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The milestone approval of a gene-edited therapeutic paves the way for gene-editing technologies.
With the rise of nucleic acid-based therapeutics, such as the mRNA vaccines, biopharma developers are working toward the next big breakthrough in personalized medicines. Over the past couple of years, the industry has seen more intense partnering activity between developers and biotech firms specializing in gene editing technologies. A look at the advances in gene editing technologies illuminates the strides gained in R&D enabling the next generation of precision medicine targets.
The approvals of Casgevy by the UK Medicines and Healthcare products Regulatory Agency (MHRA) in November 2023 (1) and FDA in December 2023 (2) mark a significant turning point in the biopharma industry. Casgevy is the first therapeutic based on clustered regularly interspaced palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) gene-editing technology to be approved by regulatory authorities anywhere in the world.
“The approval of Casgevy for sickle cell disease is a significant milestone for the industry and paves the way for a wave of gene-edited therapies, including those that leverage next-generation CRISPR-based technologies with potentially more efficient and precise genome editors,” says Tedd Elich, chief scientific officer, Life Edit Therapeutics, an ElevateBio company.
“The approval also establishes a regulatory path as more investigational therapies enter the clinic and aim to address a wider range of diseases,” Elich adds. He explains that this established roadmap is likely to yield increased attention and investment from the broader biopharmaceutical industry. An increase in investment will, in turn, further accelerate the development of novel gene-editing technologies and therapeutics.
“Most importantly,” Elich continues, “the approval of Casgevy is a monumental achievement for people living with sickle cell disease and other genetic diseases. The approval lays the groundwork for future gene-editing therapies to more specifically target—and potentially cure–disease.”
“I see the approvals for Casgevy as the opening of the flood gates for gene-editing technologies,” Kate E. Broderick, PhD, chief commercial officer, Maravai Lifesciences, affirms.
“Over 10 thousand monogenic diseases have been identified which could be positively impacted by this incredibly powerful technology, offering hope to patients with diseases [for] which, previously, symptom management was the only option.”
“There’s never been a more exciting time in medical science,” Michelle Fraser, PhD, head of Cell and Gene Therapy, Revvity, enthuses. “Casgevy is the first CRISPR-based gene therapy approved by [FDA] and UK MHRA, introducing a completely new class of therapeutic modality where the genetic cause of a disease can be permanently corrected, instead of merely treating the disease symptoms.”
Fraser points out that Casgevy, an autologous cell therapy, is the first of a healthy pipeline of CRISPR-based cell and gene therapies. “The promise of this class of therapies is a permanent reversal of the genetic cause of a range of inherited diseases and cancers,” she says.
“It’s hard to believe that CRISPR-based therapies were first used clinically only 11 years ago; the field is just getting started. As we understand more about the genetic cause of disease, gene editing technologies are rapidly evolving, offering new hope to patients by providing personalized, highly effective, and safe therapies,” Fraser notes.
Gene-editing technologies offer precision, and it is that precision that has allowed the creation of complex, biologically relevant disease models, emphasizes Fraser. These disease models have facilitated unprecedented, detailed investigations of the genetic causes of disease, she adds.
“The gene editing toolbox available today enables precise editing of coding and non-coding regions, and to edit multiple genes in the same cell to create realistic disease model cell lines.These cell lines can then be used to screen the safety and efficacy of drug candidates and understand their potential side effects,” Fraser explains.
In turn, an improved understanding of the genetic causes of disease and drug responsiveness has led to a new generation of precision diagnostics, under which a patient’s disease can be accurately diagnosed and an ideal drug treatment selected for that patient, Fraser reports.
“With the first regulatory approval of CRISPR-Cas9 gene therapies, the next phase of the precision medicine evolution has been realized—where an individual can be genotyped, their disease accurately diagnosed and characterized, and then specifically treated using gene editing.Genes can be turned on or off, reduced, elevated, or corrected using gene editing technologies,” Fraser adds.
Because gene editing technologies allow genetic material to be removed, added, or altered at a specific location in the genome, they allow companies to develop therapeutics directed at the underlying cause of disease for the most challenging genetic disorders—and otherwise intractable diseases, notes Elich, who also points out that many of these therapies also have the potential to be cures for these genetic disorders.
“Emerging gene-editing technologies across a range of modalities offer greater versatility for targeting genetic disorders and the potential to reach a wide range of patient populations,” Elich says. “This includes the full spectrum of editing modalities like we’re pursuing, including base editing and reverse transcriptase or prime editing, where the best editing approach can be matched to the disease.”
“The biotechnology and bio/pharmaceutical industries have seen significant progress in the advancement of technologies, and the first gene editing therapies are now being developed and approved—providing the first proof points for this new era of medicine,” Elich states.
Because of this newfound understanding of diseases with a genetic origin, the biopharma industry is realizing a re-emergence of personalized medicine, Elich continues. As such, the industry is making greater investments to further accelerate gene-editing technologies as well as establishing R&D collaborations with biotech companies that are at the cutting-edge of gene editing. Elich explains that, by specifically targeting an individual genetic mutation and addressing the underlying genetic defect, gene-editing therapies could potentially transform or cure disease for otherwise chronic and debilitating diseases.
“In addition to the approvals for Casgevy, this year has also shown some remarkable progress in the field of personalized cancer vaccines highlighting the impact that an individualized, tailored approach can have on the prognosis and survival outcomes for certain cancers,” says Broderick. “Like gene-editing where the treatment precisely and directly targets an individuals’ genes, personalized medicine takes the same approach—developing a bespoke treatment plan based on the individual’s genetic makeup.”
Meanwhile, Fraser explains that, traditionally, the bio/pharma industry created therapies that reduce the symptoms of a disease, and the modalities of these therapies have included small molecules and larger molecules, including antibodies and antibody drug conjugates. Often, however, patients need to take these drug therapies for prolonged periods of time or the rest of their life, and unwanted side effects are not uncommon.
“In this new era, gene editing is playing a pivotal role in the bio/pharma industry’s transition toward personalized medicines. The precision and specificity offered by gene-editing technologies, such as CRISPR, enable the tailoring of treatments to individual patients based on their unique genetic makeup. This approach allows for more targeted interventions, minimizing potential side effects and enhancing therapeutic outcomes,” Fraser says. “Whilst gene therapies are currently very expensive, the treatment is administered only once, changing the medical intervention and economic model for many otherwise chronic and life-threatening diseases.”
Looking toward the future, next-generation gene-editing technologies that are emerging include the “incredibly powerful” combination of RNA therapeutics (RNA guide and RNA- encoded nuclease) and CRISPR technology, says Broderick, who notes that this combination has the synergistic potential to impact genetic diseases that have previously had limited treatment options and challenging prognosis. “Utilizing next-generation delivery systems, such as cell targeting peptides, will allow these revolutionary therapeutics to reach their potential for disease outside just the blood,” she states.
Fraser discusses the original concept of applying CRISPR-Cas9 technology, which has been used to create a double-stranded DNA break and thereby disrupt gene function. This application has since led to newer generation base-editing and prime-editing systems that precisely correct the causative genetic mutation, she explains.
“Base editing relies on a partially active Cas enzyme to nick one of the DNA strands and a deaminase to introduce a controlled, specific single-base change on the opposing DNA strand at the target site,” Fraser continues, “Homology-directed DNA repair leads to a base change on the nicked DNA strand, altering both strands of DNA, for example, to correct a gene function.”
Meanwhile, prime editing uses a reverse transcriptase to insert a larger DNA template to, for example, introduce a functional copy of a defective gene, Fraser also explains. “Selection of the optimal editing system depends on the intended purpose.”
Fraser further explains that consideration is given to whether the need is for a single gene to be addressed, or multiple genes, or whether treatment requires changing a single base or introducing a larger genetic change—such as reducing the size of a repeat expansion. Other considerations include whether the target site is in close proximity to a protospacer-adjacent motif (PAM) sequence and therefore easily accessed, or if the target site is difficult-to-reach with no PAM sequence nearby, what degree of editing efficiency is needed to see a biological change, and the tolerability of the specific cell type to gene editing systems.
“There is no one-size-fits-all editing system,” Fraser asserts, “each has its own unique advantages and disadvantages. In the future, it is possible that multigene disorders may even be best addressed using a combination of editing systems delivered simultaneously.”
Diseases that could potentially see positive or further impact from the advancement of gene-editing technologies in the near future include cystic fibrosis, Huntington’s disease, phenylketonuria, and hemophilia, to name a few, says Broderick.
“However,” Broderick adds, “while the blood-based targets are moving forward rapidly, delivery challenges are hindering the progress to other tissues. Once more efficient and more directly targetable delivery modalities are co-developed, the full potential of gene-editing technologies will be realized.”
According to Fraser, using gene therapy to treat sickle cell disease marks the start of the next generation of personalized medicines. In her estimation, there are several diseases that are emerging as key focus areas, including:
Neurological disorders. Fraser notes that there are well-described genetic risks associated with the development of mature onset neurological conditions such as Alzheimer’s disease and Parkinson’s disease. Here, gene editing can play a role in targeted therapies to reduce these risks.
Cancer. Personalized medicine is being used in oncology to drive understanding of the underlying genetic mutations that cause a patient’s cancer and allow the tailoring of the treatment accordingly. In this area, gene editing is being used to create immunotherapies, such as chimeric antigen T (CAR-T) cells that turn the patient’s own immune response against the cancer cells.
Rare genetic disorders. Gene editing holds immense potential in addressing rare genetic diseases by correcting or modifying the faulty genes responsible for these conditions. As such, this approach goes beyond traditional treatments and offers a more targeted and effective solution that could be given prior to symptoms presenting, and perhaps even prior to birth.
Cardiovascular diseases. The use of personalized medicine in cardiovascular health involves diagnosing and then using gene-editing technologies to address genetic risk factors that influence heart disease.
Autoimmune disorders. Diseases such as rheumatoid arthritis and lupus are being explored through a personalized medicine lens, according to Fraser, who explains that understanding the individual’s genetic predisposition to developing an autoimmune disease allows for early intervention with tailored therapies. She notes that initial research has suggested that CAR-T cells created using gene editing may be an effective treatment.
Fraser goes on to say that gene-editing technologies, particularly CRISPR, play a crucial role in the evolution of personalized medicines by enabling precise modifications to the DNA code. These technologies “allow researchers to edit, add, or remove specific genes, addressing the root causes of diseases at the genetic level. This level of precision is essential for developing highly targeted and effective personalized medicines,” she states.
“As these technologies advance, they are likely to become integral in the development of a new wave of therapies that go beyond traditional cell and gene therapies, offering even more tailored and individualized treatment options,” Fraser concludes.
Elich adds that many companies are currently focusing on similar diseases, such as sickle cell disease, in which numerous corporate partnerships may already exist. “As gene editing technologies become more precise, and new CRISPR systems are discovered and engineered, we expect the pool of targetable diseases to increase significantly into more monogenic diseases and ultimately expand into polygenic diseases,” Elich states.
“With this evolution, we believe that gene editing is going to be central to new therapeutic development in the future, including gene-editing therapies to specifically target disease, as well as the mechanism driving engineered cell therapies. Each step and advancement in the gene editing field will bring us closer to true personalized medicine for patients,” Elich envisages.
1. Vertex Pharmaceuticals. Vertex and CRISPR Therapeutics Announce Authorization of the First CRISPR/Cas9 Gene-Edited Therapy, CASGEVY (exagamglogene autotemcel), by the United Kingdom MHRA for the Treatment of Sickle Cell Disease and Transfusion-Dependent Beta Thalassemia. Press Release, Nov. 16, 2023.
2. FDA. FDA Approves First Gene Therapies to Treat Patients with Sickle Cell Disease. Press Release, Dec. 8, 2023.
Feliza Mirasol is the science editor for BioPharm International.
Volume 37, No. 2
When referring to this article, please cite it as Mirasol, F. Milestone Approval to Steady Stream, Gene Editing Revs Up. BioPharm International 2024, 37 (2), 16–19,25.