Gene therapies

Meet the new medicines, page 4

Small-molecule and protein drugs both work by binding to target proteins and disrupting them. Gene therapies work in an entirely different way.

The goal of gene therapy is to replace problematic gene sequences with healthy ones, effectively stopping a disease at its source. Corrected genes are inserted into a patient’s cell, triggering that cell to make the right protein at the right time. Similarly, a harmful gene can be removed from a cell. There is no on-going medication, no “cocktail” of pills, because a single treatment should simply… work.

Although gene editing has become extremely precise with the recent advent of CRISPR technology, it is not yet perfect. One of the biggest challenges in gene editing is anticipating and mitigating “off-target” effects, which can lead to unknown, possibly serious side effects. Both public and private research organizations are working to develop more precise tools and technologies to address these issues.

RNA therapies

Messenger RNA (mRNA) plays a vital role in translating the instructions in DNA into the proteins of life. If a gene is damaged it creates damaged mRNA, which goes on to create damaged proteins and, ultimately, disease.

One type of RNA therapy uses a particular type of RNA — silencing RNA — to bind with damaged mRNA, which prevents it from being made into protein.

Another approach is to deliver corrected mRNA into cells. By giving cells the right blueprint for creating healthy proteins, mRNA therapy can prevent or treat disease. This approach has been pioneered by Moderna Therapeutics, a company co-founded by an HSCI faculty member.

Manufacturing gene and RNA therapies

A challenge for both gene and RNA therapies is getting the nucleic acid molecules into a cell. Researchers can use viruses or ‘packages’ made of lipids to deliver the therapeutic molecules.

Viral vectors

Certain types of viruses interact with human cells but do not cause disease, so they can be used to deliver nucleic acids. To deliver genes or RNA to a patient’s cells using a virus, you need to manufacture ‘viral vector’ particles, purify them, and test them for accuracy. A major challenge is how big a ‘payload’ any virus can deliver into a cell. This process is even more complicated and expensive than manufacturing protein drugs.

A lot of progress is needed in engineering and manufacturing for this type of therapy to become viable. We also need a better understanding of the underlying biology to make sure it works well.

Lipid packages

Lipid ‘packages’ are small particles made of the same type of molecule as the outside of a human cell. They can deliver nucleic acids to target cells and can be manufactured using chemical synthesis. But this process is far more complicated than synthesizing small molecules.

The product itself, the mixtures of slightly different forms, elaborate purification steps, and the difficulty of characterizing the product all make production at least as complex and costly as making protein drugs – if not many times more.

Other approaches to using nanoparticles as delivery vehicles are also being explored by HSCI researchers.

Each technique will have its own advantages and disadvantages, depending on the target cells, the type and size of gene product to be delivered, and the site of delivery in the body.