8 being the most widely used.

Fig. 2 Landscape of adeno-associated virus-based in vivo gene therapy clinical trials.

Adenovirus vector-based clinical trials

Ad vector-based gene therapy remains one of the most active areas in clinical studies. We identified 83 active clinical trials, most of which are in Phase 1 or 2. However, 24% of the trials have reached Phase 3 or 4. These identified trials involve the use of various Ad serotypes/variants, with Ad5 and Ad26 being the most widely used. Infectious diseases and cancer are two major indications that the current active trials are focused on. New areas of indications such as cardiovascular diseases and degenerative diseases are emerging.

Fig. 3 Landscape of adenovirus-based in vivo gene therapy clinical trials.

HSV vector-based clinical trials

US FDA has approved a HSV-based gene therapy for cancer applications. We identified 46 unique HSV-based gene therapy trials. Majority of the identified trials are in early-stages while one trial reached Phase 3. Analysis of HSV serotypes used in these trials revealed that HSV1 is the most used.

Fig. 4 Landscape of herpes simplex virus-based in vivo gene therapy clinical trials.

In addition to the use of novel viral vectors other than AAV, AD, and HSV for in vivo gene therapy, some of the newer viral vectors include lentivirus, arenavirus, measles virus, MVA, fowlpox virus, VSV, human cytomegalovirus, retrovirus, Sendai virus, among others. Various indications for the use of these viral vector-based gene therapies are emerging, depending on the characteristics of the particular viral vector.

Reference:

Zhao, Z.; et al. Viral vector‐based gene therapies in the clinic. Bioengineering & translational medicine. 2022, 7(1): e10258.

* For research use only. Not intended for any clinical use.

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Viral Vector-Based Gene Therapy in Clinical Applications

Potential of Engineered Viruses for In Vivo Gene Therapy

Clinically Relevant Viral Vectors

Current Clinical Trials of Viral Vector-Based In Vivo Gene Therapy

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