Contributing to the neurodegenerative disease space, AC Immune is a clinical-stage biopharmaceutical company leveraging its proprietary SupraAntigen and Morphomer technologies to generate highly specific biologics and small molecule drugs for Alzheimer’s disease, Parkinson’s disease, and certain rare indications. “The neurodegenerative field is moving towards precision science and diagnostics,” commented Andrea Pfeifer, the company’s CEO. “Identifying and targeting these misfolded proteins and related pathways in patients will be key to achieving the best possible treatment.”

Ultimately, as is the case across the board for companies developing novel therapeutics, their molecules must pass the test of receiving regulatory approval. According to Robert Fremeau, chief scientific officer of Vyant Bio, CNS-related treatments face a particular challenge: “Most drugs fail in the clinic not because of toxicity or safety concerns, but due to a lack of efficacy. This is especially true for CNS drugs where the available animal models have such poor predictive validity.”

For this reason, Vyant Bio has a drug discovery platform that combines human patient-derived organoid models of brain disease with machine learning. The company believes its human-first approach is better suited for the discovery of complex neurological and neurodegenerative disorders. As Jay Roberts, president and CEO of the company noted, “there is an emerging trend of using very innovative technologies including data science, AI, and machine learning, combined with strong biological systems. Combining science and strong biology allows for good decision making around identifying therapeutics that ultimately will become safe and effective treatments for patients.”

As CNS-related disorders continue to pose significant unmet medical needs, companies leveraging innovative technologies are pushing the needle forward.

Covid-19 provokes innovation in cell and gene therapy

Cell and gene therapies and gene editing tools such as CRISPR have progressed significantly over the past several years, but the pandemic created a sense of urgency that boosted funding from governments and private investors, as well as introduced the field into public discourse. As Covid-19 vaccines first rolled out, innovative techniques such as mRNA technologies became a part of household conversation for the first time. Most experts agree the pandemic created such a need for both the regulatory approval and implementation for this type of vaccine that the field leapfrogged a decade’s worth of progress.

When news about Covid-19 vaccines first reached the public, many onlookers did not understand the science and formed hasty conclusions about their safety. The main point of confusion regarded the fact that mRNA vaccines are incapable of altering the patient’s genetic material as the mRNA content never enters the nucleus of the cell where DNA is located. Some people were also confused about the use of viruses in the form of viral vectors, which are a popular part of a molecular biologist’s toolbox when looking to deliver genetic material into cells.

Janssen Pharmaceuticals’ Covid-19 vaccine program leveraged the company’s AdVac technology, which is based on the development and production of adenovirus vectors. “Adenovirus vectors are genetically altered forms of an adenovirus that lack the DNA needed to replicate, so the vaccine cannot cause a cold,” explained Candice Long, president of US infectious diseases and vaccines at the company. “In the case of the Covid-19 vaccine, the immune system of someone who receives our vaccine recognizes the Covid spike protein as foreign once it enters their cells, producing antibodies and activating T cells to target it. This allows the individual’s immune system to recognize the SARS-CoV-2 spike protein and be ready to defend against it.”

While some people remained skeptical, many recognized the pandemic and rapid deployment of such vaccines to be valuable insight into the future of inoculations. As Faith Salamon, a Pfizer spokesperson noted, their company will build off its current mRNA technology in the exploration of other programs: “The approval of the first mRNA-based Covid-19 vaccines was a scientific turning point, establishing mRNA as a versatile, flexible technology. The focus and drive Pfizer gave to developing our Covid-19 vaccine in partnership with BioNTech gave us a wealth of scientific knowledge in just one year. Pfizer’s next wave of mRNA scientific innovation is expanding in the infectious disease arena with development programs in flu (influenza) and shingles, also exploring its versatility in the areas of rare genetic diseases.”

Taking the approach to the next level, Arcturus Therapeutics, a late-stage clinical messenger RNA vaccine and therapeutics company, saw benefits in bringing self-amplifying mRNA into the development of a Covid-19 vaccine. mRNA vaccines that enter the recipient’s body via intramuscular injection express an antigen that provokes an immune response. Conventional mRNA vaccines elicit an antigen expression period of only few days before the mRNA molecule degrades. Self-amplifying mRNA, on the other hand, produces a longer expression period, allowing for dose levels to be dramatically lower. Arcturus Therapeutics’ lead Covid-19 vaccine candidate has only 5 micrograms per dose, for example. The lowering of dose levels helps reduce safety risks associated with higher doses. It also makes vaccines faster and more efficient to manufacture at scale.

Joseph Payne, the company’s president and CEO, sees promise in the speed at which the space is evolving. “Over the last two years, we moved swiftly from conventional mRNA to self-amplifying mRNA, as opposed to each one taking 10 years to develop and implement,” he explained. “We hope the self-amplifying mRNA will be a more durable vaccine with broader variant coverage, which is desirable as we transition into an endemic booster market.”

Covid-related advancements are also being made within the gene editing space. Mammoth Biosciences has pioneered work with CRISPR-based diagnostics and is working to augment the toolbox of CRISPR proteins to provide novel delivery possibilities. According to the company’s CEO Trevor Martin, CRISPR can be used as a search engine for biology in the sense that CRISPR proteins can be programmed with a guide RNA that targets a specific genetic sequence before using its built-in scissors to edit the genes in question.

Mammoth Biosciences had been interested in the realm of CRISPR-based diagnostics since its founding and was able to leverage its previous work to help combat the spread of the virus. “While it was impossible to have foreseen Covid-19 as a specific target, we always believed in the accessibility of testing for infectious diseases,” explained Martin. “Hence, leveraging the technology to address the pandemic was a natural progression, evidenced by how quickly we published the first available data of a CRISPR-based test for Covid-19.”

Martin is optimistic about the potential impact of this type of testing not only for Covid-19 but also for future pandemics, given the broad accessibility the platform offers. Additionally, CRISPR-based diagnostics can be created quickly in response to new variants.

The power of cell and gene therapies also lies in malleability. Speaking of the power of miRNA in particular, Roel Schaapveld, CEO of InteRNA Technologies, a clinical-stage biotech company developing a pipeline of RNA therapeutics to target human diseases like cancer, acknowledged: “Humans have approximately 2,000 microRNA’s regulating the expression of 20,000 genes. In theory, one microRNA can regulate 100 mRNA’s at the same time by recognizing a binding site in the mRNAs it is regulating and thereby influencing their respective translation to proteins.”

To accommodate the rise in cell and gene therapies, there are CDMOs that specialize in this line of work. Forge Biologics, for example, is currently working to expand its adeno-associated virus (AAV) manufacturing capabilities to better enable its clients to speed to the clinic. Timothy J. Miller, the company’s CEO and president, anticipates increased growth. “I believe that in 2022 we will see more good stories come out in gene therapy, such as therapies getting approved, more approvals for reimbursement, and more positive clinical data coming out,” he said. “AAV trials represent over 70% of the ongoing gene therapy trials, and thus, as a modality, AAV manufacturing is at a premium.”

Covid-19 advanced cell and gene therapy by at least a decade, leading to an array of companies working in a wide range of therapeutic areas. With this push, the field will remain a hotbed for innovation once the pandemic has subsided.

The power of proteins

One way to unlock the power of proteins is to work with them directly. Chris Larson recognized that while proteins execute vast amounts of cellular functions, the cell’s genome only codes for a few protein primary sequences. He helped found SNO bio to unlock the potential for drugs to manipulate the addition or removal of protein S-nitrosylation (SNO), as malfunctions in the protein can result in disease.

Larson sees immense potential in the enzymes from his company’s target discovery platform. “Nature needs mechanisms to generate sufficient size and diversity in its protein tool kit to accomplish the huge variety of functions they need to execute,” he explained. “Protein post translational modification provides this, driving the total number of different proteins in a cell over 1,000,000.”

Proteins can also play a major role in fighting viruses, as discovered by Evrys Bio. Founded on discoveries from Princeton University that took a novel approach to antiviral therapy, the company’s scientific focuses is on sirtuins, signaling proteins involved in metabolic regulation that help with intrinsic immunity on a cellular level. “Throughout evolution, cells have had to defend themselves against foreign DNA from viruses, and sirtuins are part of the cell's natural defense,” explained president and CEO Lillian Chiang.

According to Chiang, two critical properties arise as a result of engaging the natural defenses of the cell: first, the unique approach seems to be effective against a variety of virus types, meaning treatment does not have to be designed down to the strain and can provide broad-spectrum coverage. Second, a sirtuin-based approach helps avoid the problem of virus mutations. This means that Evrys Bio’s antiviral treatments have the potential to be broadly prescribed without the same worry for drug resistance.

As the industry invests in understanding the nuances of proteins and protein manipulation within the human body, our ability to use this approach towards treatment opens new doors to advancing the standard of care across a variety of therapeutic areas.

Image courtesy of AC Immune