Changing a living organism’s DNA sounds like something out of science fiction, but recent strides in genome (gene) editing have given scientists exactly that ability. Through gene editing processes, genetic material can be added, removed, or changed in specific locations.
The most recently developed of the gene editing methods, CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats), is increasingly used. This system offers novel solutions for several scientific fields. It’s generating an excited buzz among scientists worldwide.Learn more about the history and science behind CRISPR.
While development and application of CRISPR is an important step in treating a variety of disease indications within the clinical development industry, its recency leaves room for much to change. Where is CRISPR technology headed as it’s used in more treatments? To find out, we spoke with Amy Raymond, PhD, Director of Therapeutic Expertise, Center for Rare Diseases and Jim Wise, VP, Head of Center for Immuno-Oncology, Cellular, & Gene Therapy.
What implications does CRISPR have for clinical research?
AR: In this fairly early wave of clinical trials using CRISPR technology, we see several platforms that minimize risk and potential exposure to trial participants by applying the technology to patient cells outside the body, then returning these gene edited cells to the participant. To oversimplify, they perform the following steps:
- Remove cells from the disease patient
- Edit the cells outside of the patient (ex-vivo) using CRISPR/Cas technology
- Returning the cells to the patient
In some ways, executing these types of trials leverages all of the logistics and expertise from cell therapies in the Immuno-oncology space. Trial success relies mainly upon two things. The first is partnering with the subset of clinical research sites who have the facilities and capabilities to execute these trials. The second is applying specialists, such as our Cell Therapy Logistics Coordinators, to drive the fine details that have essentially no margin for error in sample management and transport. That said, not all of the early CRISPR-based treatments in development are cell-based therapies. We’re seeing in-vivo treatments (which will not be a cell therapy type of treatment) moving into the clinic.
It’s expected that patient populations with high unmet need, especially rare disease and oncology patient communities, will be the first beneficiaries of this technology. We will collectively learn more about the safety profile of the techniques from current and upcoming trials. Just as important, though, dedicated scientists such as David Liu and Feng Zheng and countless others continue to mature the technology, expanding and refining these tools. They are the ones driving this translation from the research bench to the research clinic.
JW: CRISPR technologies are being used in drugs studied globally, yet country regulations and reviewing bodies all have their own requirements and considerations for these types of drugs. There is no one global standard. This means that sponsors and CROs must digest and navigate those differences carefully as they solicit scientific review, submit clinical trial applications, monitor long term patient (and population) safety, and design their commercial platforms.
What has CRISPR changed in terms of drug development?
AR: Just as regulators and patient families weigh the risk/benefit of allowing or taking part in any clinical trial, drug developers also weigh the potential benefits of a new treatment against the probability that it will truly be safe and effective.
With the development of CRISPR/Cas systems, drug developers have tools for editing DNA and RNA with high specificity. These tools reduce the chances of an unintended change in the DNA, which could potentially lead to an unintended consequence. Also, the original gene editing techniques didn’t have the ability to edit RNA.
Now that we’re able to edit RNA, we’re able to alter the protein being expressed by a gene without necessarily changing the heritable DNA. Moreover, CRISPR/Cas systems are highly efficient and lower in cost than some predecessor technologies. Using the CRISPR/Cas system brings all of the goals of gene editing closer to reality while lowering risks.
There are loads of diseases with a known genetic driver—one that may be inherited or one that may be unique to that patient—all of which become more addressable with a more powerful gene editing technique. CRISPR may or may not address all of the challenges around gene editing. Time will tell, but it’s leap forward in terms of capability.
What are the biggest limitations to the adoption of CRISPR to mainstream healthcare?
AR: In some ways, the use of CRISPR doesn’t really change our fundamental challenge: to answer whether an experimental treatment of any kind is safe and effective. However, in this context it becomes critical that we collect the appropriate long-term data to capture later adverse events, especially ones which could be associated with the treatment.
With the potential for a durable treatment, the drug development community is always rightly concerned about durable adverse events potentially associated with the treatment. Only data can guide us there. There isn’t necessarily a limitation to adoption at this stage—it’s more a need to test these treatments which leverage CRISPR/Cas thoughtfully and completely. This is true whether the treatment is a CRISPR-modified cell or whether CRISPR is the treatment itself.
Drug developers of today benefit from what we’ve learned along the way. This includes developing AAV-mediated gene therapies—especially in terms of how savvy regulatory bodies have become—and making patient education a part of any patient-centered treatment.
Just a few years ago, gene replacement therapies seemed like science fiction. Now, those treatments are receiving approval for use in major markets. I have every confidence that regulators will weigh the data collected in current and upcoming trials on its merits. When/if the data supports it, those regulators will likewise approve CRISPR-based therapies for marketing approval. The only real barrier is collection of high-quality data to reflect the true value of the intervention for intended treatment—a barrier all experts agree should be in place.
Besides the therapeutic areas like cancer and rare disease, where CRISPR is already being used in clinical trials, where do you see CRISPR headed in the future? How wide of an impact will it have?
AR: The forerunner gene editing methods, such as transcription activator-like effector nucleases (TALENs) and zinc-finger nucleases (ZFNs) are still being used in clinical development. However, programs leveraging CRISPR/Cas technology are proliferating rapidly as we speak.
The use cases that are furthest along are indeed rare diseases (across several therapeutic areas) and oncology. We can definitely say the pre-clinical evidence is compelling—regulators are satisfied that development of these treatments humans is warranted, and that the long-term follow up data will provide an additional layer of understanding once efficacy has been determined.
The fundamental ethical drivers of Good Clinical Practice look at the risk/benefit ratio of any new treatment. Patient communities who stand the most to gain are the ones who face the most dire health consequences because they don’t have sufficiently effective treatments. That’s where we expect to see development focus initially.
This lack of meaningful treatments is a dilemma for many rare diseases, as well as cancer patients who fail to respond to proven treatments (“refractory” patients) or have a disease recur after receiving a treatment that was effective for them before (“relapsed” patients).
The therapeutic areas with the greatest CRISPR-based treatment development are:
Ongoing or upcoming clinical trials in the following therapeutic areas:
- Cardiovascular diseases
- Ophthalmology (Corneal Transplantation in the Treatment of Refractory Viral Keratitis; also, rare disease Leber Congenital Amaurosis 10 - this is one of the few examples of in-vivo CRISPR-based therapy)
- Non-Malignant Hematology (rare disease hemoglobinopathies of Beta Thalassemia and Sickle Cell Disease)
- Malignant Hematology (Relapsed/Refractory Leukemia or Lymphoma)
- Oncology (such as Metastatic Gastrointestinal Epithelial Cancer, Renal Cell Carcinoma)
Pre-clinical programs meant to lead to future clinical development programs:
- More Cardiovascular diseases (ischemic heart conditions)
- Metabolic disorders (rare diseases such as Hereditary Tyrosinemia Type I and Alpha-1 Antitrypsin Deficiency)
- Infectious Diseases (HIV, Herpes Simplex Virus)
- Immune (severe Congenital Neutropenia)
- Additional indications in Malignant Hematology and Oncology (ie, Hepatocellular carcinoma, etc)
- Many, many more
How will companies like PRA keep pace with CRISPR as it’s tested and added to more treatments?
JW: PRA has adapted by bolstering our regulatory understanding of the implications of gene-edited drug platforms. We’ve also established operational solutions that can accommodate the complex supply chain logistics management required. Specialty courier vendors have even stepped up with highly customized services that meet the needs of transporting these drug products.
The ways in which PRA and sponsors work together across manufacturing, logistics, and operations strategies is of critical importance. Due to CRISPR-enabled therapeutics, a new paradigm has been established specific to the Cell and Gene Therapy (CGT) space that is expanding rapidly. There are also a host of other things we have had to adapt to as an industry, such as patient education and consenting for trials that involve gene edited drugs.
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