Classical HCU Therapeutic Avenues
The current therapeutic objective is described in the Guidelines for the diagnosis and management of cystathionine beta-synthase deficiency. Click here to view the Guidelines.
There are several approaches being investigated for the treatment of classical homocystinuria. See our Investigational Therapies Research Map.
SYSTEMIC ENZYME THERAPIES TO DEGRADE HOMOCYSTEINE
- Enzyme replacement therapy (ERT) is a treatment that replaces an enzyme in a patient where the enzyme is defective due to a genetic defect. The product currently in development for classical homocystinuria, pegtibatinase (Sponsor: Travere Therapeutics), is a synthetic recombinant version of the cysteine beta synthase or CBS enzyme and is expected to be administered by subcutaneous injection. This enzyme is designed to do what CBS does, convert homocysteine directly to cysteine, to hopefully restore the normal biochemical pathway.
- The safety and effectiveness of ERT has been shown in the treatment of some lysosomal storage diseases including Gaucher disease type I, Fabry disease, MPS I (Hurler syndrome), MPS II, MPS VI, and Pompe. ERT does not correct the underlying genetic defect and is not a curative approach but rather requires lifelong administration.
- An alternative enzyme is in development which is an engineered human enzyme, homocystinase, that degrades both homocysteine and homocystine (which is 2 homocysteine molecules bound together). This product, called pegtarviliase, is being developed by Aeglea Biotherapeutics and is expected to be administered by subcutaneous injection.
- This enzyme would be expected to lower homocysteine levels, and similar to Pegtibatinase, would not be curative and would need lifelong administration.
ORAL (GI) THERAPIES TO PREVENT ABSORPTION OF METHIONINE
- An engineered methionine-gamma-lyase enzyme is being developed by Codexis, CDX-6512. This is an orally administered, GI-stable therapeutic enzyme to potentially treat HCU by degrading methionine from food/protein intake in the GI tract, so that the methionine is not absorbed and converted to homocysteine.
- This product would need to be taken daily with lifelong administration.
- An engineered probiotic, which is a Methionine-Consuming Synthetic Biotic Medicine, or SYNB1353, is being developed by Synlogic. This product is taken orally and is designed to consume methionine from food/protein intake in the GI tract so that the methionine is not absorbed and converted to homocysteine.
- This product would need to be taken daily with lifelong administration.
GENE THERAPY: DELIVER DNA TO ENABLE BODY TO PRODUCE CBS ENZYME
Gene therapy is a treatment approach that involves delivering genetic material (DNA) into a person’s cells to compensate for defective genes. The process involves using a vector (e.g. the adenovirus or common cold vector which is inactivated and has no biologic activity) to deliver the genetic material into the body. The cells in the body (in the case of classical HCU, the liver cells) will then transcribe the DNA and produce the CBS enzyme. The CBS enzyme would then be expected to function as normally and restore the biochemical pathway. It is unknown how long the product will last and whether readministration will need to occur over time.
CHAPERONE THERAPY: ADMINISTER SMALL MOLECULES (USUALLY ORAL THERAPIES) TO RESTORE ENZYME ACTIVITY
- Small molecules can be chemically synthesized and often taken in tablet or capsule form, in contrast to enzymes or other “biologics”, which are made via living organisms and too “large” to be taken in tablet or capsule form so require injection or infusion. There is a screening project underway, funded by a grant from HCU Network America, to identify small molecules that would activate the function of the CBS enzyme thereby increasing its effectiveness in lowering homocysteine levels.
- Any product resulting from this research would be expected to be administered on a daily basis for lifelong administration
METABOLIC PATHWAY MODIFICATION:
Research has shown that the administration of a metabolic compound called formate can reduce levels of homocysteine in mice, especially when combined with betaine. This study was supported by a grant from HCU Network America and HCU Network Australia, with additional funding from the William R. Hummel Homocystinuria Research Fund. Additional work is required to determine an appropriate dosage form, but if successfully developed would be expected to be taken on a daily basis with lifelong administration.
A study was conducted using thiol-based reductants in combination with ERT to potentially achieve greater reduction in homocysteine, which was funded by HCU Network America and HCU Network Australia. The thiol-based reductants have been shown to free up homocysteine by breaking down bonds that homocysteine forms and the ERT can then metabolize a greater amount of homocysteine leading to a greater reduction in HCY levels. This approach would need to be formally studied in combination with one of the systemic enzyme therapies described above and would need to be taken on a lifelong basis along with the enzyme therapy.
Taurine is a naturally occurring sulfinic acid that acts to increase tissue levels of the major cellular antioxidant glutathione by exerting a cysteine-sparing effect. In an animal model of HCU, the co-administration of taurine acted to normalize blood-clotting parameters, decrease inflammation in the vasculature, and increased the effectiveness of the betaine response. In a short-term human pilot trial, taurine reversed endothelial dysfunction in human subjects with HCU. Further studies of taurine are being considered.
Here is a schematic overview showing the biochemical cascade and how emerging therapeutic interventions address the biochemical or disease process.
