Sangamo Therapeutics is a leader in translating ground-breaking science into genomic therapies that can have a major impact on patients who are suffering from genetic diseases. Sangamo has developed strong capabilities in gene therapy and editing to produce therapeutics proteins to generate new types of therapies. Leading Sangamo in this cutting-edge new medicine is president and CEO Sandy Macrae, M.D.

Macrae has had a long career in drug development, including various executive roles at GlaxoSmithKline (GSK), such as Senior Vice President, Emerging Markets Research and Development. In that position, he helped create a first-of-its-kind group to expand GSK’s global reach by providing R&D strategies, clinical development, and regulatory resources to enter emerging markets and Asia-Pacific. Macrae also served as Vice President, Business Development at GSK, where he was responsible for scientific assessment and business development project leadership for the neurology, psychiatry, cardiovascular, and metabolic therapeutic areas. Earlier in his career, he worked for SmithKline Beecham, where he was responsible for clinical development in the therapeutic areas of neurology and gastroenterology.

WuXi AppTec Communications, as part of a new industry series, recently interviewed Macrae about the clinical direction and goals of Sangamo, as well as what the future looks like for this new ground-breaking treatment.

WuXi: What diseases are best treated with therapeutic gene editing and how will Sangamo play a role on the field’s advancement?

Sandy Macrae: Therapeutic gene editing is a new approach to medicine that we expect will transform the standard of care for many debilitating genetic diseases. Genome editing technologies like Sangamo’s zinc finger nucleases (ZFNs) are currently being applied toward monogenic diseases, which caused by a single gene defect, with significant unmet medical need.

Sangamo scientists have developed expertise across a range of genomic therapeutic areas, including gene therapy, gene regulation and cell therapy, in addition to genome editing. With our technology, we also see opportunities to treat diseases such as sickle cell disease and beta thalassemia through gene edited stem cells. There is great potential for neurodegenerative diseases as well. In Huntington’s disease, for example, we can use zinc finger protein transcription factors to specifically downregulate the longer, mutant huntingtin gene allele responsible for causing the disease, while leaving the normal functioning copy of huntingtin untouched.

WuXi: What is unique about Sangamo’s technology platform?

Sandy Macrae: You may remember our scientists publishing the first demonstrations of endogenous gene editing in mammalian cells, and in vivo for disease model animals, using ZFNs. Around the same time, and this may be surprising to some, Sangamo scientists also published the first high-efficiency TAL nuclease (TALEN) architecture, which remains in use across the field.

Due to clinical advantages in specificity and greater targeting flexibility, Sangamo chose to focus therapeutic programs on zinc finger proteins — specifically on ZFNs and zinc finger protein transcription factors (ZFP-TFs) for targeted gene regulation. Today’s zinc finger protein platform is markedly more advanced in terms of performance and speed of development. We can target any chosen base pair in the human genome and with off-target cleavage reduced to levels that are at or below the limit of detection, even under conditions of very high on-target activity. More importantly, these results are achievable at clinical scale, using clinical delivery conditions, and in clinically relevant cell types.

Engineering ZFNs is now fast and straightforward. With our existing catalog of several thousand zinc finger motifs, we can precisely target 60% of sites in the human genome within 10 days. Through an iterative process of molecular engineering and on-target and off-target performance analysis, we can deliver an optimized pair of highly specific ZFNs that can target any chosen base pair in the human genome within approximately one month, with high levels of gene editing efficiency and undetectable off-target activity.

However, Sangamo is not solely a genome editing company. We have also developed best-in-class capabilities in the areas of cell and gene therapy, enabling us to address life-threatening genetic diseases with the best therapeutic approach for a given indication. Our lead gene therapy for hemophilia A, SB-525, was recently licensed by Pfizer, and a Phase I/II clinical trial is currently underway.

WuXi: How does your company’s approach differ from other companies in the gene editing field?

Sandy Macrae: We are pleased to see the energy and investment around CRISPR. Genome editing is a new field of medicine, and its future will be driven by many different gene editing tools, including Sangamo’s zinc finger nucleases, many variations of CRISPR/Cas systems, TALENs, and likely new approaches that have not yet been reported.

While CRISPR has enabled remarkable progress in bench research applications, clinical applications have different requirements. This is where ZFNs have distinct advantages. We can target a cleavage event to any chosen base pair in the genome or, if not there, the immediate base pair next to it. This is compared to one site in every 10 to 30 base pairs with CRISPR variants.

WuXi: Can you give us an update on Sangamo’s clinical trials?

Sandy Macrae: We recently initiated three clinical trials of in vivo genome editing for people living with hemophilia B, MPS I (Hurler syndrome) and MPS II (Hunter syndrome). All three diseases result from a gene mutation leading to an absent or poorly expressed protein. Our ZFN-based therapeutics, delivered as a one-time intravenous dose, will permanently insert a functional gene encoding the missing protein into a specific site within the albumin gene of hepatocytes (liver cells). The new gene will produce and excrete the therapeutic protein from a small percentage of ZFN-modified hepatocytes for the rest of those people’s lives.

This will mark the first time a human will have a new gene inserted precisely into the genome of their own cells. If we are successful, we’ll open the door to the next frontier of medicine, where genome editing is a viable therapeutic approach to curing many other diseases. This is at the cutting edge of molecular medicine, and it is our responsibility to do it carefully and thoughtfully, and to take our time to ensure the safety of the patients we are trying to serve.

We are excited that this protein replacement strategy using the powerful albumin promoter represents an easily extensible approach to treat many conditions caused by a missing protein. Just as in these three trials, we can use the same pair of ZFNs to target the same site of the albumin gene and only change the therapeutic gene payload to be inserted into this specific site in order to treat a different disease.

WuXi: How do global partnerships enhance your pipeline?

Sandy Macrae: Our pipeline is focused on rare genetic diseases, starting with our lead clinical programs in hemophilia A, hemophilia B, MPS I and MPS II. Behind that are pre-IND programs including gene therapy for Fabry disease and autologous stem cell programs for beta thalassemia and sickle cell disease. We also have pre-clinical research ongoing in CNS diseases and oncology.

We are focused on indications with a few hundred to a few thousand patients. For indications with greater numbers of patients, where large trials and significant investment are required, we will partner with the right companies. In oncology, we have the ability to edit T-cells which could be an interesting approach for allogeneic T-cell therapies. In central nervous system (CNS), we have zinc finger protein transcription factors (ZFP-TFs) to turn down the expression of the tau gene which is implicated in Alzheimer’s and other tauopathies. Preclinical animal data for our ZFP-TFs indicate it may be possible to control the Alzheimer’s or dementia process by significantly reducing all forms of tau protein in several regions of the brain. Similar to other companies with strong research platforms, we open our technical expertise to partners who bring therapeutic specific disease area expertise and a common desire to deliver medicines that will transform patients’ lives.

We recently signed the largest deal for a gene therapy, licensing our lead hemophilia A program and several follow-on hemophilia A gene therapies to Pfizer for $70 million upfront, an additional $475 million in milestone payments, and royalties. We have a strong partnership with Bioverativ to develop cell therapies for beta thalassemia and sickle cell disease by reactivating fetal hemoglobin using our genome editing capability in stem cells. Shire is also partnered with us to treat Huntington’s disease, using our ZFP-TFs to selectively downregulate the longer, mutant huntingtin allele.

WuXi: How will gene editing technology evolve over the next five years?

Sandy Macrae: We will see in clinical trials a deeper understanding of the therapeutic potential for genome editing, as well as the clinical requirements and risks for its use. What will allow the field of genomic medicine to truly take off, however, is innovation around delivery. At the moment, we all use AAVs with strong tropism to certain organs, for example the liver. Resolving specific delivery mechanisms to other tissues will open other diseases to gene editing. We are on the cusp of having new vectors that can take us into the CNS, so companies such as Sangamo that can modulate expression of tau protein, for example. Cystic fibrosis is another disease amenable to gene editing, but what remains to be solved is delivery to the lung, past the mucus, and then to stem cells. The focus now is on delivery – how you can get your editing technology to the right tissue.

The moment we can deliver our zinc finger proteins to tissues beyond the liver, the therapeutic potential of genome editing opens up dramatically. We are working on novel AAV serotypes and also on lipid nanoparticles that can potentially improve safety profiles and enable repeat dosing.

WuXi: What will the pricing look like for this field?

Sandy Macrae: This is such a transformative technology and way of practicing medicine that we should focus on creating these therapies for real unmet medical needs and not dwell on the specifics of reimbursement for the time being. We believe the funding will naturally follow if we are successful in creating valuable new medicines.

Let’s take hemophilia for instance. The lifetime economic burden of obtaining factor alone is $6 million, which doesn’t include time in the hospital, doctor visits or work hours lost. A one-time infusion for long-lasting gene therapy, or a permanent solution in the case of genome editing, would deliver clear benefits.

The commercialization model will eventually need to be addressed, and the medical community will find a solution once we cross that road. At that point, this also means that society will need to carefully consider how we view medicines that give you a cure for life as opposed to something you must take on a regular basis.

WuXi: What are the major challenges you face in helping patients understand how gene editing therapies will impact their health?

Sandy Macrae: As a physician, I have a responsibility to the patient and his or her family to ensure they understand how the treatment works and the risks it presents. This involves significant work on the part of companies like Sangamo, and not just in educational efforts. We need to prove that in vivo genome editing therapy is safe, effective, and has been exhaustively studied in pursuit of “unknown unknowns.” It’s crucial that patients and their advocacy groups are involved in this process. The Mucopolysaccharidoses (MPS) patient groups, in particular, are eager to see genome editing progress and are enthusiastic about contributing to discussions about for whom and when this therapeutic approach should be considered.

However, patients and clinicians must be guided in understanding that gene editing won’t be as simple as a typical prescription. Gene editing adds a new layer of complexity to decisions on a course of care, and thus will require more careful and deliberate planning. Although there is excitement in where the field is headed, as rightly there should be, we must also remain sensible and remember that this is a completely new form of treatment. We must take a long-term view, and rise above excitement to ensure patients are protected.