ALS Association helping to move ORY-4001 into animal studies

Investigative therapy to promote health and workings of nerve cell axons

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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The ALS Association has given Oryzon Genomics nearly $500,000 to advance ORY-4001, a potential treatment of amyotrophic lateral sclerosis (ALS), into preclinical studies.

The $498,690 grant was provided via the association’s Lawrence and Isabel Barnett Drug Development Program. Oryzon intends for laboratory studies in mouse disease models to pave the way for ORY-4001 to be tested in clinical trials.

“We are proud to help drive the crucial transition from preclinical to clinical development for potential new ALS therapies like ORY-4001,” Kuldip Dave, PhD, senior vice president of research at the ALS Association, said in an organization press release.

“Getting promising treatments out of the laboratory and into clinical testing as quickly as possible is key to making ALS a livable disease until we can cure it,” Dave added.

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ALS Association grant supports work needed to bring ORY-4001 into a trial

ORY-4001 is a highly selective inhibitor of histone deacetylase 6 (HDAC6), part of a family of enzymes that regulate cellular activity through a chemical modification to proteins called deacetylation.

HDAC6 has been linked to cellular processes involved in neurodegenerative disease, and blocking it has emerged as a possible treatment strategy for conditions such as ALS.

Particularly, HDAC6 activity regulates alpha tubulin, a protein involved in cellular protein transport. Impaired axonal transport — the movement of proteins needed for nerve cell health and survival along a cell’s fiber-like projections (axons) — is a feature of ALS and other neurological diseases.

Preclinical studies have shown that HDAC6 inhibition protects against axonal transport deficits in models of ALS and may be able to slow neurodegeneration.

Oryzon has been evaluating the therapeutic potential of various HDAC6 inhibitors for neurological diseases, and earlier this year selected ORY-4001 as its clinical development candidate.

The therapy’s initial development efforts have been focused on Charcot-Marie-Tooth disease type 1 (CMT1), an inherited disease affecting peripheral nerves, those that participate in communication between the brain and the rest of the body.

Therapy showed potential in model of disease also marked by muscle wasting

In a mouse model of CMT1, the molecule improved neuromuscular function, prevented axon damage, and prevented the loss of myelin, the substance that surrounds and protects nerve cell axons, Oryzon reported.

Both CMT1 and ALS are characterized by muscle weakness and wasting, as well as altered axonal transport. Disturbed proteostasis, the process by which proteins are regulated to maintain cellular health, also is evident in both conditions.

Given this overlap and previous preclinical studies of HDAC6 inhibitors in ALS, the scientists believe ORY-4001 may be a promising treatment candidate.

“The rationale linking ORY-4001’s mechanism of action to the disease is sound,” said Jordi Xaus, PhD, Oryzon’s chief scientific officer.

In addition to testing ORY-4001 in an ALS mouse model, the company is conducting the toxicology studies required before a therapy can be tested in humans.

“If these preclinical results are positive, we plan to extend the clinical development of ORY-4001 … to include ALS and explore its therapeutical potential for people living with this devastating disease,” Xaus said.

“It is an honor to have the support of the ALS Association,” he added.