Is Gene Therapy For Huntington’s A Sign Of Greater Things To Come?

Last month, news of a new one-time treatment that significantly slows the progression of Huntington’s disease hit the headlines. Huntington’s disease, an incurable condition inherited through a dominant gene, results in progressively worsening motor and cognitive symptoms. The treatment, AMT-130, uses a harmless virus to deliver a gene therapy that prevents the disease gene from producing the corresponding protein. Delivering this treatment is no straightforward matter – it must be infused directly into the brain through a hole in the skull. Nevertheless, many believe it represents a turning point for the treatment of Huntington’s disease. It may also be a turning point in our approach to treating neurodegenerative diseases in general.

The success of AMT-130 and possible approval later next year marks an increasing acceptance by regulators of gene therapies that produce long-lasting or even permanent changes in recipients. This is good news for those looking to take new approaches to treating diseases that have proven resistant to more conventional treatments, with the closest parallel being age-related neurodegenerative diseases.

Efforts to treat age-related neurodegenerative diseases over the last several decades have yielded next to nothing, and it’s likely that new innovations will be needed. Increasingly powerful gene therapies like AMT-130 are one such innovation. A company called YouthBio Therapeutics is currently trying to develop an Alzheimer’s gene therapy using a principal that has so far been unexplored in humans – partial reprogramming.

The company’s lead Alzheimer’s candidate is called YB002. Like AMT-130, it works by using a virus to deliver genetic material into the brain. But while AMT-130 works by interfering with the production of a single disease protein, the causes of Alzheimer’s disease are more complex, not fully understood, and require a more general approach. YB002 delivers genetic material encoding a group of proteins called Yamanaka factors. These proteins, also known as reprogramming factors, effectively ‘turn back the clock’ in aged cells, reverting them to a younger state. They achieve this by erasing epigenetic modifications – alterations to the DNA molecule that occur throughout life – in a process known as epigenetic reprogramming. The genes encoding Yamanka factors will be introduced in a way that, once present in the recipient’s cells, they become activated only when the patient takes a specific drug. This will allow the expression of Yamanaka factors to be controlled after the gene therapy has been administered.

Research in animal models shows that epigenetic reprogramming can rejuvenate animals and improve cognitive function in models of neurodegenerative disease. Care has to be taken when using Yamanaka factors, as reprogramming cells too far can cause them to revert to being stem cells. That’s why the expression of Yamanaka factors needs to be tightly controlled to ensure that only partial reprogramming occurs. This is just one of several safety concerns, but the payoff is significant, and it seems as though regulatory bodies are beginning to view the risk as acceptable. In a recent meeting with YouthBio, the US’s FDA (Food and Drug Administration) officially recognised that existing preclinical data supported YB002’s potential, providing a clear path towards clinical trials in humans.

Given the incurable nature of Alzheimer’s disease, the risks associated with partial reprogramming can be seen as more acceptable. However, if partial reprogramming is found to work safely in humans, this could open the doors for it to be tested in other age-related diseases, and perhaps eventually for the purposes of delaying ageing in general.