Danaher Corporation

Demaris Mills

Sickle cell disease (SCD) is an inherited disorder of the red blood cells where abnormal sickle-shaped red blood cells clump together to block capillaries and deprive tissues and organs of oxygen, resulting in cellular damage and severe pain. “Pain crises” are the most common cause of hospitalization for people with SCD, with many frequently spending days, weeks, or even months in the hospital [3]. Without treatment, SCD can lead to serious complications such as organ damage, pulmonary hypertension, and heart failure [4]. Currently, the only curative treatment for SCD is hematopoietic stem cell transplantation [5]; however, more than 80 percent of patients do not have a matched donor.

Scientists are researching new potential cell and gene therapies based on novel genetic technologies, including CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats) gene editing to target disease-related genes identified using next generation sequencing (NGS). For instance, Dr. Matthew Porteus and his research team at Stanford Medicine are pioneering the development of CRISPR-Cas9 based approaches into genomic medicines for SCD and beta-thalassemia, another inherited blood disorder [6,7]. Similarly, the Hendel Lab headed by Dr. Ayal Hendel at Bar Ilan University in Israel is developing CRISPR-Cas9 based genome editing as a curative therapy for genetic diseases, focusing on hematopoietic genetic disorders such as severe combined immunodeficiency (SCID) [8].

Alongside the development of new therapies for individuals with rare and orphan diseases, genomic medicines are also being developed for people with more common diseases, such as cancer. Dr. Katy Rezvani and her lab are looking into whether CRISPR-Cas9 gene editing can be used to further modify and improve the effectiveness of natural killer cells already engineered with chimeric antigen receptors (CAR-Ts) [9,10]. At Integrated DNA Technologies (IDT), we have worked with many translational medicine developers, including all three of the researchers just mentioned, and are witnessing first-hand how rapidly genomic medicine is evolving, with new approaches being considered all the time.

Challenges still hinder the genomic medicine revolution

As promising as these genetic-based therapeutic approaches seem, several key hurdles must still be overcome before we can realize the full potential of the genomic medicine revolution. A critical issue is how to address the broad range of scales required for manufacturing clinical grade genomic medicines, from as little as a one-shot treatment personalized for a single patient to billions of vaccine doses for the world’s population. The requirement to be able to simultaneously scale out and up is a serious challenge for biopharmaceutical companies.

Traditionally, the main business model of pharma and biopharma companies relies on the economies of scale gained by increasing the manufacture and distribution of drugs to large markets. But what if the market is comprised of just one patient? Biopharmaceutical companies are now exploring how they can meet the needs of a single patient or small groups of patients who can be treated with medicines required only in small scales, such as with autologous cell therapies, antisense oligonucleotide therapies, RNA interference therapies, or CRISPR-based therapies. An obvious answer is the achievement of economies of scope, where the same know-how, methodologies, and equipment can be used to produce a raft of similar yet different medicines. This is particularly feasible with genomic medicines, as they rely on nucleic acid sequences that are eminently programmable by nature.

Another important aspect of genomic medicine that is continually being assessed is the incidence and impact of off-target effects (OTEs). Improving the specificity of CRISPR genome editing and other genomic medicine technologies to minimize OTEs is an important goal, with tools constantly being developed and refined for in silico, in vitro and, finally, in vivo experiments [11]. Similarly, methods continue to be developed and improved to enable more specific genetic and genomic engineering, for instance, to knock-in genes as well as knock them out, with high specificity and efficiency [12].

Collaboration is the key to expediting the genomic medicine revolution

Some of these tools have been provided by companies like IDT once these needs have been determined, often through collaborations with researchers in the field. It was by collaborating with Dr. Ayal Hendel that we developed a new research-use-only strategy for the quantification of multiple CRISPR-Cas9 off-target sites in a single assay using rhAmpSeq™ technology (it is not intended for clinical or therapeutic applications) [13]. Similarly, we worked with Dr. Bill Skarnes and his team from The Jackson Laboratory (JAX) on refining their iPSC genome editing methods, using IDT’s homology-directed repair (HDR) reagents and Design Tool [14,15]. This HDR Design Tool is also now proving invaluable for research led by Dr. Anand Narayanan and his collaborators where genes are precisely knocked-in rather than out using CRISPR. The findings of this research are expected to inform the development of translational medicine studies aimed at advancing personalized medicine [12].

Collaboration has also proven vital for the development and refinement of fundamental elements of CRISPR technologies. For example, development of our high-fidelity Alt-R™ HiFi Cas9 nuclease was tested with Dr. Porteus in real-world preclinical experiments in a cellular model of SCD [16]. Moreover, IDT has partnered with Aldevron to supply a Good Manufacturing Practice (GMP) grade of the enzyme for clinical use, which is being employed in clinical trials by Dr. Porteus [17]. We are not only working with frontline physician scientists and academics providing core services, we are also partnering with other companies, such as 10X Genomics, which is striving to provide new solutions that will help researchers unravel the mysteries of disease and better intervene to treat or even prevent them.

"It is heart breaking to see my child go through this. When my son was five years old, he had a sickle cell crisis and the doctors told me that he might have a 50/50 chance of surviving. My heart just broke in half,” said the eight-year-old boy’s mother"

The role of vendor and core service companies is evolving. Pharma and biopharma companies increasingly outsource and turn to external providers for advice and solutions regarding support for research, ranging from basic life science experiments in silico at the therapeutic target and drug discovery phases through to in vivo studies at the translational medicine stage. As such, companies like as ours are recognizing expanded responsibilities in the biopharma ecosystem. For us, this includes supporting the next generation of scientists by helping with education and volunteering at schools and universities.

Ultimately, and even more so since the pandemic, many companies and other stakeholders have realized how much can be achieved through close and continued collaboration. We need to continue fostering this, especially if we are to make progress in our goal of developing the myriad of genomic medicines needed to treat patients who suffer from rare and orphan diseases, as well as the millions worldwide who live with chronic and common conditions.