Eight applications where gene therapy shines

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Gene therapy represents a transformative approach in modern medicine, with the potential to address and cure a wide array of genetic disorders. By introducing, modifying, or repairing genetic material within a patient’s cells, gene therapy aims to rectify underlying genetic defects, thereby treating or preventing disease. Gene therapy encompasses various techniques and applications, including the replacement of faulty genes with healthy ones, the inactivation of malfunctioning genes, or the introduction of new genes to aid in disease resistance.

The field has witnessed significant milestones, with several gene therapy products receiving regulatory approval. For instance, Zolgensma has been approved for the treatment of spinal muscular atrophy, offering a one-time gene replacement therapy that addresses the root cause of the disease. Similarly, Luxturna has been approved for inherited retinal diseases.

Gene therapy is very versatile and in this article, we take a look at eight areas where gene therapy could bring new solutions to patients, some better known than others.

Gene therapy for hematological disorders

In hematological gene therapy, hematopoietic stem cells (HSCs) are harvested from the patient, genetically modified to correct or replace defective genes, and then reintroduced into the patient’s bloodstream. These modified stem cells localize in the bone marrow, where they proliferate and differentiate into various blood cell lineages, producing functional proteins necessary for normal hematopoietic function.

For instance, gene therapy is used to treat hemophilia A and B. Hemophilia A is a disorder caused by mutations in the F8 gene, leading to a deficiency in clotting factor VIII. This protein is essential for the blood clotting cascade, and its absence results in prolonged bleeding episodes, even from minor injuries. Patients often require regular intravenous infusions of factor VIII to manage the condition. The symptoms of Hemophilia B are similar but its genetic causes are different as it is a mutation in the F9 gene causing a deficiency in the clotting factor IX.

Pfizer’s Beqvez targets hemophilia B and was approved in April 2024. It delivers a functional copy of the F9 gene directly to the liver cells using an adeno-associated virus (AAV) vector. Once delivered, the introduced gene enables liver cells to produce sufficient amounts of clotting factor IX thereby addressing the root cause of the disease.

With a similar mechanism for hemophilia A, BioMarin Pharmaceuticals’ Roctavian was approved by the U.S. Food and Drug Administration (FDA) in 2023. Pfizer is also advancing giroctocogene fitelparvovec, a candidate for the same indication, and recently reported positive phase 3 data.

Gene therapy for neurological disorders

Neurological disorders and neurodegenerative diseases are other promising applications for gene therapy. This strategy often involves the delivery of therapeutic genes to neurons, aiming to correct mutations or restore essential protein functions.

A notable example is Zolgensma, an AAV9-based gene therapy and the first approved by the FDA for the treatment of spinal muscular atrophy (SMA). SMA is a severe neurodegenerative disease caused by mutations in the SMN1 gene, leading to a deficiency in the survival motor neuron (SMN) protein. Zolgensma delivers a functional copy of the SMN1 gene to motor neurons, thereby restoring SMN protein levels.

Beyond SMA, gene therapy research is exploring treatments for other neurodegenerative diseases. In Huntington’s disease, a hereditary disorder characterized by progressive motor dysfunction and cognitive decline, gene silencing techniques are being investigated to reduce the expression of the mutant huntingtin protein responsible for neuronal damage. Similarly, in Alzheimer’s disease, strategies are being developed to target and reduce the accumulation of amyloid-beta plaques and tau tangles, which are hallmark features of the disease.

In Huntington’s disease, UniQure has been at the forefront of gene therapy research with its investigational treatment, AMT-130. This therapy employs an AAV vector to deliver microRNAs that silence the mutant huntingtin gene, reducing the production of the toxic protein responsible for neuronal damage. In July 2024, uniQure announced positive interim results from a phase 1/2 trial.

Additionally, in October 2024, Lexeo Therapeutics reported positive interim data from a phase 1/2 study of LX1001, a gene therapy targeting the APOE4 genetic variant associated with increased Alzheimer’s risk. The therapy aims to modify the expression of APOE4, potentially altering disease progression.

Gene therapies for eye diseases

Gene therapy offers an interesting application in addressing ophthalmological disorders, especially inherited retinal diseases (IRDs) that cause gradual vision loss. The idea is to deliver functional genes directly to retinal cells, with the goal of correcting the effects of genetic mutations that drive these conditions.

Spark Therapeutics’ Luxturna is the first FDA-approved gene therapy for an inherited retinal disease. Luxturna is designed for patients with RPE65 mutation-associated retinal dystrophy, a condition that can result in severe vision impairment or blindness. The therapy utilizes an AAV vector to deliver a normal copy of the RPE65 gene directly to retinal cells via subretinal injection. Before this treatment was approved, the focus of existing therapies was primarily on managing the symptoms rather than treating the disease.

Beyond Luxturna, several gene therapies are under investigation for various ophthalmological conditions. Developed by Regenxbio and AbbVie, RGX-314 is an AAV-based gene therapy for age-related macular degeneration (AMD) designed to deliver a gene encoding for an anti-VEGF protein, aiming for sustained protein production by retinal cells.

SparingVision is developing SPVN06, a gene therapy targeting rod-cone dystrophy but the candidate is still in the preclinical stages.

Gene therapy for Duchenne muscular dystrophy

Duchenne muscular dystrophy (DMD) is a genetic disorder that primarily affects boys and leads to progressive muscle weakness and degeneration. The condition is caused by mutations in the DMD gene, which encodes dystrophin, a protein involved in maintaining the structural integrity of muscle fibers. Without dystrophin, muscle cells are highly susceptible to damage during contraction, resulting in muscle wasting, loss of mobility, and, ultimately, complications such as respiratory or cardiac failure.

Treatment options have historically focused on managing symptoms and complications, but advancements in the applications of gene therapy are now offering the possibility of addressing the root genetic cause of the disease.

A notable advancement in this field is the development of Elevidys, a gene therapy approved by the FDA. Like many other gene therapies, Elevidys relies on AAV vectors for the delivery of a gene encoding micro-dystrophin – a shortened yet functional version of dystrophin – into muscle cells. This approach aims to restore the production of a functional protein, improving muscle strength and function in affected individuals.

Gene therapy for cancer

How can we talk about gene therapy applications without mentioning oncology? Unlike traditional cancer treatments such as chemotherapy or radiotherapy, gene therapy focuses on modifying genetic material to restore normal cell function, silence oncogenic drivers, or sensitize cancer cells to other treatments.

One of gene therapy’s strategies in oncology is tumor suppressor gene replacement. Many cancers arise when tumor suppressor genes like TP53 or RB1 lose function, resulting in unchecked cell growth. Gene therapy aims to reintroduce functional copies of these genes into tumor cells, thereby reinstating their ability to regulate cell division and induce apoptosis.

For example, Advexin developed by Introgen Therapeutics delivers the TP53 gene using an adenoviral vector. However, despite initial promises, the therapy failed to obtain approval and was dropped. As of today, the landscape of tumor suppressor gene replacement therapies remains largely in the research and clinical trial phases, with no therapies having received regulatory approval.

However, REQORSA, developed by Genprex, which focuses on delivering the TUSC2 tumor suppressor gene to non-small cell lung cancer (NSCLC) cells is in several phase 1/2 studies. TUSC2 is frequently deleted or underexpressed in NSCLC, contributing to tumor development.

Another promising avenue is the use of gene silencing techniques to target oncogenes – genes that promote cancer when mutated or overexpressed. Approaches like antisense oligonucleotides (ASOs) and RNA interference (RNAi) allow researchers to downregulate harmful genes like KRAS, which is frequently mutated in pancreatic and colorectal cancers.

Although it qualifies as cell therapy, CAR-T therapy can be referred to as a cell-based gene therapy. It involves genetically modifying a patient’s own T cells to enhance their ability to identify and eliminate cancer cells. This approach has shown remarkable success in treating hematological cancers. Several CAR-T therapies have achieved regulatory approval, including Yescarta and Kymriah, which target CD19, a protein expressed on the surface of B-cell malignancies.

Gene therapy for hearing loss

Genetic mutations are a significant cause of congenital hearing loss, with conditions like autosomal recessive deafness 9 (DFNB9), a form of hereditary deafness caused by mutations in the OTOF gene, which encodes the otoferlin protein essential for auditory function. Traditional interventions, such as hearing aids and cochlear implants, offer limited benefits for certain genetic forms of deafness. However, gene therapy might be the way to go.

In a recent trial, gene therapy targeting DFNB9 restored hearing and speech recognition in children with otoferlin deficiency. This study demonstrated that delivering functional copies of the OTOF gene via AAV vectors could result in “obvious” improvements,

Another promising application is the use of dual-gene therapy approaches for conditions like Usher syndrome type 1F, which causes both deafness and progressive blindness. Researchers have developed a method to deliver large genes by splitting them into two halves, delivering them via AAVs, and reassembling them in the target cells. This approach has shown success in restoring hearing and balance in mouse models, with potential implications for human treatment.

Gene therapy for cystic fibrosis

Cystic fibrosis (CF) is a genetic disorder caused by mutations in the CFTR (cystic fibrosis transmembrane conductance regulator) gene, leading to defective chloride ion transport in epithelial cells. This results in the accumulation of thick, sticky mucus in the lungs, chronic respiratory infections, and progressive lung damage.

One of the most advanced candidates is 4D-710, a CFTR gene therapy developed by 4D Molecular Therapeutics. This therapy uses AAV vectors to deliver the CFTR gene to the airway epithelial cells. A phase 1/2 clinical trial is currently underway, assessing its safety and preliminary efficacy in patients with advanced CF lung disease.

Another promising candidate is being developed by ReCode Therapeutics, which is exploring a non-viral approach using lipid nanoparticles to deliver a corrected CFTR gene. This delivery system is designed to overcome the challenges posed by the lung’s complex structure and mucus barrier, which often impede effective gene delivery. This week, the company received funding from the Cystic Fibrosis Foundation to advance this technology.

Additionally, Spirovant Sciences is working on a CF gene therapy based on a lentiviral vector system. Unlike traditional AAV-based therapies, lentiviral vectors can integrate into the host genome, potentially providing longer-lasting therapeutic effects. Spirovant’s therapy is still in preclinical development.

Gene therapy for metabolic disorders

Metabolic disorders, often resulting from genetic mutations that lead to enzyme deficiencies, disrupt normal metabolic pathways and cause the accumulation of toxic substances in the body. Traditional treatments, such as dietary restrictions and enzyme replacement therapies, primarily manage symptoms without addressing the underlying genetic causes. This is where gene therapy comes in.

Kebilidi is a gene therapy developed by PTC Therapeutics for the treatment of aromatic l-amino acid decarboxylase (AADC) deficiency, a rare and potentially fatal enzyme deficiency disorder. This condition affects fewer than 1,000 people in the U.S. Kebilidi is a one-time treatment administered by delivering the AADC gene into nerve cells in the brain, helping them produce the missing enzyme to manage dopamine levels. The U.S. FDA approved Kebilidi only a week ago, on November 13, 2024.

Another interesting candidate is DTX401, an investigational gene therapy developed by Ultragenyx Pharmaceutical for the treatment of glycogen storage disease type Ia (GSD Ia), a genetic disorder that impairs the body’s ability to regulate blood sugar levels. The therapy is currently in phase 3 and Ultragenyx shared positive topline results earlier this year.

Gene therapy: one of the most versatile technologies

The boundaries between gene and cell therapy are often blurred, as seen in CAR-T technology which uses gene and cell therapy techniques. Beyond the applications we’ve covered in this article, gene therapy holds potential in many fields, including diabetes – by reprogramming genes responsible for the regulation of insulin – or in cardiovascular diseases.

This is why gene therapy is such a vast market. Indeed, according to Global Market Insights, the value of the gene therapy market in 2023 was $9 billion and could grow at a CAGR of over 19.4% between 2024 and 2032, potentially reaching $44.5 billion in eight years. The market is currently dominated by AAV-based therapies but there is a growing interest in non-viral vectors as they offer a safer alternative.

However, the area isn’t without challenges and a significant hurdle is, as pointed out, the delivery of these therapies. Viral vectors, while effective, carry risks such as toxicity, inflammatory responses, and unintended effects on gene regulation.

Also, in some cases, the therapeutic effects of gene therapy may be temporary, necessitating multiple treatments. Achieving long-term expression of the therapeutic gene is a significant challenge. There are also concerns about the accessibility of gene therapy as it might be one of the most costly treatments for patients. For instance, at the time it was approved, the IRD gene therapy Luxturna sparked concerns with its $850,000 price tag per patient.

While gene therapy is one of the most promising in the biotech industry and one with the most applications , there is still work to be done on the delivery of the therapy and its accessibility.