An Integrated Approach to Non-Viral Gene Therapy for Serious and Rare Diseases
SmartPharm Therapeutics is a second-generation gene-encoded therapeutics company that has benefited from the first decades of learning in gene therapy development to produce an evolved therapeutic platform. We integrate these insights with key technologies and engineering capabilities to enable us to produce optimal gene-encoded therapeutics for patients.
Biologics from within
“At SmartPharm, our vision is to transform the nature of biologics therapy to improve effectiveness of therapy, enhance patient quality of life, and extend the global reach of such treatments.”
SmartPharm is focused on “gene-encoded therapeutics”
Three Ways to Deliver Therapeutic Proteins: pDNA can be inserted into bacteria or Chinese hamster Ovary (CHO) cells to make recombinant proteins given to people; mRNA or pDNA can be delivered ex vivo to human cells capable of making the proteins in the patient (cell therapy). mRNA or pDNA is delivered to human tissues that make proteins in the body (gene encoded therapy).
The bulk of modern biologics therapy is built on gene engineering. In traditional biologics therapy, genes are inserted into bacterial, fungal, or human cell lines to make different kinds of therapeutic proteins for use in patients. More recently, human cells outside the body have been genetically altered and then delivered to patients as therapy (cell therapy). Gene therapy is where the genetic alteration of human cells is performed inside the body. The most recent offshoot of this approach is to deliver a gene-editing platform, such as TALEN or CRISPR/Cas9 into cells to alter the genome of a patient for therapeutic purposes (genomic therapy). Other gene therapy approaches use nucleic acids to turn off unwanted or abnormal proteins inside cells, shut down specific cellular processes, and even to make unwanted cells (like cancer cells) undergo programmed cell death.
A subset of gene therapy seeks to insert nucleic acids (mRNA or DNA) into cells to make normal versions of a missing or abnormal program or to produce an entirely new type of protein that has therapeutic benefit. This approach eliminates the need for administering a recombinant therapeutic protein—the body itself becomes the factory for protein production. SmartPharm Therapeutics is focused on this approach to gene therapy, which we call “gene-encoded therapeutics.”
The GET segment is dominated by companies developing viral-vectored gene therapy. Specific viruses have evolved to learn how to effectively infect human cells and induce these cells to make proteins encoded by the virus. This evolutionary capability has been applied to gene therapy and a number of viruses have been adapted to delivering genes to make therapeutic proteins. Viral-vectored GETs are currently leading the way for the treatment of rare and orphan diseases. However, this approach has two significant limitations.
- Viral-vectored gene therapies result in significant immune responses. While viruses have evolved to effectively infect human cells, the immune system has also evolved to fight off these viruses. As a result, viral administration has to overcome significant immune obstacles. In some cases, patients require immune suppressive therapy in advance of treatment. Patients must be carefully monitored for unwanted immune responses after administration of the virus. In most cases it is unlikely that patients can be retreated with the same drug as they will have developed significant adaptive and cellular immunity against the carrier virus. This means that current viral-vectored gene therapy is a “one and done” approach with no means to re-dose if patients do not initially respond to treatment or therapeutic effects fade over time. Finally, some patients already have significant pre-formed antibodies to these viruses, excluding them therapy.
- Viral-vectored gene therapies are very expensive and complex to manufacture. The process of producing viral vectored gene therapies are very complex and expensive. These processes are currently not scalable, meaning that costs of producing 100,000 doses are the same per dose as for 1,000 doses. Unless this manufacturing dilemma is addressed, gene encoded therapy will largely be limited to million-dollar therapies for rare diseases.
Non-viral therapy using evolved, second-generation plasmids and mRNAs is capable of minimizing immune responses and can make it possible to obtain long-term gene expression (with plasmid DNAs) and to re-dose treatment as needed. Non-viral platforms can be efficiently and economically scaled for treatment of large patient populations and avoid the complexities that make regulatory compliance and clinical production challenging. We believe that non-viral gene therapy will play an important role in expanding the application of gene-encoded therapeutics beyond rare diseases to include diseases that affect hundreds of thousands or millions of patients.
SmartPharm brings together best-in-class technology and engineering capabilities to produce optimized gene-encoded therapeutics for patients. Our customization formula is:
The Right Nucleic Acid
There is no “one-size-fits-all” approach in gene-encoded therapeutics. Different tools are required for specific therapeutic outcomes. Most companies in the non-viral gene-encoded therapeutics segment field either an mRNA or a pDNA nucleic acid platform. However, the capabilities of these two approaches are rather different.
DNA plasmids typically need to penetrate into the cell nucleus to function and often only small quantities are delivered there. However, once minimally-immunogenic pDNA gets into the nucleus, the duration of expression can be quite long. DNA plasmids are also capable of containing large amounts of genetic information, making it possible to produce large proteins or multiple proteins.
In contrast, messenger RNA (mRNA) GETs do not need to get into the nucleus and more readily result in high-yield protein expression by the cell. However, the duration of expression tends to be short and the amount of genetic information that can be transmitted in each mRNA construct is limited.
As a result, DNAs may be more suitable to situations where long-term, chronic expression is desired whereas mRNA is more suitable for short-term, “burst” protein expression. SmartPharm can implement either type of platform to fit the therapeutic goals. It has proprietary mRNAs and pDNAs that are characterized by low immunogenicity, high expression profiles and the proven ability to be scalably and economically produced at cGMP standards for clinical use.
SmartPharm utilizes a “second generation” plasmid DNA construct (core technology licensed from another company) that is modified to minimize immunogenicity, address transcriptional silencing, and is capable of durable, high level protein expression. Our RNAs are also engineered to minimize immunogenicity. Both platforms have the proven ability to be produced at scale under cGMP with cost of goods that are a fraction of viral delivery systems.
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| Large antibiotic coding region | Minimal non-coding region |
| Antibiotic resistance gene | No antibiotic resistance gene |
| Hundreds of CPG motifs | Few CPG motifs |
| Inherent transcriptional silencing | No transcriptional silencing |
| Scalable economic production | Scalable economic production |
| Proven cGMP manufacturing | Proven cGMP manufacturing |
*Core technology licensed from another company.
The Right Delivery System
Use of non-viral nucleic acids require specialized carriers, such as liposomes or polymer nanoparticles, to protect the nucleic acids outside the cell and help them get into the cytosol inside the cell. SmartPharm does not utilize electroporation approaches that, while successful in some clinical trials, are unlikely to be a clinically desirable approach for wide application of GETs. For other types of delivery platforms, solutions that incorporate important lessons learned in the gene therapy field on key safety and regulatory parameters are essential to advance GETs into clinical use.
SmartPharm can combine either mRNAs or pDNAs with a number of different types of delivery systems depending on the tissue target and expression profile desired. We utilize multiple different kinds of non-viral delivery technologies that are minimally immunogenic, mitigate safety and regulatory risks, and are capable of scalable, economic manufacture at cGMP standards.
| Cationic Lipid-based Nanocarriers | Polymer-Based Nanocarriers |
|---|---|
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The Right Protein Sequence
SmartPharm optimizes the sequence of the nucleic acid to optimize protein expression and limit expression only to desired tissues or cells. It also enhances protein design for stability, secretion, and uptake by target cells.
We have used our tool box to create a scalable and cost-effective solution for creating pop-up immunity in people against coronavirus that has the capability to be rapidly scaled to deliver millions of doses. Our solution starts with our novel DNA plasmid that can express protein in muscle for weeks. This plasmid will be used to express an antibody capable of binding to and neutralizing the SARS-CoV-2 virus. This type of DNA plasmid has already been produced for other products in a fully cGMP-compliant manner and at significant quantities.
We plan to combine this DNA with a new, GMP-compliant polymer solution that may significantly enhance DNA expression in skeletal muscle. This polymer has been demonstrated to have the kind of safety profile to make it appropriate for use in humans. These two components would be delivered together through a standard hypodermic needle—a standard approach typically used in vaccines. Our approach eliminates the need for electroporation devices, which are currently being used in the delivery of these types of DNA-based antibody treatments.