How Gene Therapy Is Curing Diseases

GENE THERAPY was first conceptualized in the 1960s but got its official start in 1972 when Theodore Friedmann and Richard Roblin published a paper in Science titled, “Gene therapy for human genetic disease?” which cited Stanfield Roger’s proposal in 1970 that exogenous good DNA could be used to replace defective DNA in people with genetic disorders.¹

The 1980s mostly consisted of research, and in the 1990s, the first clinical trials were conducted. But the death of three patients in 1999, 2003 and 2007 put a damper on gene therapy research. However, since the 2010s, research has been moving forward again with promising results.

The U.S. Food and Drug Administration (FDA) describes gene therapy as a technique that modifies a person’s genes to treat or cure disease. Gene therapies can work either by replacing a disease-causing gene with a healthy copy of the gene; inactivating a disease-causing gene that is not functioning properly; or introducing a new or modified gene into cells to help treat a disease.² 

Pfizer Inc.

On April 26, 2024, FDA approved Pfizer Inc.’s BEQVEZ to treat adults with moderate to severe hemophilia B who currently use factor IX (FIX) prophylaxis therapy; have current or historical life-threatening hemorrhage; or have repeated, serious spontaneous bleeding episodes, and do not have neutralizing antibodies to adeno-associated virus (AAV) serotype Rh74var (AAVRh74var) capsid, as detected by an FDA-approved test.

BEQVEZ is a one-time gene therapy with the potential to transform care for appropriate patients by reducing both the medical and treatment burden over the long term compared to factor replacement prophylaxis.

BEQVEZ is an AAV-based gene therapy designed to introduce in the transduced cells a functional copy of the FIX gene, encoding a high-activity FIX variant. For eligible patients living with hemophilia B, the goal of this gene therapy is to enable them to produce FIX themselves via this one-time treatment rather than having to receive frequent infusions of FIX, which is the current standard of care. 

BEQVEZ is now available by prescription to eligible patients. “As we focus our attention on ensuring access and operational readiness, we have proactively worked with payers and treatment centers to help ensure healthcare systems are appropriately prepared to deliver BEQVEZ. We are also launching a warranty program based on durability of response for patients, with the goal of providing greater certainty to payers, maximizing access for eligible patients who receive BEQVEZ and offering financial protection by insuring against the risk of efficacy failure,” says Sonal Bhatia, MD, senior vice president and head of U.S. specialty care medical affairs at Pfizer.

BEQVEZ will be administered via a one-time single-dose intravenous infusion in U.S. hospitals and other clinical centers, under the supervision of a physician experienced in the treatment of hemophilia. Many hemophilia patients receive care from designated hemophilia treatment centers, which play an important role in educating and caring for patients considering gene therapy. Due to the special handling requirements for gene therapies, Pfizer has established a process to evaluate the facilities and gene therapy capabilities of potential infusion sites, which has been initiated with several hemophilia treatment centers. Pfizer is committed to ensuring eligible patients who are prescribed BEQVEZ have access to it.

The standard of care for hemophilia B treatment is regular prophylactic intravenous infusions of FIX replacement therapy, often administered multiple times a week or multiple times a month, to control and prevent bleeding episodes.

With the approval of BEQVEZ, physicians and patients now have another choice in the treatment of hemophilia B. A one-time dose of BEQVEZ has provided sustained bleed protection relative to standard of care in a pivotal clinical trial and may allow patients to avoid years of medical burden associated with prophylaxis. For healthcare systems, this could also reduce and offset the ongoing costs of hemophilia B disease management, lowering resource utilization compared with the current standard of care.

According to Dr. Bhatia, “Our hope is that BEQVEZ could allow people living with hemophilia more time for the things they love and support their ability to engage in the workforce, school and society. For context, research has shown that nearly 40 percent of employed patients with severe hemophilia reported experiencing restrictions in performing their job due to their disease, and a wide range of at least 13 percent of people living with hemophilia have faced unemployment due to disease-related complications.”

Krystal Biotech Inc.

In May 2023, Krystal Biotech Inc.’s VYJUVEK was approved by FDA. VYJUVEK is the first and only redosable gene therapy for the treatment of dystrophic epidermolysis bullosa (DEB). VYJUVEK addresses the genetic cause of DEB to provide wound healing in a topical gel indicated for the treatment of wounds.

VYJUVEK is a herpes-simplex virus type 1 (HSV-1) vector-based gene therapy indicated for the treatment of wounds in patients 6 months of age and older who have DEB with mutation(s) in the collagen type VII alpha 1 chain (COL7A1) gene.

DEB is a type of epidermolysis bullosa that is a serious genetic disease. It is caused by mutations in the COL7A1 gene, resulting in the lack of functional type VII collagen, which disrupts the formation of anchoring fibrils in the skin and prevents adhesion of the epidermis to the dermis. There are two types of DEBs based on inheritance patterns: dominant (DDEB) and recessive (RDEB).  

DEB can lead to serious symptoms and complications. Symptoms primarily include skin fragility, blistering and wounds, and it can also result in damage to the mucosa and epithelial lining of organs. Some complications include infection of open wounds, esophageal stricture, gastrointestinal and genitourinary issues and cutaneous squamous cell carcinoma (SCC). DEB wounds can increase the risk of developing cutaneous SCC regardless of genetic subtype — RDEB or DDEB — size or chronicity.

VYJUVEK delivers two functional copies of the COL7A1 gene directly into keratinocyte and fibroblast cells of open wounds. (VYJUVEK does not replicate in the patient’s cells nor does it integrate into the patient’s cells’ native genetic material.) The functional genes allow the body to produce type VII collagen protein, which is used to create and assemble anchoring fibrils. Anchoring fibrils help bind the epidermis and dermis together to promote wound closure. Results of GEM-3, the Phase III confirmatory study, showed that 66.7 percent of wounds that were closed at three months were also closed at six months. The primary endpoint of the study showed that primary wounds with complete wound healing was 100 percent closure at six months, and the key secondary endpoint of the study showed that primary wounds with complete wound healing was 100 percent at three months.

CRISPR Therapeutics

Founded in 2013, CRISPR Therapeutics was one of the first companies formed to utilize the CRISPR gene editing platform to develop medicine for the treatment of rare and common diseases. Emmanuelle Charpentier, PhD, CRISPR Therapeutics co-founder, and Jennifer Doudna, PhD, co-discovered CRISPR-Cas9, a gene therapy tool that edits genes by precisely cutting DNA and then harnessing natural DNA repair processes to modify the gene in the desired manner. The tool can disrupt (inactivate), delete (remove) or correct or insert genes, and it can edit cells in vivo or ex vivo.

CRISPR Therapeutics has a dedicated team called CRISPR-X that focuses on innovative research to develop next-generation editing and delivery modalities, such as all-RNA gene correction, whole gene insertion and non-viral delivery of DNA. The company says these cutting-edge technologies could underlie the next wave of gene-editing therapies.

FDA approved CRISPR Therapeutics’ CASGEVY in 2023, the first-ever approved CRISPR-based therapy. CASGEVY is a CRISPR/Cas9 gene-edited therapy for patients 12 years and older who have sickle cell disease (SCD) or transfusion-dependent beta thalassemia (TDT). The company also has five clinical and 10 preclinical programs across hemoglobinopathies, oncology, diabetes and cardiovascular disease.

CASGEVY is a one-time therapy used to treat patients with SCD who have frequent vaso-occlusive crises (VOCs) and patients who have TDT who need regular blood transfusions. CASGEVY is made specifically for each patient, using the patient’s own edited blood stem cells, and increases the production of a special type of hemoglobin called hemoglobin F (fetal hemoglobin or HbF). Having more HbF increases overall hemoglobin levels and has been shown to improve the production and function of red blood cells. This can eliminate VOCs in patients with SCD and eliminate the need for regular blood transfusions in patients with TDT.

After receiving CASGEVY, SCD patients who had recurrent VOCs were VOC-free, had no in-patient hospitalization for VOCs and achieved no hospitalization out to 45.5 months, and TDT patients who were transfusion-dependent achieved transfusion independence out to 45 months.

In the clinical study, 93.5 percent (29 out of 31) of SCD patients aged 12 to 35 did not have a severe VOC for at least 12 months in a row after receiving CASGEVY. In the clinical study, 91.4 percent (32 out of 35) of TDT patients were transfusion-independent for at least 12 months in a row after receiving CASGEVY.

CSL Behring

In November 2022, FDA approved CSL Behring’s HEMGENIX, the first-ever FDA-approved gene therapy for hemophilia B.  HEMGENIX is a one-time gene therapy for the treatment of adults 18 years and older with hemophilia B who currently use FIX prophylaxis therapy or have current or historical life-threatening bleeding or have repeated, serious spontaneous bleeding episodes.  HEMGENIX is administered as a single intravenous infusion and can be administered only once. HEMGENIX is not intended for women or children.

Hemophilia B, a life-threatening rare disease caused by a mutation on the F9 gene, results in low levels of functional clotting FIX. Patients who have this condition are particularly vulnerable to bleeds in their joints, muscles and internal organs, leading to pain, swelling and joint damage. Current treatments for moderate to severe hemophilia B include lifelong prophylactic infusions of FIX to temporarily replace or supplement low levels of the blood-clotting factor.

HEMGENIX is a gene therapy that reduces the rate of abnormal bleeding in eligible patients with hemophilia B by enabling the body to continuously produce FIX, the deficient protein in hemophilia B. It uses an AAV5, a non-infectious viral vector. The AAV5 vector carries the naturally occurring Padua gene variant of FIX to the target cells in the liver, generating FIX proteins that are five to eight times more active than normal. These genetic instructions remain in the target cells but generally do not become a part of a patient’s own DNA. Once delivered, the new genetic instructions allow the cellular machinery to produce stable levels of FIX.

Based on the Phase III HOPE-B clinical trial to evaluate the safety and efficacy of HEMGENIX, results have shown that 1) 37 percent of patients’ average FIX activity was elevated and sustained for years; 2) patients had greater bleed protection versus routine FIX prophy; 3) 94 percent of patients discontinued FIX prophy and remained prophy-free in the clinical trial; and 4) annualized bleed rate for all bleeds decreased from an average of 4.1 for patients on prophy during the lead-in period to 1.9 (a 54 percent reduction) in months seven to 18 after treatment.

HEMGENIX does not eliminate hemophilia B; rather, it provides patients with hemophilia B with a working copy of the F9 gene and the ability to make their own FIX. Therefore, patients treated with HEMGENIX still have the mutation that causes hemophilia B.

AstraZeneca

Over the last several years, AstraZeneca has been building its CRISPR toolbox, including tools such as CRISPR GUARD, CRISPR VIVO and DISCOVER-Seq. These tools help establish how CRISPR can be used as a precise and effective gene therapy in the clinic.

Steve Rees, senior vice president of discovery sciences, biopharmaceuticals research and development at AstraZeneca, says, “CRISPR is the most exciting life science discovery in the last decade. It allows us to identify and validate new targets for medicine discovery, and as a medicine allows us to edit genes to enable the treatment and hopefully cure many genetic diseases.”

More recently, the company’s CRISPR toolbox has grown to include three new tools and technologies that have the potential to further improve the efficacy and precision of CRISPR-based medicines.

In 2022, AstraZeneca’s scientists developed Prime Editor nuclease (PEn) technology that can efficiently introduce precise genetic insertions through multiple double-stranded DNA repair pathways. In addition to enhancing the efficiency of generating insertions, editing with PEn leads to a reduction of unwanted large deletions, reducing the frequency of off-target effects. This new gene editing approach drives efficient genetic insertions, with a reduced risk of unwanted edits, advancing the potential for therapeutic use.

The company’s scientists have also developed a strategy called 2iHDR, which aims to improve the success of gene editing by suppressing two pathways of gene repair — called non-homologous end joining (NHEJ) and microhomology-mediated end joining (MMEJ) — that can lead to imprecise gene editing. Using a combination of two inhibitors, the efficiency of CRISPR gene editing can be dramatically improved while reducing the risk of off-target effects. This strategy holds great promise for both cell therapies and gene therapy.

AstraZeneca’s scientists have also developed an enhanced CRISPR system that utilizes an engineered enzyme, SpOT-ON. This enzyme cuts DNA with similar efficiency to the traditional enzyme, SpCas9, with enhanced specificity for the target site in the genome. In a proof-of-concept preclinical study of hypercholesterolemia, SpOT-ON successfully targeted the PCSK9 gene, resulting in reduced plasma levels of the associated PCSK9 protein. This recent research emphasizes the increasing safety features being built into CRISPR, making it more amenable to therapeutic applications and applying these in vivo for the first time.

“By altering DNA repair pathways with 2iHDR and harnessing a highly specific Cas9 variant with SpOT-ON, we can achieve targeted genetic modifications with enhanced precision and efficacy, driving further advancements in the field,” says Sandra Wimberger, a senior scientist of discovery sciences, biopharmaceuticals research and development at AstraZeneca.

Looking Forward

David Barrett, JD, CEO of the American Society of Gene and Cell Therapy, says the top three issues facing gene therapy today are the adequate delivery of gene therapy in the clinical setting; creating additional manufacturing capacity for the rapid development of new gene therapy technology; and changes that need to be made on how payers provide coverage for one-time gene therapies.

Although gene therapy research has been conducted for more than 30 years, it was not until 2017 when gene therapies started to receive FDA approval. “Now that there are several FDA-approved gene therapies available, and many more are expected in the near future, we need the appropriate support infrastructure to get gene therapies from the manufacturer to the clinical setting in a cost-effective, efficient and safe manner,” says Barrett. 

With the rapid development of new technology, the addition of new manufacturing capacity needs to be created. “There has been enormous advancement in gene editing technology since 2016 when CRISPR was discovered. There are now four or five primary ways to edit a genome, which is a faster, more widely application to use, and in the last three or four years, there have been two new gene editing technologies — prime editing and base editing. After new gene therapies have been approved by FDA, we need to get them manufactured in a cost-effective, efficient and safe manner.”

Unlike pharmaceuticals, which are taken regularly over long periods of time or a lifetime until a disease is cured or being managed well, gene therapy is usually a one-time application, and the entire cost of the gene therapy must be paid upfront. However, unlike pharmaceuticals, gene therapies usually last either many months or years or indefinitely, so the one-time cost of the gene therapy must be compared to the long-term cost of taking pharmaceuticals for long periods of time or a lifetime.

“Payers need to make changes to how they provide coverage for one-time gene therapies, as opposed to pharmaceuticals, as the cost for a one-time gene therapy does not fit the same mold as reimbursing a patient for pharmaceuticals, as a patient typically pays for pharmaceuticals over a long period of time or a lifetime, not all at once,” says Barrett. “There are 7,000-plus genetic diseases that currently have no treatment. Through genetic testing, we need to identify faulty genes and what causes the genes to become faulty, then we need to develop an appropriate tool(s) to find the faulty genes, and then we need to apply the most applicable gene-editing tool to find and replace or correct the faulty genes.”

ASGCT is very hopeful researchers will make breakthroughs in the next five to 10 years. “We never know when a breakthrough might happen that could advance research tremendously and very quickly move us forward to the next stage of gene therapy that could help to diagnose and cure more people of their genetic diseases,” adds Barrett.