Gene Therapy Has Potential to Treat Underlying Cause of Sanfilippo, Review Study Finds

Gene therapy has the potential to effectively target the underlying cause of Sanfilippo syndrome and delay or prevent neurodegeneration, according to a review study.

Data from ongoing and future clinical trials are expected to help determine the most effective delivery strategies with the fewest associated risks.

These novel approaches not only can open new doors for the treatment of Sanfilippo syndrome and other lysosomal storage disorders, but also for other genetic neurodegenerative diseases, the researchers noted.

The review study, “In Vivo Gene Therapy for Mucopolysaccharidosis Type III (Sanfilippo Syndrome): A New Treatment Horizon,” was published in the journal Human Gene Therapy.

Sanfilippo syndrome, also known as mucopolysaccharidosis type III (MPS III), is a rare genetic lysosomal storage disorder. It is characterized by the absence or reduced activity of enzymes involved in the breakdown of a complex sugar molecule called heparan sulfate, leading to its toxic accumulation.

While this toxic buildup occurs throughout the body, nerve cells are particularly sensitive to heparan sulfate accumulation. The central nervous system (CNS, brain and spinal cord) is the most affected organ in people with Sanfilippo syndrome, who develop progressive and severe neurodegeneration.

With no specific therapy approved to date that targets the cause of the disease, current treatments for people with Sanfilippo syndrome have focused on easing its symptoms. While there have been increasing efforts to develop enzyme replacement therapies that would regularly deliver a healthy version of the deficient enzyme to the body, these approaches face an important challenge: reaching the brain.

Large molecules, such as enzymes, cannot reach the brain due to the existence of the blood–brain barrier — a protective membrane that restricts the passage of certain molecules from the blood into the brain. The barrier protects the neural tissue from toxins and pathogens, but also blocks therapies from reaching the brain.

CNS-targeted gene therapy, which uses harmless viruses, has the potential to overcome this challenge, with the advantage of requiring a single treatment to administer.

This type of therapy relies on a mechanism known as cross-correction, in which the enzyme produced by one cell can be released and subsequently taken up by neighboring cells, resulting in the correction of more cells than those directly targeted during the therapy.

Spanish researchers have now reviewed the preclinical and clinical data on current investigational gene therapies for Sanfilippo syndrome.

Most of these gene therapies rely on modified and harmless adeno-associated virus (AAV) to deliver a functional copy of the mutated gene to the CNS. Previous preclinical studies in small and large animal models of Sanfilippo syndrome have shown that different routes of gene therapy administration are safe and effective in halting or preventing neurodegeneration.

Three different routes of administration have been evaluated: through local injections into the brain (intraparenchymal administration); through the bloodstream, using AAV subtypes that are able to cross the blood-brain barrier (intravenous, or into-the-vein administration); and through the cerebrospinal fluid (CSF), the liquid surrounding the brain and spinal cord (intra-CSF administration).

Researchers have noted that there are considerable differences between these administration routes in terms of procedure-associated risks, potential toxicity, required dose of virus, and limited effectiveness due to natural immune responses against the virus.

Previous studies have shown that intraparenchymal administration has limited distribution in the CNS. Intravenous administration is the least invasive approach and is able to reach not only the CNS, but also the liver and other organs. Notably, the liver is the most important source of circulating enzymes. However, IV administration requires high-dose therapy to induce significant effects, and its efficiency may be compromised by immune responses against the viruses in the blood.

More recently, intra-CSF administration was developed to maximize gene therapy delivery to the CNS, while minimizing the therapeutic dose. In animal models, this type of approach led to a widespread and even distribution of the virus throughout the CNS, and a portion of the viruses reached the liver through the bloodstream. Evidence also suggests that its effectiveness in the CNS is not affected by immune responses.

Gene therapy administration into the brain

The safety and effectiveness of intraparenchymal gene therapy administration has been evaluated in clinical trials involving people with Sanfilippo type A (NCT01474343) and B (NCT03300453). Data from both trials suggested that gene therapy was safe and promoted some behavioral and cognitive improvements. However, long-term data is required to discriminate between the gene therapy’s effects and those of immunosuppressive treatment given to these patients.

An ongoing Phase 2/3 clinical trial (NCT03612869) is evaluating LYS-SAF302 — a gene therapy being developed by Lysogene that is delivered directly into the brain — in Sanfilippo type A patients. That trial, which dosed its first patient in June 2019, is still recruiting. Go here for more information on the trial’s locations and here for eligibility criteria.

The researchers also noted that Phoenix Nest is preparing the first-in-human trial investigating a gene therapy (also through intraparenchymal administration) in people with Sanfilippo type C.

Gene therapy administration into the blood and CSF

Two Phase 1/2 clinical studies are evaluating two different gene therapies, both delivered intravenously, in people with Sanfilippo type A (NCT02716246) and B (NCT03315182). Both trials are still recruiting. For more information on the type A study, visit here. More information on the type B trial can be found here. So far, data from both studies support the safety and effectiveness of these therapies in reducing heparan sulfate levels and halting or preventing neurodegeneration.

To date, the only clinical study evaluating a gene therapy administered directly into the CSF in this patient population is a Phase 1/2 trial (2015-000359-26) for people with Sanfilippo type A. No results have been reported thus far.

Overall, further data from the ongoing clinical trials “should shed light on which gene transfer strategy leads to highest clinical benefits while minimizing risks,” the researchers said.

They also pointed out that these gene therapy data will help to determine the importance of reducing non-CNS damage in these patients. That will become more relevant as treated individuals will likely live longer due to reduced neurodegeneration.

“The development of all these strategies opens a new horizon for the treatment of not only MPSIII and other [lysosomal storage disorders], but also of a wide range of neurological diseases,” the researchers concluded.