A Bright Future for Genomic Medicines

Patients and their families facing debilitating neurological diseases have long gone without adequate treatments, despite efforts from the life sciences industry. The emergence of genomic medicines is changing that, by offering promising new ways to potentially target the underlying genetic causes of disease. Unlike traditional treatments that may only alleviate symptoms, genomic therapies have the potential to directly modify the gene - or genes - responsible for the neurological disorder. Targeting these conditions at the DNA level may enable fine-tuning of gene expression and reduce therapeutic complexity.

Creating genomic medicines for neurodegenerative diseases has been limited by various factors, including the complexity of genetic interactions within the brain, understanding of disease biology, and technological limitations in gene editing and delivery methods. Nonetheless, advancements in multi-omics technologies, gene editing techniques, and increased collaboration among researchers are seeking to address these obstacles and paving the way for more extensive exploration and development of potential neurology genomic medicines.

At Sangamo, our mission is to translate ground-breaking science into medicines that transform the lives of patients and families afflicted with serious neurological diseases. To do so successfully requires two critical components: the therapeutic cargo, which can tune the expression of target genes, and the means to deliver that cargo to the intended location within the body, in this case using a delivery capsid. Because brain cells rarely divide, if ever, this approach may provide a one-time therapy for neurological disorders with a durable effect for the lifetime of the patient.

Getting medicines to where they need to go

Many neurological diseases affect multiple brain regions, if not the whole central nervous system (CNS), so it is critical to be able to deliver a treatment in a widespread manner. One approach to achieving this is to utilize the brain’s blood vessel network, which is intimately connected to all brain cells.

However, in order for a potential medicine to move from the blood into the brain, it must cross the blood-brain barrier (BBB), which acts as a filter to regulate the movement of molecules, including vital nutrients, and to keep toxins and pathogens from affecting the CNS. Although the BBB is important for a healthy nervous system, it poses a challenge when designing potential therapeutics that must enter the brain to target devastating neurological conditions. The traditional capsids that have been used to-date in genomic medicines are not able to efficiently cross the BBB. A new approach is required.

Exploring the potential of a promising BBB-penetrant capsid

Through our proprietary AAV capsid engineering platform SIFTER (Selecting In vivo For Transduction and Expression of RNA), we can now engineer capsids with enhanced CNS targeting to potentially advance our innovative preclinical programs to the clinic. Using SIFTER, we recently identified STAC-BBB (Sangamo Therapeutics AAV Capsid-BBB), which has demonstrated a profound ability to penetrate the blood-brain barrier and achieve widespread brain distribution after a single intravenous dose. Our recently released data show that the capsid reaches all key areas of the brain associated with disease pathologies, including hard-to-reach deep brain regions. Importantly, STAC-BBB is a neurotropic capsid, meaning it preferentially targets neuronal cells compared to other cell types in the brain or other organs. This characteristic helps to both increase efficacy, by promoting expression in brain cells, and limit concerns with off-target expression in other organs.

A commercial-ready drug must also be manufacturable at scale to be able to treat a patient population. Sangamo is leveraging our established AAV manufacturing platform, which has already manufactured capsids for clinical use. Importantly, we have manufactured STAC-BBB up to a 50L scale, and further scale up to 500L is in progress, in order to support our future clinical programs targeting neurological disorders.

Delivering an effective therapeutic cargo

Complementing these notable delivery capabilities, Sangamo’s zinc finger cargo allows for potential disease modifying interventions for neurological diseases. Derived from human proteins, zinc fingers are highly versatile, extremely customizable, and very compact, meaning they can be easily packaged into viral vectors. Zinc fingers recognize DNA to induce a variety of outcomes, such as epigenetic activation or repression.

Our STAC-BBB capsid enables delivery of zinc finger repressors for the potential treatment of prion disease, a devastating condition with no existing approved disease modifying therapies, that is typically fatal within 12-15 months of diagnosis.

Our recent preclinical data show robust distribution of STAC-BBB throughout the brain, with a corresponding widespread expression of the prion-targeted zinc finger repressor, highlighting promise for this therapeutic route, as prion disease affects the whole brain. Importantly, this expression also correlates to reduction of prion gene expression, which is believed to be critical for slowing or halting disease progression and neurodegeneration.

Sangamo’s zinc finger repressor (ZFR) for tauopathies, such as Alzheimer’s which impactions millions of patients globally, also showed compelling results. Our preclinical studies with STAC-BBB demonstrate a dose-dependent increase in ZFR expression that correlates to a dose-dependent decrease of tau expression. Using this capsid and cargo combination, Sangamo could potentially halt disease progression in Alzheimer’s disease and other tauopathies – a goal that many in the industry have been in search of for years.

Delivering the future of genomic medicines

Leveraging the potentially powerful combination of our capsid and cargo technologies could be ground-breaking for the field. We look forward to further developing these programs in preclinical and clinical studies to potentially address the needs of patients suffering with debilitating neurological disorders.