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State of Therapeutic Programs

From a gene mutation to a lethal disease

HD is caused by a single mutation in a region of the HTT gene, located at the beginning of the gene (in exon 1), which contains a repeat sequence comprised of CAG repeats; in the normal range, people have between 17-22 repeats on average; in HD individuals, an expansion greater than 39 leads inevitably to disease. The longer the number of repeats, typically, the earlier the individual affected starts showing visible symptoms of the disease.

This means that every person with HD has the same type of mutation in only one gene, making HD an unusual disorder. most other common neurodegenerative diseases have many different origins, and only between 2-5% of all cases of Alzheimer’s, Parkinson’s or ALS have a genetic basis. 

A lot of research has been dedicated to finding out how the mutation in the HTT gene leads to HD, and a lot of potential cellular mechanisms have been identified. The impact of the mutation has devastating consequences for many brain cells, and the theory goes that if we can understand how this happens, we might be able to develop therapies to treat the disease. However, these efforts have been largely unsuccessful thus far. Some symptomatic therapies, targeting one or another mechanism thought to go awry in humans affected with HD are under development (see Table below).

Another approach to treat HD is to target specific symptoms of the disease thought to arise from alterations in specific brain circuits. Mutant HTT leads to a loss of cells and brain fibers in specific circuits in the brain, which partially explain many of the symptoms of the disease. Therefore, strengthening or restoring those circuits might offer some benefit. In the case of HD, many circuits are affected, but the major ones involve the connection between various cortical areas and the basal ganglia, although other changes are known in the cerebellum and hypothalamus.

This is the ‘traditional’ approach taken for symptomatic therapies in every degenerative disorder, and one that has been effective in controlling some symptoms. For example, it led to the development of tetrabenazine for choleric movement control, and to the use of antipsychotic medications targeting the dopaminergic system for irritability, for example. However, at the moment we lack therapies that target the most debilitating symptoms of HD – cognitive alterations and apathy.

In this class of therapeutic agents might fit the most advanced current program for the treatment of HD, involving the current Phase 3 trial (now recruiting) of pridopidine, also formally known as ACR16, being pursued by the company Prilenia. ACR16 was formerly developed by Teva.

Pridopidine has been investigated as a treatment for HD in three randomized, double-blind, placebo controlled clinical trials: HART, MermaiHD, and PRIDE-HD. Initial studies in HD focused on the effects of pridopidine in the motor endpoints, under the hypothesis that pridopidine had an effect on dopaminergic control of movement. Indeed, a small effect on motor endpoints was seen in the HART and MermaiHD studies, although people also saw a small effect on the total functional capacity scale (TFC) and extended the phase 2 study in an open-label modification to 52 weeks.

In the PRIDE-HD study, pridopidine dosing demonstrated a small but beneficial effect on TFC and this effect seemed to be more pronounced for early HD participants, which led the investigators to extend these observations in a Phase 3 study, PROOF-HD, currently enrolling and using the UHDRS-TFC score as the primary endpoint.

The final two areas both involve targeting mechanisms or genes thought to play a causal role in the progression of HD; the first one is the HTT gene itself; the second, the targeting of other genes identified in human patients who progress at different rates. Although this latter area is only now emerging as a novel therapeutic strategy, it is making rapid advances towards the clinic.

Below you can find a comprehensive table showing all the current clinical trials ongoing or recruiting for the treatment of Huntington’s disease, based on

You can see the full table as a PDF by clicking on it.

HTT targeting gene therapies

By far the major area of investment to develop effective treatments for HD is targeting the expression of the Huntingtin gene. Ample research over many years in animal models of HD support the targeting of HTT expression as a disease modifying therapy. We know with certainty in mouse models that if one can decrease mutant HTT expression enough, symptoms can be minimized or altogether reversed. However, mouse models of HD lack significant features of the disease – most importantly, the death of brain neurons and an inflammatory environment. In addition, people with HD in the symptomatic stages have very extensive loss of neurons in several cortical areas and most nuclei of the basal ganglia, the regions most affected in HD. Therefore, we must be cautious assuming that the human HD brain will respond similarly to lowering HTT expression, given these very significant differences.

Most therapies currently in development (see Table above) target both copies of the HTT gene, both the mutated version and the normal (or ‘wild type’) copy. There is significant concern that lowering of the normal copy might lead to untoward effects after prolonged silencing. We know also from mouse studies that a complete loss of both copies of HTT is lethal during embryonic development. In the adult, the results are more mixed and significant loss (but not complete) of HTT can be better tolerated. In humans, we know that a few individuals have been found with only one copy of the HTT gene, and they seem to be fine. however, individuals with mutations in both copies of the HTT gene and that show very low expression of HTT develop brain abnormalities during childhood. Therefore, lowering HTT too much is likely deleterious in humans as well.

This is a potential issue that might have derailed the Ionis/Roche program, which in Phase 3 clinical trials was stopped due to adverse events. In this trial, which generated a lot of expectations and hope for a first disease-modifying therapy in HD, the subjects exposed to the highest dose of Tominersen (an antisense oligonucleotide or ASO) exhibited a worsening in most clinical measures of HD, enlarged brain ventricles, and elevation of measures of toxicity and inflammation as judged in CSF collection analysis, leading to the trial being terminated prematurely.

Around the same time, in March 2021, two other ASO programs being developed by Wave Therapeutics, were also stopped, this time in Phase 1/2, due to a lack of pharmacological effects of the expression of mHTT in the CSF of dosed patients. Compared to the Roche trial with Tominersen, the Wave ASOs failed to lower mHTT enough in the CSF, leading to the company stopping their development.

However, it is difficult to know why Tominersen led to the unfortunate events uncovered in the Ionis/Roche trial – it could be explained by a loss of normal HTT function due to excessive lowering in some parts of the spinal cord or the brain cortex (the areas most targeted by these spinal cord infusions); but it could also be a consequence of the agent employed: antisense oligonucleotides can be pro-inflammatory, and their accumulation after repeated dosing could also explain some of the issues encountered. We do not know at this point.

The next most advanced program in the clinic at the moment, Uniqure’s AMT130, is a virally delivered agent, a microRNA (mRNA) also targeting both copies of the HTT gene, currently in Phase 2 studies. We expect an initial data release at the end of 2022, even though the trial has a duration of five years. This AAV (adeno-associated virus) therapy is invasive, requires neurosurgery, and is administered directly into the caudate and putamen, the two structures of the basal ganglia of the brain most affected in HD. Preclinical studies in rodents, non-human primates and pigs have shown the therapy to be well-tolerated up to 1 year. Due to the properties of the AAV serotype employed (AAV-5), the therapeutic agent distributes broadly throughout the brain, being transmitted via the brain fibers that pass through and innervate the striatum. We will see whether this therapy is well tolerated in the long term.

Other gene therapy efforts also employ AAVs, albeit each company pursuing these agents have chosen different viral types; in the case of Voyager, with an open IND and expected to start clinical studies in HD in 2021, they chose AAV-1. The agent delivered via this virus, also targets both copies of the HTT gene, and therefore will be important to compare its effects to those of the Uniqure program.

Finally, the last company to probably start gene therapy trials in HD with a mHTT-selective agent is Takeda, who is developing a zinc-finger repressor (ZFP) agent that selectively decreases very significantly the expression of mHTT without affecting normal HTT expression, also being delivered by AAV-9. There is a lot of expectation about this therapy, which was initially developed by Sangamo Therapeutics, as this is the only allele-selective therapy in development. This program,  if it proceeds successfully, will lead to an IND by beginning of 2022.

Enter small molecule oral drugs lowering HTT

The latest therapeutic agents to emerge are a new class of oral small molecule agents targeting HTT expression throughout the body. These agents were initially identified in phenotypic screens targeting expression levels of the spinal motor neuron (SMN)-2 gene, as a treatment for spinal muscular atrophy (SMA).

Branaplam (also called LIM070) is a Novartis drug which acts to  increase levels of SMN protein. Currently, branaplam is in phase 2 for the treatment of SMA . Selectivity analysis showed that branaplam can decrease the expression of both copies of the HTT protein via splicing modulation of the HTT mRNA. The mechanism of action of branaplam seems to be lead to the decay of the HTT mRNA and decreasing protein levels. Recently, Novartis received US FDA Orphan Drug Designation for branaplam in HD, and a phase 2b trial is planned for 2021.

Another company pursuing splicing modulators to lower HTT is PTC therapeutics. The company is conducting a Phase 1 trial with their drug PTC518 in healthy volunteers, expecting results in 2021, with a potential Phase 2 trial later in the year.

The entry of these agents in HD enables the possibility, for the first time, to test oral and brain penetrant drugs to lower HTT expression throughout the body, which circumvents the distribution issues encountered with gene therapy agents. However, it remains to be seen if the chronic, systemic lowering of both alleles of the HTT gene will be well tolerated in adult patients. 

The impact of human genetics on new therapeutic development for HD

In the last couple of years, new targets have been identified that seem to be implicated in how slow or fast a person with the mutation advance to a clinical stage. The age-of-onset (AOO) in HD is defined as the date where a clinical neurologist diagnoses an individual with having motor symptoms of HD. This ‘milestone’ in the progression of HD was chosen as an important time in the disease advancement to evaluate whether genetic influences can affect the rate of progression. It was well known for many years that some individuals can develop motor symptoms of HD much earlier or much later than the ‘average’ of HD positive individuals with a mutation bearing the same length of CAG repeats in the HTT gene. The research groups were able to identify a dozen or so genes that were associated with this change in the average rate of progression. This work, in a large GWAS (genome-wide association study) study, led to the identification of genes implicated in DNA repair and the expansion of the CAG repeats in somatic cells (all other cells besides reproductive cells of the body). The mechanistic understanding of how potentially these genes modify the progression of HD prior to clinical symptoms has led to some companies trying to develop therapies targeting this mechanism. The most advanced program thus far targets the expression of the Msh3 gene, which has been shown to modulate somatic instability of the HTT CAG repeat. Triplet is a company developing ASOs targeting Msh3, and they plan to file an IND in 2021.


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