New Optimism for Treating Machado-Joseph Disease

 

Dimeric calpains are calcium-activated cysteine proteases which help to regulate cell function. If these calpains are overactive, it could lead to fibrosis (tissue scarring) and tissue damage. In the past, researchers have suggested that overactive calpains may also play a role in neurodegeneration, preventing abnormal or damaged proteins and toxic protein aggregates from being cleared from the body. According to a recent news release from biopharmaceutical company Blade Therapeutics, Inc. (“Blade”), the company recently published preclinical data highlighting how calpain inhibition offers neuroprotective benefits for Machado-Joseph disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3). Interested in learning more? Take a look at the full set of preclinical findings published in Cells.

The Research

Within this particular set of in vivo studies, researchers used zebrafish models of Machado-Joseph disease. The researchers sought to understand the impact of treating these zebrafish models with BLD-2736, a novel and proprietary calpain inhibitor. To learn more about targeting calpains, check out this helpful primer from Blade.

After treatment, researchers compared the treated zebrafish models with an untreated group. Findings include:

  • BLD-2736 significantly improved swimming ability (movement) and reduced the amount of toxic or insoluble protein aggregates. This was true even when researchers delayed treatment, suggesting that BLD-2736 could improve patient outcomes even if treated in later stages.
  • Alternately, the untreated group of zebrafish saw increased protein aggregation, higher levels of neurodegeneration, and worse movement abilities.
  • BLD-2736 also improved autophagy, or the removal of dysfunctional proteins.

In the future, Blade looks forward to continuing to develop its pipeline and create therapeutic options for patients with neurodegenerative conditions. For example, the company hopes to begin a Phase 1 clinical trial evaluating another calpain-inhibiting therapy, BLD-2184, in the earlier half of 2022.

Machado-Joseph Disease (MJD)

Machado-Joseph disease (MJD) sits under the larger umbrella of spinocerebellar ataxia, or hereditary conditions which occur when certain parts of the nervous system (the parts which control movement) are damaged. ATXN3 gene mutations cause this rare inherited ataxia. According to the National Organization for Rare Disorders (NORD):

Three forms of Machado-Joseph Disease are recognized: Types MJD-I, MJD-II, and MJD-III. The differences in the types of MJD relate to the age of onset and severity [with] earlier onset usually [producing] more severe symptoms.

In each case, the genetic mutations cause toxic or mutant protein to accumulate within nerve cells, causing neurodegeneration within the hind-brain. There is no cure for Machado-Joseph disease, though treatment can be symptomatic. This condition affects males slightly more than females, and is also found disproportionately in those of Portuguese descent.

Symptoms

Symptoms and onset vary. For example, patients with Machado-Joseph Disease type I (MJD-I) often experience symptom onset between ages 10-30. This is a fast progressing form of the condition. While patients’ mental and intellectual capacities remain untouched, other symptoms may result in:

  • Bulging eyes
  • Muscle spasticity or rigidity
  • Damage to muscles controlling eye movement
  • Slurred speech
  • Severe muscle weakness in the arms and legs
  • Ataxia
  • Difficulty swallowing
  • A slow, staggering gait

Next, patients with Machado-Joseph Disease type II (MJD-II) often experience symptom onset between ages 20-50. Many symptoms are similar to the symptoms found in MJD-I. However, MJD-II is slower-progressing and also presents as spastic muscle movements, poor or difficult coordination, and an unsteady gait. Finally, Machado-Joseph Disease Type III (MJD-III) appears between ages 40-70 and is the slowest to progress. Additional symptoms include loss of muscle mass, motor polyneuropathy, lack of pain sensitivity, and diabetes.

Jessica Lynn

Jessica Lynn

Jessica Lynn has an educational background in writing and marketing. She firmly believes in the power of writing in amplifying voices, and looks forward to doing so for the rare disease community.

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