Gene Therapy for Sanfilippo: Where We Are Now

Brian Murphy, Ph.D. avatar

by Brian Murphy, Ph.D. |

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Gene therapy is a promising approach for a number of rare genetic diseases as it has the potential to treat the underlying cause. Here is more information about gene therapy, its challenges, and its current status as a treatment for Sanfilippo syndrome.

About gene therapy

Gene therapy is a treatment that uses small pieces of genetic material to modify how a person’s genes work. It includes the use of a vector (typically a harmless virus) that can deliver the new piece of genetic material into a patient’s cells. The two most common viral vectors used in gene therapy are adeno-associated viruses (AAV) and lentiviruses.

Gene therapy can be in the form of an injection or infusion into the bloodstream, into the area around the spinal canal (intrathecal), or into the brain (intracerebral), depending on the vector and the types of cells targeted.

In some cases, gene therapy uses stem cells from the patient. Researchers modify these in the laboratory before returning them to the patient, a method called ex vivo autologous gene therapy.

Gene therapy for Sanfilippo

Sanfilippo syndrome is caused by mutations in genes that encode for enzymes which break down long chains of sugar molecules.

The goal of gene therapy for Sanfilippo is to deliver correct copies of the faulty gene to patients so that their cells can produce functional enzymes to breakdown and prevent the accumulation of these sugar molecules.

Challenges of gene therapy

There are several challenges of gene therapy for Sanfilippo syndrome patients:

Disease subtypes caused by different genes

The first is that each of the four subtypes of Sanfilippo syndrome is due to a mutation in a different gene, so each subtype requires a separate target for gene therapy. In other words, one gene therapy will not work for all Sanfilippo patients. Each subtype will require its own specifically modified viral vector that researchers will need to develop and test in the clinic, which also increases costs.

Type of viral vector to use

Another challenge in gene therapy is the selection of the viral vector to use. It is still not clear whether AAV, lentiviral, or a combination of both vectors is most effective.

Route of administration

The route of administration is another challenge for gene therapy. Sanfilippo syndrome primarily affects the central nervous system (CNS), consisting of the brain and spinal cord. The blood-brain barrier protects the CNS, preventing many medications and viruses from crossing and entering the brain. To solve this problem, a viral vector that can cross the barrier is necessary. Alternatively, the infusions must go directly into the cerebrospinal fluid.

Ability to reach different parts of the body

Another factor to consider is that the buildup of sugar molecules can affect other tissues besides the CNS, such as the eyes and the bones. If treatment is administered to the brain and cannot reach the rest of the body, it will not help with these other symptoms.

On the other hand, if a viral vector that can access the brain is given through the veins to target other cells in the body, it might not reach a sufficient number of nerve cells in the brain to have an effect.

Immunity against viral vectors

Viral vectors also pose another potential problem. If the body has already come in contact with a similar virus, it produces antibodies against it. These antibodies might stop and destroy the viral vectors carrying the healthy gene before they reach their targets, reducing their effectiveness.

If a gene therapy was not successful enough the first time, patients usually cannot receive it a second time because of these antibodies. A possible solution to this challenge would be to use an AAV and a lentiviral vector as two separate doses to increase the effectiveness of the treatment.

Lack of patients for clinical trials

Another potential obstacle for gene therapy is the translation of treatment approaches from cell and animal experiments to humans. Researchers have been able to develop models of Sanfilippo syndrome but some treatments that work in animals might not always work in humans. Therefore, researchers have to test the treatments in human clinical trials.

The rarity of Sanfilippo syndrome can make it difficult to find sufficient numbers of participants to prove the safety and effectiveness of treatments before regulatory agencies can approve them. The difficulty in finding participants can lead to longer times to complete clinical trials.

Current gene therapy approaches for Sanfilippo

A number of gene therapies are currently under investigation for the treatment of Sanfilippo syndrome:


LYS-SAF302 is a gene therapy being developed by Lysogene to treat Sanfilippo type A. The treatment uses an AAVrh.10 vector to deliver the instructions for a working copy of the SGSH gene, the gene that is faulty in patients with this disease type.

Researchers are currently investigating the treatment in a Phase 2/3 trial called AAVance (NCT03612869). In the trial, patients receive infusions at six different locations in the brain during a single procedure.

Initial results from the first nine of 19 children showed that LYS-SAF302 was able to reduce the levels of heparan sulfate (the complex sugar that accumulates in Sanfilippo syndrome) in the fluid surrounding the brain and spinal cord of patients at six and 12 months after treatment. There was no reduction in the blood levels of heparan sulfate, however. The trial is ongoing and expected to conclude in March 2022.

OTL-201 and OTL-202

Orchard Therapeutics is investigating gene therapies for Sanfilippo type A (OTL-201) and type B (OTL-202). For both treatments, researchers harvest blood-forming stem cells from the bone marrow of the patient. They then modify them using gene therapy to contain the correct version of the SGSH gene or the NAGLU gene, depending on the disease subtype. The modified stem cells are then infused back into the same patient. The aim is for these cells to return to the bone marrow so that they can grow and produce cells that contain the healthy gene — a process called engraftment.

OTL-202 is still in preclinical testing but researchers are studying OTL-201 in a Phase 1/2 trial (NCT04201405). Three patients have been treated so far. Initial data from the first patient three months after treatment showed an increase in the levels of sulfamidase — the missing enzyme in Sanfilippo type A — and a decrease in heparan sulfate levels. Researchers expect to conclude the trial in October 2024.

ABO-101 and ABO-102

Another company, Abeona Therapeutics, is also developing gene therapies for two types of Sanfilippo. ABO-101 is for type B while ABO-102 is for type A disease. Both treatments use an AAV9 vector that is able to cross the blood-brain barrier. Therefore, the treatments can be given as an infusion into the bloodstream.

ABO-101 is being tested in a Phase 1/2 trial, Transpher B (NCT03315182). Early data showed that treatment reduced heparan sulfate in the fluid around the brain and spinal cord, blood, and urine of patients. This trial is still recruiting participants. Investigators expect to conclude it in October 2022.

Researchers are also investigating ABO-102 in two trials, one in younger patients called Transpher A (NCT02716246) and one in older patients called study ABT-003 (NCT04088734). Some initial results from Transpher A showed that patients tolerated the treatment well. Moreover, the therapy lowered heparan sulfate levels in the fluid around the brain and spinal cord. It also helped preserve cognitive development in patients.

Both studies are currently still recruiting participants. Researchers expect to conclude Transpher A in December 2022 and ABT-003 in December 2023.

EGT-101 and EGT-201

Esteve is developing EGT-101 and EGT-201 for Sanfilippo type A and B, respectively. Each treatment uses an AAV9 vector to deliver the gene therapy into the brain as a single injection. EGT-201 is still in preclinical study, and EGT-101 is being investigated in a Phase 1/2 trial in Spain.


Researchers at Phoenix Nest are investigating a new type of AAV, called AAV-TT, to deliver gene therapy to patients with Sanfilippo type C. After acquiring the rights to the treatment from the University of Manchester in 2018, the company is raising funding for research and plans to run a clinical trial in the future.


Last updated: Feb. 16, 2021


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