Huntington's disease

 

Promising New Approaches to Treat Huntington's disease

 

These three drug development programs are conducted by other biotech companies and are listed here to show the major difficulties of finding new effective treatments for Huntington's disease.

 

ALN-HTT

An RNAi therapeutic, ALN-HTT, is being developed in collaboration with Alnylam Pharmaceuticals, Medtronic, and CHDI Foundation, Inc. to silence the huntingtin mRNA and decrease mutant Htt protein production. Alnylam Pharmaceuticals has filed for Investigational New Drug (IND) application with the FDA and began Phase II clinical trials.

 

PBT2

Prana based in Melbourne, Australia, is developing PBT2 which is targeting metals associated with pathological protein aggregation in neurodegenerative diseases. 2014 Prana announced positive findings in its Phase 2 clinical trial for Huntington’s disease (Reach2HD) and is planning for further clinical trials. The claims of cognitive, functional and imaging benefits are not supported by enough evidence.

 

CRISPR-CAS-Mediated Targeted Genome Editing

There are several biotech companies developing drugs with this new platform: Editas, CRISPR Therapeutics Intellia Therapeutics.

This new technology is very promising for treatment of Huntington's disease. But there are major unresolved issues which have to be overcome before new therapies can be developed:

(1) Off-target mutations and oncogene activation possible;

(2) The therapy delivery is difficult, even with intrathecal injection, it will not penetrate the brain deeply enough;

(3) CRISPR cannot yet discriminate between mutant and healthy huntingtin genes

 

 

Background

 

 

Huntington’s disease (HD) is a fatal neurodegenerative disorder affecting 1 in 10,000 persons of European descent. In 1872, a 22-year-old American neurologist published the first complete description of the disease. George Huntington accurately described the clinical presentation of HD as a triad of motor, emotional, and cognitive disturbances. The hallmark symptom of HD is the presence of involuntary movements, called chorea. But HD has peripheral manifestations as well, such as skeletal muscle dysfunction, cardiac failure and weight loss. Symptom onset typically occurs in midlife and the disease progresses over the next 15 to 20 years. HD is an autosomal dominant disease caused by a CAG repeat expansion in the huntingtin gene that encodes huntingtin (Htt). Normal alleles of the huntingtin gene have glutamine (CAG) codons of anywhere between 7 and 36 contiguous glutamine residues. Disease onset is earlier the longer the glutamine length in a highly correlative nature.