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Heligenics: fulfilling the promise of the functional genome to enable precision medicine

The impact of genomic variation on drug effectiveness and resistance can be considerable, yet the functional and clinical effects of most genetic variants are largely unknown; conventional attempts to identify variants through clinical associations with disease or drug therapy are slow. Fortunately, the cutting-edge biotech company Heligenics has the solution and is on a mission to prevent, diagnose and treat illness through advanced experimental analysis of the function of genetic variation.

Heligenics has developed a first-of-its-kind platform to concurrently and precisely determine the functional and clinical impact of huge numbers of genetic changes, including the vast number of variants of unknown significance. Using its synthetic gene-mutation libraries and one-pot single-cell GigaAssay technology, the company can generate over a million variants in any region of the genome. The functional and clinical effect of each is accurately measured to produce comprehensive Mutational Effect on Gene Activity Maps (MEGA-Maps).

“In just four to five months, we can simultaneously measure how all possible single-nucleotide or other variants in a gene affect the molecular function or process in a live human cell,” explained Martin Schiller, CEO. “It takes other technologies decades to identify just a single marker. To date, there are no other commercialized high-throughput functional-genomic assays that assess biological function.”

This flexible platform is disrupting and redefining genetic diagnostics and drug discovery by using genetic information at each step along the drug development pipeline. By determining the function of genetic variants, the GigaAssay/MEGA-Map technology can be harnessed for wide-ranging applications, such as biologic lead screening, improved diagnostics, re-designing clinical trials, and training artificial intelligence.

Directing optimal drug treatment with companion diagnostics

Heligenics has developed a revolutionary new product in which its GigaAssay/MEGA-Map technology is used to map drug resistance for companion diagnostics, powering precision prescriptions with whole-gene drug-resistance profiling.

Genetic testing is used for diagnosis and to guide treatment in current clinical oncology practice. However, few patients benefit because most approved precision drugs target a single genetic variant despite the likelihood that many other variants have a similar impact on gene function and disease. Moreover, although many patients eventually die from acquiring resistance to a drug, there is no systematic approach to identifying the variants that cause target-derived drug resistance.

Heligenics has the solution: using MEGA-Maps from cells treated or not treated with drugs to comprehensively identify all resistance mutations in a drug target in just months instead of years. “By identifying resistance and connecting cancer patients with targeted therapies, we can select among different drugs for more effective data-driven treatment,” said Schiller.

For example, in human epidermal growth factor receptor family positive (HER+) breast cancer, Heligenics has generated a MEGA-Map for variants in the drug target and produced a comprehensive clinical-decision tree (Fig. 1). A biopsy can be sequenced for the HER2 gene, guiding treatment with the appropriate drug. “The beauty is that the patient can be re-biopsied a few months later to see if they have acquired resistance to the drug they are being treated with and, if so, treatment can be modified/redirected according to the clinical-decision tree,” explained Schiller. “Our MEGA-Maps allow patients to be continually monitored and their treatment adjusted. This has never been done before.”

Application of Heligenics’ technology for selecting optimal drug treatment

Fig. 1 | Application of Heligenics’ technology for selecting optimal drug treatment. The example shows potential treatment options for cancer with Her2 variants. The decision tree is based on Her2 variants for susceptibility and resistance to three drugs: LAP, Tykerb (laptinab); NER, Nerlynx (neratinib); TUC, Tukysa (tucatinib).

Super-precision clinical trials

Genetic variation can often limit the efficacy of a given drug but trying to identify all variants of concern during clinical testing is very laborious. Consequently, problematic variants may sometimes be discovered only after an expensive clinical trial fails. Heligenics, however, can identify all missense genotypes that are sensitive to a drug, eliminating many non-responders before a clinical trial begins. Using these comprehensive genetic data to stratify patients can rescue a failed conventional trial, expand a conventional targeted trial (previously focussed on just a single variant), and/or convert failed traditional drugs to approved targeted therapies. “This is a new data-driven approach to precision clinical-trial design that improves efficacy, reduces risk and increases success,” said Schiller.

Improving existing biologics

There are likely many variants of native biologics that have stronger therapeutic activities, but conventional approaches to identify them are limited. Heligenics, however, can use GigaAssay/MEGA-Map technology to mutagenize an existing biologic drug and test ~10,000 variants against its exact cell-physiological activity. This way, it can identify variants that outperform the existing drug with, for example, increased half-life or stronger biological activity—a disruptive approach that enables the rapid development of new biosimilars and biobetters.

Partnering

Heligenics is currently partnering with The Jackson Laboratory (Bar Harbor, Maine, USA) for Her2 diagnostics, and is seeking partners to conduct clinical trials on new diagnostics and biologics or for licensing some of its existing completed products. By connecting variants to health, Heligenics’ products are set to transform the medical industry.

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